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      Anti-Infective Drugs Advisory Committee

                 September 7, 2010

             8:00 a.m. to 12:18 p.m.

      Washington Hilton DC North/Gaithersburg
                 620 Perry Parkway
              Gaithersburg, Maryland

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      Thomas Moore, M.D., Acting Chair

      Minh Doan, Pharm.D., Designated Federal Official


      Thomas Moore, M.D., F.A.C.P. (Chair)
      Chairman Department of Infectious Diseases,
      Ochsner Health System,
      New Orleans, LA

      W. Kemper Alston, M.D., M.P.H.
      Professor of Medicine, Infectious Diseases Unit,
      Fletcher Allen Health Care, University of Vermont,
      College of Medicine,
      Burlington, VT

      Dean Follmann, Ph.D.
      Assistant Director for Biostatistics,
      Chief Biostatistics Research Branch,
      National Institute of Allergy and Infectious,
      Diseases/National Institutes of Health,
      Bethesda, MD

      Matthew Bidwell Goetz, M.D.
      Professor of Clinical Medicine,
      David Geffen School of Medicine at UCLA
      Chief, Infectious Diseases Section,
      VA Greater Los Angeles Healthcare System,
      Los Angeles, CA

      Sheldon L. Kaplan, M.D.
      Professor and Vice Chairman for Clinical Affairs Head,
      Pediatric Infectious Disease Section,
      Department of Pediatrics,
      Baylor College of Medicine Chief,
      Infectious Disease Service Head,
      Department of Medicine Texas Children's Hospital,
      Houston, TX

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      Peter Katona, M.D.
      Associate Professor of Clinical Medicine,
      David Geffen School of Medicine at UCLA,
      Los Angeles, CA

      Kent A. Sepkowitz, M.D.
      Vice Chairman, Clinical Affairs Director,
      Hospital Infection Control,
      Memorial Sloan-Kettering Cancer Center,
      New York, NY

                      TEMPORARY VOTING MEMBERS

      John E. Bennett, M.D.
      Head, Clinical Mycology Section,
      National Institute of Allergy and Infectious Diseases,
      National Institutes of Health,
      Bethesda, MD

      Erica Brittain, Ph.D.
      Mathematical Statistician,
      Biostatistics Research Branch,
      National Institute of Allergy and Infectious Diseases,
      National Institutes of Health,
      Bethesda, MD

      William J. Calhoun, M.D., F.A.C.P.
      Renfert Professor in Internal Medicine,
      Vice Chair for Research,
      Department of Internal Medicine,
      University of Texas Medical Branch,
      Galveston, TX

      Diane Cappelletty, Pharm.D.
      Associate Professor Pharmacy Practice,
      The University of Toledo College of Pharmacy,
      Toledo, OH

      Thomas R. Fleming, Ph.D.
      Professor of Biostatistics,
      University of Washington,
      Seattle, WA

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      Mr. Rodney Mullins (Acting Consumer Representative)
      National Public Health Advocates and Consultants,
      Duluth, GA

      Michael N. Neely, M.D.
      Assistant Professor of Clinical Pediatrics,
      Division of Pediatric Infectious Disease,
      University of Southern California,
      Keck School of Medicine,
      Los Angeles, CA

      Jan E. Patterson, M.D., M.S.
      Professor of Medicine, Infectious Diseases and Pathology,
      Director, Center for Patient Safety and Health Policy,
      University of Texas Health Science Center at San Antonio,
      San Antonio, TX

      L. Barth Reller, M.D., D.T.M.&H.
      Professor of Medicine and Pathology,
      Director of Clinical Microbiology,
      Duke University Medical Center,
      Durham, NC

      Allen H. Roberts, II, M.D., F.A.C.P.
      Associate Professor of Medicine, Attending Physician,
      Pulmonary, Critical Care, and Sleep Medicine,
      Georgetown University Hospital,
      Washington, DC

      Yu Shyr, Ph.D.
      Professor and Chief,
      Division of Cancer Biostatistics,
      Vanderbilt University School of Medicine,
      Nashville, TN

      James M. Steckelberg, M.D., F.A.C.P.
      Professor of Medicine,
      Mayo Clinic College of Medicine,
      Rochester, MN

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      Allan R. Tunkel, M.D., Ph.D.
      Chair, Department of Medicine,
      Monmouth Medical Center,
      Long Branch, NJ

      Bernhard L. Wiedermann, M.D., M.A.
      Professor of Pediatrics,
      The George Washington University,
      School of Medicine and Health Sciences,
      Attending, Infectious Diseases,
      Children’s National Medical Center,
      Washington, DC

                     TEMPORARY NON-VOTING MEMBER
      Joseph Camardo, M.D. (Acting Industry Representative)
      Independent Consultant,
      Merion Station, PA

                    FDA PARTICIPANTS (Non-Voting)

      Edward Cox, M.D., M.P.H.
      Office of Antimicrobial Products (OAP), CDER

      Katherine Laessig, M.D.
      Deputy Director,
      Division of Anti-Infective and Ophthalmology Products
      (DAIOP), OAP, CDER

      Janice Pohlman, M.D., M.P.H.
      Clinical Team Leader,

      Daniel Rubin, Ph.D.
      Statistical Reviewer,
      Division of Biometrics IV (DBIV)
      Office of Biostatistics (OB), CDER

      Avery Goodwin, Ph.D.
      Microbiology Reviewer,

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      Call to Order                                8

      Introduction of Committee
         Thomas Moore, M.D., F.A.C.P.               8

      Conflict of Interest Statement
      Minh Doan, Pharm.D.                          13

      FDA Introductory Remarks
      Janice Pohlman, M.D., MPH                    17

      Sponsor Presentations: Cerexa, Inc.

      Dirk Thye. M.D.                              30

      CABP: New Challenges in Treatment,
      Donald E. Low, M.D., FRCPC                   34

      Microbiology and Clinical Pharmacology,
      Ian Critchley, Ph.D.                         38

      Clinical Design and Efficacy,
      Dirk Thye, M.D.                              51

      Clinical Safety,
      David Friedland, M.D.                        67

      CABP: Therapeutic Perspective,
      Donald E. Low, M.D., FRCPC                   75

      Questions and Clarifications for Cerexa      77

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                      A-G-E-N-D-A (CONTINUED)


      FDA Presentations:

      Ceftaroline "MRSA-active cephalosporin" with Gram-
      negative Activity,
      Avery Goodwin, Ph.D.                                  95

      Efficacy Assessment for Ceftaroline: Community-
      Acquired Bacterial Pneumonia,
      Daniel Rubin, Ph.D.                                  101

      Review of Safety for Ceftaroline,
       Ariel Porcalla, M.D., M.P.H.                         123

      Questions and Clarifications to FDA                  142

      Open Public Hearing                                   179
      Mr. Gary Ewart, American Thoracic Society            181

      Charge to the Committee,
      Katherine Laessig, M.D.                               183

      Committee Discussion of Questions                     184

      Voting                                                185

      Voting Discussion                                    186

      Adjourn                                               210

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       1                       P R O C E E D I N G S

       2                                                        (8:00 AM)

       3                             Call to Order

       4                DR. MOORE:   All right.    Good morning,

       5   everyone.    If everyone could please take their seats,

       6   we can get started.

       7                I’d like to remind everyone present to

       8   please silent your cell phones, BlackBerrys, and other

       9   devices if you’ve not already done so.        We’ll get

      10   started by going around the table and introducing

      11   ourselves.

      12                Why don’t we start on this end?     Dr. Cox?

      13                             Introductions

      14                DR. COX:   Good Morning.     Ed Cox, Director,

      15   Office of Antimicrobial Products, CDER FDA.

      16                DR. LAESSIG:   Katie Laessig, Deputy Division

      17   Director, Anti-Infective and Ophthalmology Products.

      18                DR. POHLMAN:   Janice Pohlman, Medical Team

      19   Leader, Division of Anti-Infective and Ophthalmology

      20   Products.

      21                DR. RUBIN:   Dan Rubin, Statistical Reviewer,

      22   Office of Biostatistics.

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       1               DR. GOODWIN:   Good morning.    Avery Goodwin,

       2   Microbiology Reviewer.

       3               DR. ROBERTS:   Good morning.    Allen Roberts,

       4   Attending Physician, Georgetown University Hospital,

       5   Pulmonary, Critical Care.

       6               DR. WIEDERMANN:    Bud Wiedermann, George

       7   Washington University School of Medicine and

       8   Children’s National Medical Center in Washington, D.C.

       9               DR. CAPPELLETTY:    Diane Cappelletty, the

      10   University of Toledo College of Pharmacy, Infectious

      11   Disease Pharmacist.

      12               DR. SHYR:    Yu Shyr, Vanderbilt University,

      13   Biostatistician.

      14               MR. MULLINS:   Good morning.    Rodney Mullins,

      15   National Director, Public Health Advocates.

      16               DR. GOETZ:    Matt Goetz, UCLA School of

      17   Medicine and VA Los Angeles.

      18               DR. KATONA:    Peter Katona, UCLA Infectious

      19   Diseases.

      20               DR. SEPKOWITZ:    Ken Sepkowitz, Memorial

      21   Sloan-Kettering, New York, infectious disease

      22   specialist.

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       1               DR. KAPLAN:   Shelly Kaplan, Baylor College

       2   of Medicine and Texas Children's Hospital in Houston.

       3               MS. DOAN:    Minh Doan, Designated Federal

       4   Official of AIDAC.

       5               DR. MOORE:    Tom Moore.   I’m Chairman of

       6   Infectious Diseases at the Ochsner Medical Center in

       7   New Orleans.

       8               DR. FOLLMANN:    Dean Follmann, Head of

       9   Biostatistics at the National Institute of Allergy and

      10   Infectious Diseases.

      11               DR. ALSTON:   Kemper Alston, Infectious

      12   Diseases at University of Vermont.

      13               DR. PATTERSON:    Jan Patterson, University of

      14   Texas Health Science Center at San Antonio, Infectious

      15   Diseases.

      16               DR. STECKLEBERG:    Jim Steckleberg, Mayo

      17   Clinic, Division of Infectious Diseases.

      18               DR. BRITTAIN:    Erica Brittain.   I’m a

      19   Statistician at the National Institute of Allergy and

      20   Infectious Diseases.

      21               DR. RELLER:   Barth Reller, Infectious

      22   Diseases and Clinical Microbiology, Duke University

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       1   Medical Center.

       2               DR. NEELY:    Michael Neely, University of

       3   Southern California and Children’s Hospital, Los

       4   Angeles, Pediatric Infectious Diseases.

       5               DR. TUNKEL:    Allan Tunkel, Chair of

       6   Medicine, Monmouth Medical Center, Adult Infectious

       7   Disease.

       8               DR. BENNETT:    Jack Bennett, National

       9   Institute of Allergy and Infectious Disease, NIH in

      10   Bethesda.

      11               DR. FLEMING:    Thomas Fleming, Department of

      12   Biostatistics, University of Washington.

      13               DR. CALHOUN:    Bill Calhoun, Pulmonary

      14   Critical Care, University of Texas in Galveston.

      15               DR. CAMARDO:    Joe Camardo.   I’m currently an

      16   independent consultant.     I retired from industry

      17   earlier this year.

      18               DR. MOORE:    All right, thank you.   We have a

      19   busy schedule today.      We’re going to try to fit in two

      20   full day meetings into two half days.      So, we’re going

      21   to be moving fairly quickly today.

      22               Just as an advanced warning, for topics such

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       1   as those being discussed at today’s meeting, there are

       2   often a variety of opinions, some of which are quite

       3   strongly held.   Our goal today is that today’s meeting

       4   will be a fair and open forum for discussion of these

       5   issues, and that individuals can express their views

       6   without interruption.   Thus, as a gentle reminder,

       7   individuals will be allowed to speak into the record

       8   only if recognized by the Chair.   I will look forward

       9   to a productive meeting.

      10             In the spirit of the Federal Advisory

      11   Committee Act and the Government and the Sunshine Act,

      12   we ask that the Advisory Committee members take care

      13   that their conversations about the topic at hand take

      14   place in the open forum of the meeting.   We are aware

      15   that members of the media are anxious to speak with

      16   the FDA about these proceedings.   However, FDA will

      17   refrain from discussing the details of this meeting

      18   with the media until its conclusion.

      19             For the convenience of the media

      20   representatives, I would like to identify the FDA

      21   press contacts, Erica Jefferson and Crystal Rice.     If

      22   you are present, and there they are, could you please

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       1   stand?   Thank you.     There they are.   All right.

       2               Also, the committee is reminded to please

       3   refrain from discussing the meeting topic during

       4   breaks or lunch.    Thank you.

       5               Now, I’ll pass it to Ming, who will read the

       6   Conflict of Interest statement.

       7                 Conflict of Interest Statement

       8               MS. DOAN:    The Food and Drug Administration

       9   is convening today’s meeting of the Anti-Infective

      10   Drugs Advisory Committee under the authority of the

      11   Federal Advisory Committee Act of

      12   1972.    With the exception of the industry

      13   representative, all members and temporary voting

      14   members of the committee or special government

      15   employees or regular federal employees from other

      16   agencies and are subject to Federal Conflict of

      17   Interest Laws and regulations.     The following

      18   information on the status of this committee’s

      19   compliance with federal ethics and conflict of

      20   interest laws covered by, but not limited to, those

      21   found at 18 USC Section 208 and Section 712 of the

      22   Federal Food, Drug, and Cosmetic Act is being provided

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       1   to participants in today’s meeting and to the public.

       2   FDA has determined that members and temporary voting

       3   members of this committee are in compliance with

       4   Federal Ethics and Conflict of Interest laws.

       5                Under 18 USC Section 208, Congress has

       6   authorized FDA to grant waivers to special government

       7   employees and regular federal employees who have

       8   potential financial conflicts when it is determined

       9   that the agency’s need for a particular individual’s

      10   services outweighs his or her potential financial

      11   conflict of interest.

      12                Under Section 712 of the Food, Drug, and

      13   Cosmetic Act, Congress has authorized FDA to grant

      14   waivers to special government employees and regular

      15   federal employees with potential financial conflicts

      16   when necessary to afford the committee essential

      17   expertise.

      18                Related to the discussion of today’s

      19   meeting, members and temporary voting members of this

      20   committee have been screened for potential financial

      21   conflicts of their own, as well as those imputed to

      22   them, including those of their spouses or minor

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       1   children and for purposes of 18 USC Section 208, their

       2   employers.    These interests may include investments,

       3   consulting, expert witness testimony, contracts,

       4   grants, CRADAs, teaching, speaking, writing, patents

       5   and royalties, and primary employment.

       6                Today’s agenda involves New Drug Application

       7   200327 for ceftaroline fosamil for injection submitted

       8   by Cerexa, Inc., and the requested indication for

       9   treatment of adults with Community-Acquired Bacterial

      10   Pneumonia.    This is a particular matter’s meeting

      11   during which specific matters related to Cerexa,

      12   Inc.’s ceftaroline fosamil will be discussed.

      13                Based on the agenda for today’s meeting and

      14   all financial interests reported by the committee

      15   members and temporary voting members, not conflict of

      16   interest waivers were issued in connection with this

      17   meeting.     To ensure transparency, we encourage all

      18   standing committee members and temporary voting

      19   members to disclose any public statements that they

      20   have made concerning the product at issue.

      21                With respect to FDA’s invited industry

      22   representative, we would like to disclose that Dr.

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       1   Joseph Camardo is participating in today’s meeting as

       2   a non-voting industry representative, acting on behalf

       3   of regulated industry.    Dr. Camardo’s role at this

       4   meeting is to represent industry in general and not

       5   any particular company.     Dr. Camardo is an independent

       6   pharmaceutical industry consultant.

       7              We would like to remind members and

       8   temporary voting members that if the discussions

       9   involve any other products or firms not already on the

      10   agenda for which an FDA participant has a personal or

      11   imputed financial interest, the participants need to

      12   exclude themselves from such involvement, and their

      13   exclusion will be noted for the record.      FDA

      14   encourages all other participants to advise the

      15   committee of any financial relationships that they may

      16   have with the firm at issue.

      17              Thank you.

      18              DR. MOORE:    Thank you, Ming.

      19              Let’s move on now to the FDA introductory

      20   remarks.   We’ll start with Dr. Pohlman.

      21   *FDA Introductory Remarks

      22              DR. POHLMAN:    Good morning.    My name again

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       1   is Janice Pohlman.   I’m a medical team leader in

       2   Division of Anti-Infective and Ophthalmology Products,

       3   and I would like to welcome everyone, including

       4   members of the Advisory Committee, and thank you for

       5   your time today for this discussion, especially on the

       6   heels of a holiday weekend.

       7             We’re here today to discuss NDA 200327,

       8   ceftaroline fosamil for injection.   The applicant is

       9   Cerexa, Inc., a subsidiary of Forest Research, Inc.

      10   The indications that the applicant is seeking are

      11   complicated skin and skin structure infections and

      12   Community-Acquired Bacterial Pneumonia.   The proposed

      13   dose for ceftaroline is 600 milligrams IV q 12 hours

      14   with a dose adjustment required for renal impairment.

      15   The duration of therapy is 5 to 14 days for

      16   complicated skin and skin structure infections and 5

      17   to 7 days for Community-Acquired Bacterial Pneumonia.

      18             In terms of an abbreviated regulatory

      19   submission history, the original IND was submitted in

      20   December 2004.   The Phase 2 Complicated Skin Trials

      21   were conducted in 2005.   The Phase 3 Complicated Skin

      22   and Skin Structure Infection Trials 06 and 07 were

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       1   conducted in February and March 2007 through November

       2   and December 2007, respectively.   They were non-

       3   inferiority designed with a 10 percent NI margin for

       4   which the applicant was requested to provide

       5   justification.   The primary efficacy endpoint was

       6   investigator assessment of clinical response at test

       7   of cure 8 to 15 days after completing study therapy.

       8             The Phase 3 Community-Acquired Bacterial

       9   Pneumonia Trials 08 and 09, 08 conducted January 2008

      10   through December 2008, and Trial 09 conducted July

      11   2007 through August 2008, again, was a non-inferiority

      12   design with a 10 percent NI margin, which the

      13   applicant was asked to justify.    The primary efficacy

      14   endpoint was clinical response at test of cure 8 to 15

      15   days after completing study therapy.

      16             These trials were designed prior to ongoing

      17   public discussions about trial design for these

      18   indications, including the definition and timing of

      19   primary efficacy endpoint assessment.     The complicated

      20   skin trials were completed prior to the discussions,

      21   and the Community-Acquired Bacterial Trials were

      22   ongoing during this time.

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       1               The applicant performed their primary

       2   efficacy analysis pre-specified during design of the

       3   trials with, I believe, only modification made to the

       4   primary analysis population for the Community-Acquired

       5   Bacterial Pneumonia indication, which was based on

       6   ongoing discussions and recommended by the FDA.

       7               The FDA Review Team has replicated the

       8   results of the applicant’s pre-specified primary

       9   analysis.   At the time of the Pre-NDA Meeting, the FDA

      10   Review Team recommended additional sensitivity

      11   analyses based on the ongoing trial design

      12   discussions, and these analyses were subsequently

      13   performed by the applicant.

      14               However, in addition, based on historical

      15   information identified to date, recommendations made

      16   by Anti-Infective Drug Advisory Committee in the

      17   interim and continued work on these issues, the FDA

      18   Review Team performed a number of sensitivity analyses

      19   with the data the applicant provided in the NDA

      20   submission.   These analyses utilized analysis

      21   populations and endpoints that were different from

      22   those which were pre-specified and will be discussed

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       1   in the FDA presentation.

       2             And at this point, before I just do a brief

       3   run through of the recent public developments, I just

       4   wanted to note that the applicant had provided

       5   information regarding problems with single

       6   investigator site in India.

       7             The investigator had apparently been noted

       8   for alleged fraudulent activity working on a study for

       9   another sponsor, and this was followed-up by the

      10   applicant and we received a notification on August 13,

      11   I believe, that they were unable to located source

      12   documents at this site.    So, at the recommendations of

      13   the Division of Scientific Investigations, we are

      14   excluding the seven patients from the efficacy and

      15   safety analyses performed by the FDA.

      16             In addition, there were two more sites, each

      17   with one patient enrolled, that were monitored by the

      18   same CRO, and these patients, the Division of

      19   Scientific Investigations was unable to assure the

      20   data integrity, and so, these two patients are also

      21   excluded from the analyses.

      22             The one exception I will state is that there

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       1   was one death in the site that the alleged fraudulent

       2   investigator was practicing at.

       3             So, with that aside, many of the people

       4   around the table and in the room have been around

       5   through these discussions, the public discussions on

       6   the design of clinical trials for anti-infectives, and

       7   the first work was a FDA-IDSA workshop in January

       8   2008, where discussion focused primarily on historical

       9   evidence of anti-bacterial treatment effect and

      10   primary efficacy endpoints and trial design.    This was

      11   followed a few months later by an FDA Anti-Infective

      12   Drugs Advisory Committee Meeting, where the discussion

      13   focused on whether an NI margin could be defined.

      14             The Advisory Committee at that time voted

      15   unanimously that an NI margin could be justified based

      16   on the mortality endpoint in patients with severe

      17   Community-Acquired Pneumonia.     The extrapolation to

      18   clinical endpoints, however, was less clear.    Addition

      19   discussion focused on the appropriate study population

      20   and microbiologic confirmation of bacterial etiology

      21   for this population was encouraged.

      22             And then the final public discussion, well,

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       1   actually, there’s a more recent discussion, but a

       2   specific discussion regarding trial design for

       3   bacterial pneumonia was held in December of 2009, and

       4   this discussion focused on comments received by FDA in

       5   response to the posting of the draft guidance document

       6   in March 2009 for development of antibacterial agents

       7   for treatment of Community-Acquired Pneumonia.

       8             The majority of the Advisory Committee

       9   believed historical data could support use of an all-

      10   cause mortality primary endpoint but also believe that

      11   a clinical response endpoint could be used as a

      12   primary endpoint.

      13             Based on the historical data, clinical

      14   status at 48 to 72 hours was suggested as the timing

      15   for the clinical response assessment.     The Advisory

      16   Committee supported use again of the microbiological

      17   intent to treat population as the analysis population

      18   of interest.   An enrollment of sicker patients, as

      19   classified by PORT or by CURB-65 scoring system or

      20   enrollment of patients older than 50-years-of-age was

      21   recommended as possible enrichment strategies to

      22   enroll patients at higher risk for morbidity and

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       1   mortality.

       2                I should mention, as I alluded to a more

       3   recent public discussion, FDA held a workshop early in

       4   August, and at that time, a working group called the

       5   Foundation for NIH or FNIH Biomarkers Consortium was

       6   explained.    This is a working group who’s evaluating

       7   endpoints for Community-Acquired Pneumonia and acute

       8   bacterial skin and skin structure infection clinical

       9   trials.   Members include academia, industry, and

      10   government, including the FDA.

      11                In terms of the FDA analysis that will be

      12   presented, the FDA Review Team primary efficacy

      13   endpoint, clinical definition, and timing of

      14   assessment was derived from historical data from pre-

      15   antibiotic period in early treatment studies with

      16   antibacterial agents, indicating that clinical

      17   recovery with treatment was noted around days three to

      18   five and descriptors of recovery included fall in the

      19   pulse rate, fall in temperature, resumption of normal

      20   breathing, marked improvement in toxemia, and general

      21   wellbeing of the patient, and subjective improvement

      22   observed in patients.

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       1             This graph shows the difference between the

       2   natural history of the disease and early antimicrobial

       3   treatment with Sulfapyridine.   The red bars represent

       4   a series of over 600 patients of Bullowa and show that

       5   only about 20 percent of the population had achieved

       6   clinical recovery, as described by some of the

       7   descriptors on the previous slide by day five.   The

       8   yellow bars and blue bars represent case series of

       9   patients with Pneumococcal Pneumonia, which show that

      10   70 to 80 percent have recovered by day 2 and 80 and 90

      11   percent by day 3.

      12             So, in terms of the endpoints for Community-

      13   Acquired Bacterial Pneumonia, the best evidence for

      14   treatment effect from historical studies is mortality.

      15   However, it’s difficult to enroll sicker patients in

      16   clinical trials, and therefore, morality rates are

      17   relatively low in contemporary Community-Acquired

      18   Pneumonia trials.

      19             Clinical response is meaningful, and

      20   evidence does exist in the historical literature for

      21   demonstration of treatment effect, although, price

      22   precise definitions and quantification of that effect

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       1   are not as well defined.

       2             Turning now to the complicated skin and skin

       3   structure infection indication, there was a single

       4   Advisory Committee Meeting held in November 2008,

       5   where the primary discussion focused on the use of

       6   non-inferiority trial design for this indication.

       7   Based on the historical data, the Advisory Committee

       8   voted unanimously that there was adequate evidence to

       9   support use of an NI design in complicated skin and

      10   skin structure infection trials.   The Advisory

      11   Committee also discussed appropriate timing of primary

      12   efficacy assessment, with some members suggesting

      13   endpoint assessment at an earlier time point than that

      14   used in contemporary clinical trials.

      15             The historical literature based on the

      16   studies by Snodgrass and Anderson support early

      17   assessment.   That is at 48 to 72 hours after

      18   initiation of therapy of clinical features including

      19   cessation of sporative infection and resolution of

      20   fever based on treatment of erysipelas with

      21   sulfonamide derivatives.

      22             The justification provided for the non-

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       1   inferiority margin in patients with significant

       2   cellulitis or wound infections was noted to be

       3   adequate, however, the committee and FDA have come to

       4   the conclusion that it’s unable to estimate treatment

       5   effective antibacterial agents for abscess without

       6   significant surrounding cellulitis separately from

       7   incision and drainage alone.

       8             And in terms of the two Snodgrass and

       9   Anderson studies, these were two controlled studies

      10   comparing UV light to sulfonamide derivatives.    The

      11   first was prontosil, the second was sulfonamide.

      12   Mortality was low in these studies, at 4 percent.

      13   These were not randomized trials, however, there were

      14   pre-specified endpoints indicated, and these were

      15   included duration and days of spread of the local

      16   lesion, duration of the primary pyrexia, and time to

      17   resolution of toxic symptoms.

      18             And the next slides show the results of two

      19   meta-analyses resulting from these studies.   The first

      20   is regarding the cessation of the spread of lesion,

      21   and the treatment effect of the sulfonamide

      22   derivatives versus placebo; 18.2 percent is

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       1   represented by the lower bound of the 95 percent

       2   confidence interval.

       3              Next slide is the meta-analysis for

       4   resolution of pyrexia at 48 hours, and, again, you can

       5   see the difference between the sulfonamide derivatives

       6   compared to placebo, and the treatment effect is 18.9

       7   percent, as evidenced by the lower bound of the 95

       8   percent confidence interval.

       9              And with that aside, I’m going to just turn

      10   it over to the folks at Cerexa.   This morning what

      11   we’re going to be doing is discussing the

      12   Community-Acquired Bacterial Pneumonia indication.

      13   The applicant will present their efficacy analyses,

      14   and I believe the overall safety analysis for the

      15   product.   This will be followed by the FDA analysis.

      16   Dr. Avery Goodwin will present some clinical

      17   microbiology.   Dr. Daniel Rubin, our statistician,

      18   will present the FDA clinical efficacy analyses.    Dr.

      19   Ariel Porcalla, a medical officer, will discuss the

      20   safety of the application.

      21              And I guess we have committee questions and

      22   discussion following each the applicant and FDA

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       1   presentations, followed by the open public hearing,

       2   and then committee vote and discussion revolving

       3   around that. And then we have lunch.

       4                And then the afternoon agenda is a little

       5   bit simpler.     We’re going to be discussing the

       6   complicated skin and skin structure infection

       7   indication.    Again, the applicant will present their

       8   efficacy analysis first.     This will be followed by FDA

       9   presentation by Dr. Chris Kadoorie, a statistician.

      10   And again, questions will follow both the applicant

      11   and FDA presentations.     We’ll have an open public

      12   hearing, and then the vote and discussion by the

      13   Advisory Committee.

      14                And these are just included for completeness

      15   sake.   These are the Web Sites for both of the draft

      16   guidance documents for bacterial skin and skin

      17   structure infection and Community-Acquired Bacterial

      18   Pneumonia.

      19                Thank you.

      20                DR. MOORE:   Thank you, Dr. Pohlman.

      21                I wanted to make an announcement.   At the

      22   table, we usually have a patient representative

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       1   present.   We don’t have that today.   So, just for

       2   purposes of the agenda, it’s standard protocol, but

       3   the patient representative was unable to make it to

       4   the meeting today.

       5              Before we go with the sponsor presentation,

       6   I need to make this statement:    Both the Food and Drug

       7   Administration, the FDA, and the public believe in a

       8   transparent process for information gathering and

       9   decision making.    To ensure such transparency at the

      10   Advisory Committee Meeting, the FDA believes that it

      11   is important to understand the context of an

      12   individual’s presentation.

      13              For this reason, FDA encourages all

      14   participants, including the sponsor’s non-employee

      15   presenters, to advise the committee of any financial

      16   relationship that you may have with the firm at issue,

      17   such as consulting fees, travel expenses, honaria, and

      18   interests in the sponsor, including equity interests

      19   and those based upon the outcome of today’s meeting.

      20   Likewise, FDA encourages you at the beginning of your

      21   presentation to advise the committee if you do not

      22   have any such financial relationships.

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       1             If you choose not to address the issue of

       2   financial relationships at the beginning of your

       3   presentation, it will not preclude you from speaking.

       4             Let’s move forward now.      Dr. Thye from

       5   Cerexa.

       6             Did I say your last name correctly?

       7             DR. THYE:    No, but that's okay.

       8             DR. MOORE:    Please correct me.

       9             DR. THYE:    I’ll introduce myself.

      10             DR. MOORE:    Please do.

      11                    Sponsor Presentations:

      12                          Introduction

      13             DR. THYE:    Good morning.    My name is Dirk

      14   Thye, and I’m the President of Cerexa, the sponsor of

      15   the NDA for ceftaroline fosamil.      Cerexa is a

      16   subsidiary of Forest Laboratories.

      17             Ceftaroline is a novel intravenous

      18   cephalosporin.   It has broad spectrum activity,

      19   including against gram-positive bacteria, such as

      20   Streptococcus pneumoniae and Staphylococcus aureus.

      21   It also has activity against gram-negative bacteria

      22   such as E. coli, Klebsiella pneumoniae, and

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       1   Haemophilus influenzae.

       2                What makes ceftaroline unique and novel is

       3   its potent activity against contemporary resistant

       4   pathogens, and that includes excellent activity

       5   against methicillin-resistant Staph aureus and multi

       6   drug-resistant Streptococcus pneumoniae.

       7                As you’ll hear today, we have demonstrated

       8   efficacy for the indications of Community-Acquired

       9   Bacterial Pneumonia and complicated skin and skin

      10   structure infections, and ceftaroline is well-

      11   tolerated with the safety profile that's reflective of

      12   the cephalosporin class.

      13                We are seeking approval for two indications,

      14   CABP and Complicated Skin.    This morning we’ll be

      15   discussing Community-Acquired Bacterial Pneumonia.

      16   We’re seeking approval for this indication caused by

      17   susceptible isolates of the following list of

      18   pathogens:    The proposed dose is 600 milligrams

      19   intravenously over 1 hour given every 12 hours with an

      20   appropriate dosage adjustment for subjects with renal

      21   impairment.

      22                A quick overview of our program, we have

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       1   performed 11 Phase 1 studies, and this includes

       2   studies in subjects with a variety of degrees of renal

       3   impairment in addition to different age groups and a

       4   thorough ECG study.   We have performed two Phase 2

       5   studies in complicated skin and skin structure

       6   infections, and we have completed four Phase 3 trials.

       7   Two in the indication of CABP and two in the

       8   indication of skin, and our discussions this morning

       9   were really focused on these two Phase 3 clinical

      10   trials.

      11             A brief review of the regulatory history,

      12   the IND was submitted in December of 2004, and the FDA

      13   granted ceftaroline fast tracked designation because

      14   of its potential to meet an important unmeet medical

      15   need and the indication of complicated skin due to its

      16   activity against MRSA.   Specifically, with respect to

      17   CABP, we submitted our protocol designs via special

      18   protocol assessment in January of 2007, and in

      19   September of that year, we reached agreement with the

      20   FDA on an non-inferiority margin of 10 percent in our

      21   study designs using our endpoint.

      22             Of course, we are aware of the discussions

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       1   the advisory committees and workshops that Dr. Pohlman

       2   outlined in her introduction.    We’re also aware of the

       3   draft guidance document that was published in March of

       4   2009.   We have provided the requisite analyses

       5   relevant to that guidance document to the agency, and

       6   in June of 2010, the FDA requested further analyses

       7   that were designed to time more closely to the

       8   historical evidence for the sensitivity of drug

       9   effect, and you’ll see the results of those analyses

      10   during the presentations later.

      11              After my introduction, I’ll invite Dr. Don

      12   Low to come up and give an overview of new challenges

      13   in the treatment of CABP.   We’ll then have Dr. Ian

      14   Critchley present the microbiology and clinical

      15   pharmacology associated with ceftaroline.    I’ll then

      16   return to review the clinical design and efficacy

      17   associated with our Phase 3 trials.    And then Dr.

      18   David Friedland will give you an overvi9ew of safety

      19   relevant to this indication.    Lastly, Dr. Low will

      20   return to give you his clinician’s therapeutic

      21   perspective.

      22              In addition, we have a variety of experts

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       1   with us today that can help answer specific questions

       2   during the Q and A period.    Their financial

       3   disclosures are listed on this slide, and this has

       4   been provided for you in your slide decks.

       5             So, with that, I’d like to invite Dr. Low up

       6   to give us an overview of the medical need.

       7              CABP: New Challenges in Treatment

       8             DR. LOWE:     Thank you, Dr. Thye, and good

       9   morning, everyone.

      10             My financial disclosure is that I received

      11   fees for consulting and only for travel.    As a

      12   clinical infectious disease physician and a medical

      13   microbiologist that has interest in community-acquired

      14   infections, and especially severe invasive gram-

      15   positive infections.    I’ve been asked to discuss what

      16   are the medical needs for new antimicrobials for the

      17   treatment of Community-Acquired Pneumonia.

      18             I think as all of us in this room recognize,

      19   that influenza and pneumonia are important causes of

      20   morbidity, mortality.    The seventh leading cause of

      21   death in the United States, that we see over 5 million

      22   cases of Community-Acquired Pneumonia a year, over 1

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       1   million of those requiring admission to the hospital.

       2   This results in a cost to the health care system

       3   between $8 and $10 billion a year; and recognizing

       4   that patients admitted to the hospital, the cost being

       5   25 times higher than those being able to manage in the

       6   outpatient setting.

       7             These are the pathogens that we have

       8   actually recognized for decades as important as a

       9   cause of Community-Acquired Bacterial Infection,

      10   Streptococcus pneumoniae clearly the most frequently

      11   pathogen isolated, but also the one that's associated

      12   with the greatest morbidity and mortality,

      13   Staphylococcus aureus important, especially as a

      14   secondary cause of bacterial pneumonia in patients

      15   that had previously had viral infections, but

      16   specifically influenza, as we have seen so clearly

      17   demonstrated in the previous H1N1 pandemic.

      18             Haemophilus influenzae, less important now

      19   with the success, the introductions, and widespread

      20   use of the Haemophilus influenzae serotype B vaccine.

      21   And finally, enteric gram-negative bacilli, primarily

      22   in those patients with underlying structural lung

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       1   disease and patients that are immune-compromised.

       2               So with this knowledge, why the urgent need

       3   for new antimicrobial agents for the treatment of

       4   Community-Acquired Pneumonia?

       5               Well, I think probably one of the single

       6   most important factors is what we’ve seen is the

       7   continued emergence and dissemination of antimicrobial

       8   resistance in Streptococcus pneumoniae, especially

       9   during the last several years with the recognition of

      10   the spread of non-vaccine serotype 19A associated with

      11   multi-drug resistance and even reduce the

      12   susceptibility to some of our first line agents,

      13   including three generation cephalosporins.    We’ve also

      14   seen the emergence of Community-Acquired MRSA, an

      15   important pathogen, especially in the United States.

      16               This just emphasizes the importance of

      17   serotype 19A, non-vaccine serotype 19A.     This was a

      18   surveillance study that was carried out recently in

      19   the United States.   It included, as shown here, 894

      20   isolates.   Twenty-one percent of these isolates were

      21   19A, and, as you can see here, many of these were

      22   multi-drug resistant, but I think most importantly to

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       1   point out, that about thirty-five percent of these

       2   isolates were non-susceptible to ceftriaxone and many,

       3   in fact, were resistant.

       4                This is a study that we’ve been doing

       5   ongoing, a national surveillance in Canada since 1988,

       6   and in fact, we’ve used the same sites since 1994.

       7   So, it’s a good measure of what exactly is happening

       8   out there.

       9                In Canada, we’ve been a bit late in the

      10   introduction of the conjugated vaccine.     So, we’re

      11   starting just to see some of the problems that have

      12   been recognized here in the United States for a couple

      13   of years.    And so, if you look at our surveillance

      14   study, you can see in 2009, this dramatic increase in

      15   strains of pneumococci.    They’re non-susceptible or

      16   resistant to a third generation cephalosporins,

      17   particular ceftriaxone.    In fact, 19A was the most

      18   common isolate associated with that.

      19                So, in conclusion, I think that CABP,

      20   especially Community-Acquired Bacterial Pneumonia

      21   continues to be associated with significant morbidity

      22   and mortality, that treatment of this important

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       1   illness with our first line agents is threatened with

       2   a continued evolution and dissemination of multi-drug

       3   resistant pneumococci, and the emergent of resistant

       4   Staph aureus, making the need for new and effective

       5   safe agents more urgent.

       6             I want to thank you for your attention, and

       7   now, I will call upon Ian Critchley, who will present

       8   the microbiology data.

       9           Microbiology and Clinical Pharmacology

      10             MR. CRITCHLEY:     Thank you, and good morning.

      11   My name is Ian Critchley, and I’m the Vice President

      12   of Microbiology at Cerexa.

      13             And what I’d like to do in the next

      14   presentation is provide you with a brief overview of

      15   some of the microbiological and clinical

      16   pharmaceutical attributes of ceftaroline.    This

      17   morning’s presentation will primarily focus on the

      18   activity of ceftaroline against respiratory pathogens,

      19   and, this afternoon, we’ll provide you with additional

      20   information on the activity of ceftaroline against

      21   skin organisms.

      22             So, starting with the microbiology,

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       1   ceftaroline is a broad spectrum cephalosporin with

       2   bactericidal activity against resistant gram-positive

       3   bacteria and common gram-negative organisms, and we’ll

       4   show you some of that data.   Its spectrum includes the

       5   typical respiratory pathogens, so it is active against

       6   organisms such as Streptococcus pneumoniae and

       7   Haemophilus inflenzae.   Its unique activity against

       8   the resistant gram-positive cocci is largely

       9   attributed to its ability to bind to modified

      10   penicillin-binding proteins in these organisms with

      11   high affinity.   And again, we will share some of that

      12   data.

      13             Many of the studies conducted to date have

      14   shown low potential for resistance development in

      15   vitro, and we’ll share that, and we’ll also share some

      16   data from animal efficacy models with resistant

      17   pathogens to show that the drug does demonstrate very

      18   good efficacy against some resistant organisms, and

      19   then challenging infection models.

      20             These are recent susceptibility data.   These

      21   were isolates collected in the United States during a

      22   2008 surveillance study, and we’re sharing data on

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       1   organisms that are frequently implicated in Community-

       2   Acquired Bacterial Pneumonia, and starting with

       3   Streptococcus pneumoniae, which Dr. Low has already

       4   alluded, is the most important causative agent of

       5   Community-Acquired Bacterial Pneumonia, and it is a

       6   pathogen where increasing resistance to penicillin and

       7   multi-drug resistance poses a threat to many of our

       8   existing agents.

       9             And ceftaroline is a very active agent

      10   against Streptococcus pneumoniae, and here, you can

      11   see the MIC90 for U.S. isolates is 0.12 micrograms per

      12   ml, but it’s also active against many of the multi-

      13   drug resistant phenotypes that you’ve just heard, so

      14   it is active against organisms such as the notorious

      15   serotype 19A isolates.    And also, bear in mind all

      16   isolates that we’ve identified to date in surveillance

      17   studies are inhibited by ceftaroline concentrations

      18   equal to or less than 0.5 micrograms per ml,

      19   regardless of the resistant phenotypes.

      20             Ceftaroline is also active against

      21   Staphylococcus aureus, and its activities includes

      22   both methicillin-susceptible and methicillin-resistant

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       1   isolates with MIC90s of 0.25 and microgram per ml

       2   respectively.

       3              Activity against Haemophilus influenzae is

       4   not comprised by the ability of this organism to

       5   produce beta-lactamase, and you can see MIC90 is at

       6   0.015 and 0.03 for beta-lactamase-negative and

       7   positive isolates respectively.

       8              The spectrum of activity of ceftaroline also

       9   includes common members of the enterobacteriaceae

      10   family, so it is active against organism such as E.

      11   coli and Klebsiella pneumoniae.   However, its activity

      12   is limited to non-ESBL-producing strains.    So, these

      13   are data showing you susceptibility data for

      14   ceftazidime-susceptible strains where the MIC 90s for

      15   E. coli are 0.5 and 0.25 micrograms per ml

      16   respectively.

      17              This is a Finland-o-gram showing you the

      18   comparative activities of ceftaroline, ceftriaxone,

      19   and penicillin against the approximately 900 isolates

      20   of Streptococcus pneumoniae that were procured during

      21   2008.   And the point of the slide is to show you just

      22   how potent ceftaroline is against the pneumococci, and

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       1   this is reflected by the MIC 90s that you see, with

       2   0.12 for ceftaroline.    Compare that with an MIC 90 of

       3   1 microgram per ml for ceftriaxone and 4 micrograms

       4   per ml for penicillin.

       5             The activity of ceftaroline against

       6   penicillin-resistant Streptococcus pneumoniae and

       7   methicillin-resistant Staph aureus, as I mentioned

       8   earlier, is attributed to this unique ability to bind

       9   to modified penicillin-binding proteins in these

      10   organisms, and these modify PBPs typically confer

      11   resistance to many of the ß-lactams.    And the affinity

      12   assays are measured using competitive displacement

      13   assays, where you look at the ability of the drug to

      14   compete for fluorescent penicillin, and we’re looking

      15   at the concentration of drug required to inhibit the

      16   binding of fluorescent penicillin by 50 percent.    So,

      17   the lower the IC 50 value, the higher the affinity of

      18   the drug for the penicillin-binding proteins.

      19             So, you can see the affinities of

      20   ceftaroline for PBP2X Staphylococcus pneumoniae is in

      21   the order of threefold lower than ceftriaxone and

      22   fourfold lower than penicillin, and this translates

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       1   into the lower MICs that you see for ceftaroline

       2   against these organisms.   And this is very much

       3   mirrored by what you see in MRSA, where we have high

       4   affinity for the modified penicillin-binding protein

       5   2A, which explains the activity of this ß-lactam

       6   against MRSA.

       7             Resistance development is often a question

       8   that's asked when you’re bringing forward a new drug,

       9   and in our preclinical program, we did conduct

      10   numerous single and multi-step resistance development

      11   studies with a variety of gram-positive and gram-

      12   negative organisms, including resistant phenotypes.

      13   And in the single-step resistance studies, it’s really

      14   impossible to select for resistant mutants the

      15   spontaneous mutation frequencies are very low, and

      16   that's not surprising; this is a common observation

      17   with other ß-lactams, and is largely attributed to its

      18   bactericidal mode of action.

      19             In resistance development studies, it’s

      20   really very difficult to shift the MIC more than two

      21   doubling dilutions that following serial passage.     So,

      22   the resistance profile looks pretty favorable, and

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       1   that's in common with most ß-lactams.

       2             One question though with a new cephalosporin

       3   that's often asked is the ability of the drug to

       4   induce AmpC ß-lactamases.     And we did conduct a number

       5   of studies with a collection of gram-negative enteric

       6   bacilli, where we looked at the ability of ceftaroline

       7   to induce AmpC ß-lactamases, and what we found at the

       8   MIC, that there was really insignificant induction of

       9   AmpC ß-lactamases.    It was either similar to or less

      10   than drugs like ceftriaxone and cefotaxime, and

      11   certainly nothing like what we see with the positive

      12   control cefotaxime.

      13             This is some data from a rabbit pneumonia

      14   infection model, and in this model, we infected the

      15   lungs of rabbits with three strains of Streptococcus

      16   pneumoniae, a penicillin-susceptible strain, a

      17   penicillin intermediate strain, and a penicillin-

      18   resistant strain.     The rabbits were treated with

      19   simulated human dosing regimens of either ceftaroline,

      20   which was the 600 milligram q12h or ceftriaxone 1 gram

      21   24h, and this was accomplished by connecting the

      22   rabbits up to pumps to simulate the human exposures.

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       1   And the bacterial counts were assessed in the lungs of

       2   the rabbits after two days of therapy, and what you

       3   see if you look at the results for the penicillin

       4   susceptible and the penicillin intermediate strains,

       5   there's really very little to differentiate the

       6   activities of ceftaroline from ceftriaxone.

       7             However, when you look at the penicillin-

       8   resistant strain, and bear in mind that this strain

       9   has a ceftaroline MIC of 0.25 micrograms per ml and a

      10   ceftriaxone MIC of 4 micrograms per ml, ceftaroline

      11   does retain quite nice bactericidal activity whereas

      12   ceftriaxone is less effective and barely makes a 3 log

      13   reduction in colony-forming units.   So, we have robust

      14   efficacy in terms of efficacy against resistant

      15   pathogens in animal models with MICs on the upper end

      16   of the range.

      17             Moving on to pharmacokinetics, ceftaroline,

      18   as you’ve heard, is a pro-drug, ceftaroline fosamil.

      19   The phosphonate group was originally linked to the

      20   ceftaroline molecule to improve water solubility.

      21   However, following intravenous administration, the

      22   phosphonate group is rapidly cleaved to release the

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       1   active metabolite ceftaroline.

       2              The pharmacokinetics are approximately

       3   linear for doses ranging between 50 and 1,000

       4   milligrams.    The half life is two-and-a-half hours

       5   with no drug accumulation occurring upon repeat

       6   dosing.   The protein binding is low, at 20 percent.

       7   It has low potential for drug-drug interactions with

       8   no cytochrome P450 dependent metabolism, and no

       9   inhibition or induction of cytochrome P450 enzymes.

      10   And elimination is mainly renal with dose adjustment

      11   being recommended for moderate and severe renally-

      12   impaired subjects.

      13              Moving on to the PK-PD profile, we’ll share

      14   some data around streptococcus pneumoniae.    It

      15   probably comes as no surprise that percent time above

      16   MIC is the most appropriate parameter for predicting

      17   efficacy for ß-lactams, and this is also true for

      18   ceftaroline.

      19              And the neutropenic thigh infection model is

      20   really now the standard model for the initial

      21   determination of the magnitude of the free drug

      22   percent time above MIC that's required for efficacy.

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       1   And this was initially conducted for five different

       2   strains of streptococcus pneumoniae with varying

       3   susceptibilities to ceftaroline.   And what the model

       4   showed was that we needed equal to or greater than 39

       5   percent time above MIC for efficacy.   If you fall

       6   below that, you start to see regrowth; if you have

       7   exposures that are greater than that, you get stasis

       8   or bactericidal activity.   And this was an important

       9   parameter for our dose justification and PK-PD target

      10   attainment strategies.   And in doing that, what we did

      11   was we first evaluated the MIC distributions for

      12   streptococcus pneumoniae and ceftaroline from our 2008

      13   U.S. Surveillance Study, and you can see the MIC

      14   range.

      15             The goal for therapy was to identify a

      16   dosing regimen that would provide adequate exposure to

      17   cover the entire MIC range likely to be encountered in

      18   the United States.   So, we selected the upper end of

      19   the MIC for our exposure studies, which was .5

      20   micrograms per ml.   The next step was to take the

      21   human population PK data from our clinical studies,

      22   the MIC data, and the PK-PD targets derived from the

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       1   animal infection models in Monte Carlo simulations to

       2   look at the probability of time above MIC at each MIC.

       3             And so, what you can see is actually there’s

       4   a full exposure to cover isolates with an MIC of one

       5   microgram per ml, and the rule of thumb these days is

       6   that if you have greater than 90 percent probability

       7   of target attainment that there’s a high probability

       8   that that isolate with a given MIC would be

       9   successfully treated in the infection.    So, the

      10   initial dose justification made us feel very

      11   comfortable that the 600 milligram Q12H regimen was an

      12   appropriate regimen to cover most of the clinical

      13   isolates that we would expect to encounter in the

      14   United States.

      15             So, to just briefly summarize, ceftaroline

      16   exhibits broad spectrum antibacterial activity against

      17   important respiratory pathogens.   This activity

      18   against the resistant gram-positive organisms is

      19   mediated by its unique ability to bind to modified

      20   PBPs with high affinity.   It’s got low potential for

      21   resistance development in vitro, and approximately

      22   linear PK profile with low potential for drug-drug

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       1   interactions, and certainly, the dosing regimen does

       2   look like it’s more than adequate for certainly the

       3   key respiratory pathogens that we feel we’re likely to

       4   encounter.

       5                However, before I close the microbiology

       6   presentation, I did want to make a number of comments

       7   on the interpretive criteria, particularly in light of

       8   the differences in interpretive criteria that were

       9   proposed by ourselves and the FDA.    And as you can

      10   see, there are some notable differences, and I think

      11   we all appreciate the importance of interpretive

      12   criteria in guiding physicians to select the most

      13   appropriate agent.     And a susceptible interpretation

      14   usually implies that there’s a high degree of

      15   probability that the patient will respond to treatment

      16   with the appropriate dosing regime.

      17                And there are some issues with the current

      18   FDA proposed breakpoints in terms of the clinical

      19   utility of ceftaroline, and that's largely because

      20   those breakpoints divide the wild-type MIC

      21   distributions, which is likely to result in a

      22   significant percentage of some of the key pathogens

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       1   being reported as non-susceptible, despite the

       2   availability of exposure data to show that there’s

       3   good overage, and, as you’ll see later today, good

       4   clinical efficacy data.

       5             We did provide additional information on

       6   some of our strategies for assigning the interpretive

       7   criteria that were proposed by ourselves in the

       8   addendum to the briefing book.   We do acknowledge at

       9   this point we haven't had any discussions with the FDA

      10   about where the interpretive criteria will lie, but we

      11   do hope that we can identify interpretive criteria

      12   that will allow the drug to be used appropriately in

      13   treating many of these infections.

      14             And I would just like to finally comment and

      15   say that if there are any additional questions on this

      16   topic, we would be very happy to entertain them during

      17   the Q and A session, and we do have an expert with us

      18   here today, Dr. Paul Ambrose from ICPD, who helped us

      19   with a lot of our PK-PD target attainment.   And if you

      20   so choose, we’d be happy to answer any additional

      21   questions on that later today.

      22             Thank you, and I’ll now hand it over to Dr.

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       1   Thye, who will walk you through clinical design and

       2   efficacy.

       3                  Clinical Design and Efficacy

       4               DR. THYE:   Okay, so, moving on to the design

       5   of the clinical studies, both studies were multi-

       6   center, randomized, double-blind studies.     As

       7   mentioned, they were non-inferiority in design, with a

       8   pre-specified 10 percent non-inferiority margin that

       9   was agreed by the FDA for our primary endpoint, which

      10   is the clinical response at the

      11   Test of Cure visit.

      12               These two studies are very nearly identical.

      13   There’s one exception to that.     The study termed

      14   “P903-08” administered two doses of adjunctive

      15   clarithromycin on day one, whereas no adjunctive

      16   clarithromycin was allowed in Study 09.    The reason

      17   for the brief course of adjunctive clarithromycin was

      18   to create a study design that would be more harmonious

      19   with the standard of care in the United States,

      20   specifically the IDSA and ATS Treatment Guidelines

      21   that recommend adjunctive macrolide therapy for these

      22   types of patients.

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       1             As you’ve seen in your briefing book,

       2   despite incorporating this study design element in an

       3   effort to enroll subjects in the United States, we

       4   were unable to enroll large numbers of subjects in the

       5   U.S.

       6             Very importantly, these studies were IV

       7   therapy only.   There was no oral step-down therapy

       8   allowed, which is a feature that is fairly unique and

       9   was not present in the programs for the most recently

      10   approved antibiotic in this indication.

      11             After a brief screening period, patients

      12   were randomized to one of two dosing arms.   Patients

      13   either received ceftaroline at the dose mentioned

      14   previously or ceftriaxone at a dose of 1 gram q 24

      15   hours.

      16             The total duration of therapy was five to

      17   seven days, at the end of which an end of therapy

      18   assessment was performed, and the investigators

      19   determined a clinical outcome at that visit.   The

      20   primary outcome measure was determined at the Test of

      21   Cure visit, which occurred 8 to 15 days after the end

      22   of the therapy.

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       1               The results of a late follow-up visit, which

       2   occurred 21 to 35 days after the end of therapy at

       3   which subjects were assessed for clinical or

       4   microbiological recurrence.

       5               The definition of CABP used in these studies

       6   was that all subjects had to have a new or progressive

       7   infiltrate on chest radiograph, and in addition, had

       8   to have an acute illness with at least three or more

       9   of the following list of signs and symptoms, and this

      10   list included systemic signs, such as fever or

      11   elevated white count in addition to a variety of

      12   symptoms.

      13               The main inclusion criteria included adults

      14   aged 18 years or older.     All subjects had to have an

      15   infection requiring treatment with intravenous

      16   antibiotics according to the investigator and the need

      17   for hospitalization.    Another critical feature of the

      18   study design was that our studies enrolled only PORT

      19   Risk Class III or IV.     This has never been done in a

      20   registration program.   Previous registration programs

      21   have included up to 50 percent of their subjects in

      22   the PORT Risk Classes of I and II.

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       1                PORT is typically used in these types of

       2   studies as a measure of severity, and PORT Classes I

       3   and II are associated with a low-risk for mortality,

       4   and many of these patients can be treated as

       5   outpatients.    PORT III and IV subjects have more

       6   severe disease, a higher risk for mortality, and often

       7   require hospitalization.    And PORT V subjects have a

       8   high mortality and are often admitted to the ICU.

       9                The PORT V subjects were excluded from four

      10   trials because those subjects via the standard of care

      11   get combination therapy, which, as I mentioned, was

      12   not allowed.    So, our studies were a test of ß-lactam

      13   versus ß-lactam with no confounding by concomitant

      14   antibiotics.

      15                The main exclusion criteria included more

      16   than a single dose of short-acting antibiotic.       So,

      17   you could be enrolled in the study if you had no prior

      18   antibiotics or just one dose of a short-acting prior

      19   antibiotic.    Any more than that would exclude you from

      20   the study.

      21                If you had a known or suspect ceftriaxone-

      22   resistant pathogen, such as MRSA at baseline, you were

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       1   excluded.   As I’ve mentioned admission to the ICU was

       2   an exclusion criteria, and as this was a study of

       3   CABP, health-care-associated and hospital-acquired

       4   pneumonia were not enrolled.   In addition, there were

       5   a variety of exclusion criteria related to eliminating

       6   patients that were at risk of imminent death and not

       7   likely to benefit from antimicrobial therapy.

       8               The primary efficacy endpoint was the

       9   clinical cure rate at the Test of Cure visit, and we

      10   performed a variety of secondary endpoints that are

      11   described for you in the briefing book.    I won't

      12   present data on all of these secondary endpoints

      13   because of limited time, but you do have the

      14   information in your briefing book, and these secondary

      15   endpoints included clinical and microbiological

      16   outcome measures at various time points, including the

      17   end of therapy, test of cure, and late follow-up

      18   visits.

      19               The definition of our primary endpoint is

      20   described on this slide, and it was clinical cure, and

      21   clinical cure was defined as total resolution of all

      22   signs and symptoms of the pneumonia or improvement to

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       1   such an extent that no further antimicrobial therapy

       2   was necessary.   And in cases of improvement, all

       3   subjects had to be afebrile for 24 continuous hours,

       4   and if they had underlying pulmonary disease, their

       5   signs and symptoms had to return to their baseline

       6   level of functioning.

       7              In addition, in order to be considered a

       8   cure, you could, of course, not be a failure, and

       9   failure had these components:    persistence, incomplete

      10   resolution or worsening in signs and symptoms that

      11   required alternative therapy, any adverse event

      12   leading to discontinuation of study drug, and all

      13   cause mortality.    Any of those were reasons for

      14   failure.

      15              In addition, in the ITT population, you

      16   could be considered indeterminate, and that's if you

      17   don’t have sufficient information at the Test of Cure

      18   visit to determine an outcome, and the most likely

      19   reason for being considered indeterminate would be a

      20   subject loss to follow-up.

      21              Now, this slide contains a lot of

      22   information.   It’s in your briefing book.   I’ve

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       1   simplified it because of time constraints, and

       2   therefore, I don’t provide the numbers within each

       3   population here, but I’ll qualitatively describe for

       4   you the analysis populations that were used.

       5             At the top of the slide, you can see the

       6   numbers of subjects randomized into each individual

       7   study, and you can see that randomization worked with

       8   relatively equal numbers in each treatment group.

       9             The ITT population consists of all patients

      10   randomized, and the two light green boxes represent

      11   the co-primary populations for the primary endpoint.

      12   The two blue boxes represent the microbiological

      13   populations in which the microbiological secondary

      14   outcomes were assessed.

      15             Starting with the primary outcome

      16   populations, we have the modified intent to treat

      17   efficacy population, and this consists of all subjects

      18   that received at least one dose of study drug and were

      19   in PORT Risk Classes III or IV.   The clinically

      20   evaluable population consists of all patients with

      21   confirmed disease and patients that had sufficient

      22   information to determine an outcome at the Test of

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       1   Cure visit without confounding factors such as

       2   concomitant antibiotics.

       3             The microbiological modified intent to treat

       4   efficacy population consists of all patients in the

       5   MITTE that had a typical pathogen identified at

       6   baseline, and importantly, patients with sole atypical

       7   pathogens or patients with Legionella pneumophila

       8   infection were excluded from this population.    And the

       9   microbiologically evaluable population consists of all

      10   patients that are clinically-evaluable and had a

      11   pathogen identified at baseline.

      12             Turning now to demographics and baseline

      13   characteristics, the mean age of subjects in the

      14   pneumonia studies was about 60-years-of-age with a

      15   large proportion of subjects over the age of 65, about

      16   half of all subjects, and about three-fourths of all

      17   subjects over the age of 50.   About two-thirds of

      18   subjects were male.   About 60 percent were in PORT

      19   Risk Class III, and 40 percent in PORT Risk Class IV.

      20   About 30 percent of subjects met criteria for severe

      21   CAP according to modified ATS criteria, and about

      22   three-fourths of subjects met Systemic Inflammatory

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       1   Response Syndrome criteria.   About 3.5 to 4 percent of

       2   subjects had bacteremia, and about 40 to 45 percent of

       3   subjects received a single dose of prior antibiotic;

       4   recall that more than that would exclude you from the

       5   study.   You can also see on this slide that the

       6   demographic and baseline characteristics were well-

       7   balanced between treatment groups.

       8              About 40 percent of subjects in the trial

       9   had a pathogen identified, and this is really what you

      10   would expect in these types of trials.    About 10 to 12

      11   percent of subjects had an atypical-only infection.

      12   As I mentioned, these pathogens are excluded from the

      13   microbiological populations, as neither treatment arm

      14   has activity against these pathogens.     And therefore,

      15   the microbiological populations focus on the 30

      16   percent of subjects that had atypical bacterial

      17   pathogen identified at baseline.

      18              Moving now to the most commonly procured

      19   pathogens within the study, about 40 percent of

      20   subjects had Streptococcus pneumoniae identified at

      21   baseline, and about 15 percent of subjects had

      22   Staphylococcus aureus, with about 12 to 14 percent

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       1   with Haemophilus influenzae, 10 percent with

       2   Haemophilus parainfluenzae, and then smaller numbers

       3   of subjects with gram-negative pathogens.

       4             This slide contains quite a lot of

       5   information, so, allow me a moment to describe what

       6   we’re looking at here.   On the left-hand side of the

       7   slide, I have provided the point estimates for the co-

       8   primary populations in each study for the primary

       9   endpoint, which is the clinical cure rate at TOC.    And

      10   on the bottom column, I’ve combined the studies and

      11   show you the data associated with that.    On the right-

      12   hand side of the slide is a visual depiction of the

      13   point estimates of the treatment difference between

      14   ceftaroline and ceftriaxone with the associated 95

      15   percent confidence interval.

      16             Now, as these studies were non-inferiority

      17   in design, in order to be considered successful, the

      18   lower bound of the 95 percent confidence interval for

      19   each of the co-primary populations has to be to the

      20   right of this dotted line in each study.     And if the

      21   lower bound is to the right of zero, that denotes a

      22   significant difference between treatments.

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       1                So, you can see that for both studies 08 and

       2   09, the lower bound of the 95 percent confidence

       3   interval is well to the right of this dotted line, and

       4   in fact, is about zero and about zero in the 08

       5   population.    So, these two studies easily met a non-

       6   inferiority margin of 10 percent, and in fact, would

       7   have met a non-inferiority margin as low as about 3

       8   percent.   When you combine the data, you find that the

       9   lower bound of the confidence intervals are about zero

      10   for both of the co-primary populations.

      11                Looking now at clinical cure by pathogen,

      12   Streptococcus pneumoniae, as I mentioned, is the most

      13   common pathogen, and you can see the cure rates were

      14   85 percent in the ceftaroline group and 68 percent in

      15   the ceftriaxone group.    So, we see a large treatment

      16   difference here, and we have the associated 95 percent

      17   confidence interval listed for the most common

      18   pathogens.

      19                We had smaller numbers of multi-drug

      20   resistant Streptococcus pneumoniae isolated in this

      21   study.   We had four in the ceftaroline arm, and all

      22   four were cures.    There were nine in the ceftriaxone

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       1   arm, and the cure rate was two of out nine.

       2             The cure rate for Staphylococcus aureus was

       3   72 percent in the ceftaroline arm and 60 percent in

       4   the ceftriaxone arm, and below the blue line here, you

       5   can see the cure rates for the gram-negative

       6   pathogens, which were procured at a lower frequency,

       7   and you can see that the cure rates are relatively

       8   similar between treatment groups with any differences

       9   really being due to small numbers of pathogens.

      10             Now, I’d like to show you some important

      11   subgroup data.   I’m showing you subgroup data for PORT

      12   Risk Class, age, bacteremia and prior antibiotics, and

      13   this slide is set up the same way as the previous

      14   slide with the exception of any dotted line for non-

      15   inferiority testing because it’s not appropriate to

      16   perform non-inferiority testing in these subgroups.

      17   However, what I’ve listed here in the blue shaded

      18   areas are the subgroups of interest because they are

      19   the subgroups that the FDA had identified as marking

      20   patients for a higher risk for mortality, and it’s

      21   this subgroup of patients that was used as the basis

      22   for approval for Tigecycline for this indication in

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       1   March 2009, a couple of weeks before the new draft

       2   guidance document was published.

       3                And you can see the point estimates of cure

       4   for PORT Risk Classes III and IV, with the treatment

       5   differences and associated 95 percent confidence

       6   intervals.    In patients over the age of 50, there’s a

       7   higher risk of mortality, and you can see the response

       8   rates here, and in subjects with bacteremia, the

       9   numbers are low, so you have a large confidence

      10   interval here and also, in patients with prior

      11   antibiotics or patients without prior antibiotics.

      12   And what you see is this subgroup analysis

      13   consistently favors ceftaroline over ceftriaxone,

      14   although, the confidence intervals overlap in all

      15   cases.

      16                Now, I’d like to move on to the FDA-defined

      17   exploratory primary analysis, and this analysis is

      18   important because it was designed to specifically tie

      19   closely to the historical evidence for the sensitivity

      20   of drug effect, and the FDA asked us to identify a new

      21   population which is a relatively small subset on the

      22   order of 20 to 25 percent of our population.    And the

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       1   population, as the FDA defines it, are subjects with

       2   at least one acceptable pathogen from any of these

       3   categories:   blood, pleural fluid or BAL, and adequate

       4   putum specimen which had criteria for squamous

       5   epithelial cells and white blood cells.    Positive

       6   urinary antigen tests for Streptococcus pneumoniae was

       7   acceptable, and a gram-negative rods were accepted

       8   into the population if they had a PORT Risk Class of

       9   greater than or equal to PORT III and had an

      10   appropriate isolate.

      11             Notably in the FDA population, subjects with

      12   Haemophilus parainfluenzae were excluded, and subjects

      13   with atypical pathogens were excluded.    The one

      14   difference between the FDA population and ours or an

      15   additional difference is that subjects with Legionella

      16   pneumophila were included in the FDA population.

      17             The FDA’s endpoint is called “Clinical

      18   Response at Study Day Four,” and in order to be

      19   considered a responder, you had to be both clinically

      20   stable and have success for symptoms criteria.      The

      21   clinically-stable definition was modified from an ATS

      22   publication, and you can see listed here the different

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       1   vital sign parameters that had to be met in order to

       2   be considered clinically-stable.     You had to be

       3   afebrile with a heart rate of less than 100

       4   respiratory rate, less than 24 systolic blood pressure

       5   greater than 90 in oxygen saturation, greater than 90

       6   with absent confusion.

       7               In addition, we collected signs and symptoms

       8   daily on the CRF, and one of the following four

       9   symptoms:   cough, dyspnea, chest pain, or sputum

      10   production could be worse compared to baseline, and at

      11   least one of these four symptoms had to be improving.

      12   So, you had to meet both of these two criteria

      13   separately in order to be considered a responder, and

      14   on this slide, we show you the data associated with

      15   this primary sensitivity analysis.

      16               So, we’re seeing the proportion of clinical

      17   responders at study day 4, which is after 72 to 96

      18   hours of therapy.   And the responder rate in the

      19   ceftaroline group was 71 percent versus 56 percent in

      20   the ceftriaxone group in 08 and 69 versus 60 percent

      21   in Study 09.   You can see the point estimates in

      22   treatment difference for each individual study and the

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       1   combined studies listed here.   There’s no dotted line

       2   at minus 10 because this is an exploratory analysis,

       3   and therefore, non-inferiority testing is not

       4   appropriate in this subgroup analysis.   And since it’s

       5   a small subgroup of the overall population, we’ve

       6   combined the studies to increase the power to detect a

       7   difference, and you can see that the 95 percent

       8   confidence interval in this analysis is greater than

       9   zero.

      10             So, in conclusion, ceftaroline is

      11   efficacious for the treatment of CABP, and that has

      12   been shown using pre-specific, traditional, primary

      13   endpoints of the Test of Cure visit in addition to

      14   exploratory FDA-defined early time points which are

      15   designed to time more closely to the historical

      16   evidence for the sensitivity of drug effect.

      17             In addition, secondary and subgroup analyses

      18   provide support that these results are very robust and

      19   we have demonstrated efficacy against important

      20   clinical pathogens such as Streptococcus pneumoniae,

      21   Staphylococcus aureus, and Haemophilus influenzae.

      22   So, the totality of data strongly demonstrates trends

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       1   favoring ceftaroline over ceftriaxone for the

       2   treatment of CABP.

       3                I’d now like to invite Dr. David Friedland

       4   to give you an overview of the safety.

       5                          Clinical Safety

       6                DR. FRIEDLAND:   Good morning.   I’m David

       7   Friedland, and I’m Vice President of Clinical Sciences

       8   at Cerexa.

       9                This morning, I’ll be presenting the safety

      10   of ceftaroline fosamil, and as you can see from this

      11   slide, the safety database included a total of 1,745

      12   subjects that were treated who received at least one

      13   dose of ceftaroline fosamil.     I’ll be showing you the

      14   adverse event profile of ceftaroline, focusing on the

      15   Community-Acquired Pneumonia Program, where 613

      16   subjects received ceftaroline and 615 received

      17   ceftriaxone.

      18                I will also show you some combined data

      19   combining the skin and the Community-Acquired

      20   Pneumonia Programs together for a total of 2,600

      21   subjects, where we will look at body systems as well

      22   as some special events of interest relevant to the

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       1   cephalosporin class.    This afternoon, I was going to

       2   be presenting safety, the adverse event profile in the

       3   Skin Program.

       4             When we look at the overall adverse event

       5   profile, you see that the incidences of treatment

       6   emergent adverse events, serious adverse events,

       7   treatment of limiting adverse events, as well as

       8   deaths, was similar between the two treatment groups.

       9             With regards to the adverse events, the

      10   majority were assessed by the investigator as mild,

      11   and there was only 6 to 7 percent of adverse events

      12   that were assessed as severe in both treatment groups.

      13             The most common adverse events were similar

      14   between the two treatment groups in the Community-

      15   Acquired Pneumonia Program.    No adverse event occurred

      16   in more than 5 percent of subjects in either treatment

      17   group, with diarrhea being the most common adverse

      18   event being reported.

      19             There was no adverse event that differed by

      20   more than 2 percent between the two treatment groups.

      21   So overall, similar results.

      22             Serious adverse events, as well, were

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       1   similarly distributed between the two treatment

       2   groups.   There was no SAE that occurred in more than 2

       3   percent of subjects, and there was no SAE that

       4   differed by more than 1 percent between the two

       5   treatment groups.     The majority of the SAEs in the

       6   Community-Acquired Pneumonia Program were related to

       7   the underlying infection that was being studied here,

       8   which is pneumonia.

       9              Limiting adverse events were low and similar

      10   between the two treatment groups, approximately 4

      11   percent in both treatment groups.    Few of these

      12   adverse events were assessed as study drug related by

      13   the investigator.   You can see 0.8 for ceftaroline and

      14   1 percent for ceftriaxone, and there was no individual

      15   adverse event leading to discontinuation that occurred

      16   in more than two ceftaroline subjects.

      17              With regards to unstudied deaths, there were

      18   a total of 27 subjects that died before the late

      19   follow-up visit or within 30 days after the last dose

      20   of study drug if there was no late follow-up visit.

      21   And these were distributed 15 on ceftaroline and 12 on

      22   ceftriaxone.

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       1             There were an additional five deaths that

       2   were reported after the late follow-up visit, and this

       3   was one on ceftaroline and four on ceftriaxone.    And

       4   in the next few slides, if there is no drug listed,

       5   ceftaroline is always listed first and ceftriaxone

       6   second.

       7             There was one patient who died in each study

       8   group that was assessed as possibly related to study

       9   drug, and this was equally distributed one in either

      10   treatment group.    The subject on ceftaroline had an

      11   undetermined cause of death, and the subject on

      12   ceftriaxone died of multi-organ failure.    Both of

      13   these two cases, the patient narratives are described

      14   in our briefing book.

      15             There were five subjects who died, two on

      16   ceftaroline and three on ceftriaxone, where the death

      17   was assessed as being due to the primary infection,

      18   and that was by the investigator.    We looked at the

      19   causes of death, and they were varied, and so, no

      20   predominant cause of death could be identified.    And

      21   when we looked at the timing of deaths, there were few

      22   deaths that occurred while on therapy; two on

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       1   ceftaroline and four on ceftriaxone, and then when we

       2   look at the day 14 and day 30 mortalities, you saw

       3   equal or similar numbers.

       4             So, when we look at the adverse event

       5   profile of ceftaroline, you see very similar results

       6   to that of ceftriaxone, and what you’d expect for the

       7   cephalosporin class.

       8             I’m now going to focus on the pooled Phase 3

       9   studies, and just to let you know that in the skin

      10   studies, we used vancomycin plus aztreonam as the

      11   comparator agents, and we’ll be looking at some organ

      12   systems, as well as events relevant to the

      13   cephalosporin class.

      14             So, first of all, with the organ systems,

      15   what you see is similar safety compared with

      16   ceftriaxone and vancomycin plus aztreonam.   With

      17   regards to renal safety, the adverse event profile was

      18   low in both treatment groups and relatively similar,

      19   as was the potentially clinically-significant changes

      20   in creatinine or creatinine clearance.   You can see

      21   the numbers are all fairly low and similar between the

      22   treatment groups.

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       1             We did see an increase in Coombs

       2   seroconversion about 11 percent on ceftaroline and

       3   about 4 percent on the pooled comparator agents.   This

       4   is a known effect of cephalosporins.   In the

       5   literature, there are rates between 3 and 16 percent

       6   reported, and the 16 percent actually is

       7   Cephapine, which is the most recently-approved

       8   cephalosporin.

       9             However, when we looked the adverse events,

      10   we found when we looked at the anemia adverse events,

      11   the rates were very low and similar between the

      12   treatment groups, and further, there was no adverse

      13   event of hemolytic anemia recorded in the clinical

      14   program, and there was no other signs of hematological

      15   disturbances in the studies.

      16             There was no significant QT prolongation

      17   using a super therapeutic dose in the thorough QTc

      18   study we preformed, and no evidence of cardiac

      19   toxicity was identified in the clinical pharmacology,

      20   the Phase 1 or the Phase 3 Programs.   And with regards

      21   to hepatic safety, similar instances of adverse events

      22   were seen, and no ceftaroline subject met Hy's Law

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       1   criteria for drug-induced liver injury.

       2             When we look at events of interest that are

       3   relevant to the cephalosporin class, first of all,

       4   with seizures, these were uncommon, and they occurred

       5   in two subjects on ceftaroline and one subject on

       6   ceftriaxone.

       7             The two subjects on ceftaroline, these

       8   occurred after the end of therapy and making it

       9   unlikely due to study drug, and the one subject on

      10   ceftriaxone had the seizure on the last day that they

      11   received the ceftriaxone, but the investigator

      12   assessed that as unrelated to study drug.

      13             Allergic reactions are a common complication

      14   of all antibiotics or most antibiotics, and especially

      15   ß-lactam antibiotics.   When we looked at the incidents

      16   of treatment emergent adverse events for potential

      17   allergic reactions, and these are pooled events, the

      18   rates were 5.4 on ceftaroline and 8.5 percent on the

      19   pooled comparative.    So, it’s slightly higher on the

      20   pooled comparatives.

      21             When we looked at the serious or severe

      22   potential allergic reactions, these occurred

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       1   infrequently:    three ceftaroline subjects, six pooled

       2   comparative subjects.

       3               Antibiotic-associated diarrhea is another

       4   common problem with antibiotics, and when we looked at

       5   the incidents of diarrhea, it was 4.5 percent versus

       6   3.2 percent.    The majority of these diarrheas were

       7   mild.   There was only one severe diarrhea reported in

       8   the clinical programs, that was on the ceftaroline

       9   group, and then there were two subjects in both

      10   treatment groups that discontinued study due to

      11   diarrhea.   So, very low rates.

      12               Clostridium difficle toxin was found in

      13   three subjects during the clinical program.    All of

      14   them in the complicated skin and skin structure

      15   infection studies, two on ceftaroline and only one on

      16   vancomycin plus aztreonam.    There were no subjects in

      17   the Community-Acquired Bacterial Pneumonia, where C.

      18   difficle toxin was identified.

      19               So, therefore, in summary, when we look at

      20   the safety profile of the adverse events, we see that

      21   ceftaroline safety is similar to ceftriaxone with

      22   regards to adverse events, serious adverse events,

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       1   treatment limiting adverse events and deaths, and when

       2   we combine the data, we saw no safety signal in review

       3   of the organ systems or safety events of interest to

       4   the cephalosporin class.

       5              So, our conclusion is that ceftaroline is

       6   well-tolerated and has a safety profile that's

       7   reflective of the cephalosporin class.

       8              Thank you and I’ll now call Dr. Low to

       9   finish the presentation.

      10                 CABP: Therapeutic Perspective

      11              DR. LOW:   Thank you, David.

      12              So, let me conclude with a personal

      13   perspective in having the opportunity to look at this

      14   data.   I believe that the evidence provided this

      15   morning supports a contention that ceftaroline meets

      16   many of the medical needs for a new antimicrobial for

      17   the treatment of Community-Acquired Bacterial

      18   Pneumonia that has been found to have been a broad

      19   spectrum of activity against both gram-positive and

      20   gram-negative pathogens that caused Community-Acquired

      21   Pneumonia and has demonstrated a proven effectiveness

      22   for its treatment.

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       1                I think it’s particularly important to note

       2   that in both Study P903-08 and P903-09 that each not

       3   only met the pre-specified efficacy endpoints, but

       4   showed trends favoring ceftaroline over ceftriaxone,

       5   which is one of our first line agents for the

       6   treatment of Community-Acquired Pneumonia in the

       7   hospitalized patient.

       8                So, where would I use ceftaroline?   I would

       9   use ceftaroline as part of a regimen for the first

      10   line empiric treatment of patients with mild to severe

      11   Community-Acquired Bacterial Pneumonia requiring

      12   hospitalization, especially those patients at risk for

      13   an infection due to a pathogen resistant to our

      14   current first line agents, and as an alternative

      15   therapy for patients having failed other antimicrobial

      16   treatment.

      17                Thank you for your attention this morning,

      18   and this brings to a close the sponsor’s portion of

      19   the presentation, and I will turn it over to the

      20   chairman.    Thank you.

      21                DR. MOORE:   Thank you, Dr. Low.   I want to

      22   thank Drs. Thye, Low, Critchley, and Friedland from

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       1   the sponsor for their presentations.

       2              We’ll now take questions or clarifications

       3   of the sponsor.   We’re running a little behind on

       4   schedule, but we’ve got time to ask a few questions.

       5              Are there any from the panel?

       6              Questions and Clarifications

       7              DR. MOORE:    Dr. Kaplan?

       8              DR. KAPLAN:    I had a couple of questions

       9   related to there was nothing about urinary tract

      10   infection subsequent to treatment.     So, I’m assuming

      11   there were nosocomial urinary tract infections in

      12   either group, especially due to Enterococcus.

      13              And related to that, there was some

      14   information about Enterococcus susceptibility to this

      15   agent.   I was curious if you could expand on that a

      16   little bit.

      17              And finally, there was mention of CSF

      18   penetration in rabbits.    I wonder if you have any

      19   human information, as well.

      20              DR. THYE:    Sure.

      21              DR. MOORE:    Dr. Thye?

      22              DR. THYE:    Yes, I’ll take those questions

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       1   one at a time.

       2             With respect to our clinical programs, I’m

       3   not aware of any UTI caused by Enterococcus that

       4   occurred in the programs, but we would have to review

       5   the listings.    It certainly was not a common event,

       6   and I can’t remember a single case, but we will try

       7   and review the listings to see if we have any data.

       8   And if so, I’ll get back to you on that.

       9             I’d like to invite Dr. Critchley up to

      10   discuss for you the activity of ceftaroline against

      11   Enterococcus, followed by Dr. Riccobene, who will

      12   describe for you what we know about CSF penetration.

      13             DR. CRITCHLEY:    Okay, we can show you the

      14   susceptibility data for Enterococcus, and when that

      15   data comes up, but the MIC 90s are atypically between

      16   four to eight, so, they’re a bit above what we would

      17   consider to be the appropriate therapeutic exposure

      18   for that pathogen.

      19             DR. MOORE:    Thank you.

      20             MR. RICCOBENE:    Todd Riccobene, Clinical

      21   Pharmacology at Forest Research Institute.

      22             We did not specifically look at the

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       1   penetration of ceftaroline in the CSF of humans.    We

       2   only have the pre-clinical data, which you referred

       3   to.   And in the pre-clinical model, we showed

       4   approximately 15 percent penetration into the CSF in

       5   infected rabbits and about 3 percent in unaffected

       6   animals, and we’d expect the penetration to be similar

       7   to other cephalosporins.

       8             DR. MOORE:    Thank you, Dr. Thye.   Did you

       9   have another comment?    No.   Okay.

      10             Dr. Fleming?

      11             DR. FLEMING:     One of the strengths here of

      12   this program was your focusing on PORT III and IV,

      13   and, yet, even though Dr. Low pointed out that

      14   CABP is pneumonia’s seventh leading cause of death, I

      15   think probably due to low enrollment of patients with

      16   co-morbidities, I think they’re only 27 deaths in the

      17   CABP Program, and then there were 3 in SSSI.

      18             The deaths did break out 18 to 12 overall in

      19   2 programs, and I think specifically according to your

      20   briefing document, neoplasms were 5 against 0, and

      21   respiratory were 3 against 0, so, 8 against 0, are

      22   those correct numbers, and do you have any added

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       1   insights you can provide us about that?

       2              DR. THYE:   Yes, certainly.   I’ll ask Dr.

       3   Friedland to discuss that.

       4              DR. FRIEDLAND:    So, the neoplasm number is

       5   correct.   The respiratory, there was one on

       6   ceftaroline of acute respiratory failure.      So, it was

       7   three versus one.

       8              With regards to the deaths, first of all,

       9   let’s take the neoplasms, as you mentioned.     I have

      10   data for the Community-Acquired Pneumonia Program, and

      11   there were the four deaths in the CABP program and one

      12   then in the Skin Program.    As you can see, all the

      13   subjects received seven days of therapy, and the study

      14   days were all well after the end of therapy.     So,

      15   these deaths were all assessed by the investigator as

      16   unrelated to study drug.    You can see that three of

      17   them had lung cancer that was diagnosed by CT scans,

      18   and the other one had metastasis to the CNS.

      19              Now, as a cephalosporin, ceftaroline would

      20   have no known mechanism of action that could cause a

      21   neoplastic process, and we showed that in preclinical

      22   studies that ceftaroline does not bind to RNA or DNA,

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       1   that in the preclinical studies, there was no in vivo

       2   genotoxicity observed on ceftaroline, and that the

       3   majority of these neoplasms were in the lung, and the

       4   rate of neoplasms that we saw in the lung are very

       5   similar to what you would expect for patients with

       6   pneumonia.

       7                So, we looked in the literature, and here

       8   are three papers.    The first paper has 40,000

       9   subjects, and in the second and the third paper have

      10   1,000 and 1,300 subjects.     And this looked for the

      11   evidence of postobstructive pneumonia due to cancer,

      12   and you can see the rates were between 1.3 percent and

      13   2.5 percent, and our rate was 1.5 percent in our

      14   study.    So, it’s just very similar.      I think you just

      15   get used to seeing small numbers.        So, in conclusion,

      16   there does not seem to be any risk of neoplasms with a

      17   short-acting cephalosporin use.

      18                DR. MOORE:   Dr. Fleming?

      19                DR. FLEMING:   And then three respiratory

      20   deaths.   I think they were all on your regimen.      Two

      21   in CABP and one in SSSI.      Respiratory failure.

      22                DR. FRIEDLAND:   Right, and as I said, there

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       1   was one acute respiratory failure on ceftriaxone.     So,

       2   in all three cases, these events were assessed by the

       3   investigators and not related to study drug, and so, I

       4   think in one of the subjects actually, the subject -–

       5   okay.   So, in all these three cases, as I said, the

       6   event was not related to study drug by the

       7   investigator; it was due either to the underlying

       8   comorbidity or complications that the patients

       9   developed after end of therapy.

      10              DR. MOORE:   Dr. Calhoun, did you have a

      11   comment or question?

      12              DR. CALHOUN:   I did, thank you.

      13              So, in your slide 42, you’re looking at

      14   clinical cure by subgroup.    I noted that in each case

      15   where the expected outcome might be less good, that is

      16   in PORT IV versus PORT III in age greater than 50

      17   versus age less than or equal to 50, and in those with

      18   versus those with bacteremia.    The evidence of

      19   efficacy is less robust in those who might be expected

      20   to do less well.

      21              And so, the question is:   Is there some

      22   differential in the kinds of organisms that were

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       1   identified in PORT III versus PORT IV age less than 50

       2   versus those greater than 50, those were bacteremic

       3   versus those who were not that might explain that

       4   difference in the robustness of the efficacy?

       5             DR. THYE:     So, we’ll just look at the slide

       6   you’re referring to.    Slide 42 here shows the subgroup

       7   analyses that you’re referring to.    I don’t believe

       8   there are any discernable differences in the

       9   microbiology profile of these various subgroups, but I

      10   think with respect to the patterns of subgroup

      11   response, what we do see is that for each given

      12   treatment, the response rates in general follow the

      13   pattern that you would expect with more severe

      14   patients not doing quite as well.

      15             Now, the difference between treatments is

      16   certainly variable, but I think what we’re seeing here

      17   in the subgroup analysis is just the variability

      18   associated with multiple comparisons, and I think when

      19   you look within each subgroup, you have overlapping

      20   Confidence Intervals.    So, I think we’re careful not

      21   to over-interpret some of the patterns we’re seeing

      22   here, but in general, just to say that ceftaroline

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       1   does very well in all of these subgroup analyses.


       3               So, it shows consistency of results which

       4   mimic the primary endpoint, and that would be my

       5   conclusion from that slide.

       6               DR. MOORE:   We’re going to go with Dr.

       7   Steckelberg.    You were next.

       8               DR. STECKELBERG:     Thank you to all the

       9   presenters.    They were very nice presentations.

      10               In the introductory remarks, Staphylococcus

      11   aureus was, of course, singled out as an important

      12   pathogen and a reason for new, therapeutic

      13   developments.   But in the PK-PD data, it was just

      14   pneumococcus that was presented.

      15               Was a similar analysis done for the dosing

      16   regimen for Staphylococcus aureus?

      17               DR. THYE:    Yes, absolutely.   And in fact,

      18   you’ll see that this afternoon during the Skin

      19   presentation.

      20               DR. MOORE:   Dr. Wiedermann, did you have a

      21   question?

      22               DR. WIEDERMANN:    Yes, thank you.   You

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       1   presented us information, I think, through only 13

       2   patients with multi-drug resistant pneumococcus

       3   enrolled.   Of course, far too few to make any

       4   conclusions, but I was wondering if you had

       5   information on a breakdown of MICs to ceftaroline and

       6   ceftriaxone for those 13 isolates?

       7               DR. THYE:   We do have cure rates by MIC for

       8   streptococcus.   Dr. Critchley can describe those for

       9   you, cure rates by MIC by MDRSP.    It may be less

      10   informative due to the small numbers, but Dr.

      11   Critchley can describe for you what we have.

      12               DR. CRITCHLEY:   We should have a slide that

      13   shows you the breakout of MIC for the MDRSP strains,

      14   but, first of all what I’ll do is do we have the

      15   comparative slide with the MDRSP coming up?    Oh,

      16   great, you’re ahead of me.    Here we go.

      17               So, actually, maybe I can talk to it.    I

      18   can’t quite point from here with the speaker, but you

      19   can see in the ceftaroline group there were four

      20   isolates.   You can see that the MICs for those four

      21   MDRSP, the ceftaroline MICs ranged from equal to or

      22   less than 0.015 to 0.12, and for the ceftriaxone

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       1   creatinine group, and this is actually in the ME

       2   population as opposed to the MITTE, but there were 4

       3   in the ME population, and you can see there were 3 out

       4   of the 4 failures were with MICs ranging from 0.12 to

       5   2 micrograms per ml.   And you can see where the

       6   failures were.

       7             DR. MOORE:   Okay, Dr. Bennett, did you have

       8   a question or clarification?

       9             DR. BENNETT:   More than 90 percent of these

      10   patients were being studied in countries where English

      11   is not the primary language.    So, my question for the

      12   sponsor is whether or not the case report forms where

      13   the language of the country are in English?

      14             I say this because subjective decisions

      15   about whether toxicity or a death is due to the drug,

      16   it’d be important to know that language was not

      17   impairing that understanding.

      18             DR. THYE:    All of the CRFs were in English,

      19   and all of the foreign countries where the studies

      20   were conducted, we had local assistants with monitors

      21   who worked with the investigators to help them fill

      22   out the forms if the English language was a problem.

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       1   But the vast majority of investigators speak English.

       2             DR. MOORE:   Thank you.   Dr. Goetz and then

       3   Dr. Sepkowitz.

       4             DR. GOETZ:   I'm interested in the statement

       5   by -- I think it was Dr. Critchley on slide 21,

       6   talking about the induction of resistance.    I believe

       7   there had been some reports of induction of resistance

       8   with serial passage to related so-called

       9   cephalosporins of activity, ceftobiprole, in induction

      10   of resistance.

      11             Does that work, have relevance to

      12   ceftaroline?   Are you aware of any induction of

      13   resistance with other serial passage data?

      14             DR. FRIEDLAND:   No, we’re not.    The study

      15   that we did was we did do serial passage studies with

      16   gram-negative with a variety of gram-negative

      17   organisms, and we did not pick up any induction of

      18   AmpC ß-lactamases, and the studies that we did that

      19   were conducted by Dr. Livermore at the Health

      20   Protection Agency, what he did was he exposed mid-

      21   exponential phase organisms to a variety of

      22   cephalosporins and at various concentrations ranging

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       1   from 0.25, 0.514, and 16 fold the MIC and measured the

       2   induction of ß-lactamase spectrophotometrically with

       3   nitrocefin and showed that in a variety of the gram-

       4   negative enteric bacilli that there was insignificant

       5   induction of AmpC ß-lactamases in those organisms.

       6                And if you compared the fold induction of

       7   AmpC induction, it was either similar to ceftriaxone

       8   or cefotaxime.     So, there was no evidence in our

       9   studies of AmpC induction.

      10                DR. MOORE:   Okay, in the interest of time,

      11   my apologies.    We’re going to go with Dr. Sepkowitz

      12   and then Dr. Reller, and that’ll have to do.

      13                DR. SEPKOWITZ:   I have two different

      14   questions.    One, if there’s a vast difference in the

      15   Coombs Seropositivity, seroconversion between the two

      16   groups?   A study drug, for instance, the ceftriaxone,

      17   although, that was not clinically-relevant, do you

      18   have a biologic explanation for that and are you

      19   concerned?    I think it’s 10-point-something percent

      20   versus four-point-something percent.

      21                DR. FRIEDLAND:   So, we have Dr. Davenport

      22   here today, and maybe he could answer the question for

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       1   you.

       2               DR. DAVENPORT:   I'm Rob Davenport; I’m from

       3   the University of Michigan.    I’m here as a consultant

       4   for which I receive compensation.    I have no equity

       5   interest here.

       6               Yes, we did see a difference in the Coombs

       7   positivity.   That in and of itself is not concerning

       8   to me.   There are several well-established mechanisms

       9   for this.   It’s well-known that cephalosporins as a

      10   class cause non-specific absorption of immunoglobulin

      11   onto red blood cells.   So, we looked carefully for

      12   evidence of immune hemolytic anemia using both the

      13   Coombs criteria, evidence of anemia, and evidence of

      14   hemolysis in elevation of LDH, elevation of bilirubin.

      15               We found two individuals in the ceftaroline

      16   group who met our screening criteria, which were

      17   sensitive for immune hemolysis, but by no means

      18   specific.   Both of them had a clear alternative

      19   explanations.    One head and neck carcinoma, the other

      20   one -- they’re described in the briefing book.

      21               DR. SEPKOWITZ:   But the 10 percent rate is

      22   still quite high, and even for the cephalosporin

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       1   class, which suggests that there is something

       2   occurring that is, to me, not altogether clear.

       3             DR. FRIEDLAND:    So, I just wanted

       4   to remind you, as I said in my presentation, the rates

       5   in the literature go up to 16 percent.    So,

       6   cephapine in the product label have rates as high as

       7   16 percent, and the incidents of hemolytic anemia

       8   associated with cephapine use, which has been on the

       9   market for a number of years now is exceptionally

      10   rare.

      11             DR. MOORE:    Thank you.   Dr. Reller, and then

      12   we’ll move on.

      13             DR. RELLER:    In your presentation, slide 25,

      14   you present the PK-PD target attainment for

      15   ceftaroline.   Do you have a comparable slide for

      16   ceftriaxone?   And the reason I ask is when one looked

      17   at the clinical responses in the higher MIC range

      18   versus the true drugs, the dose of the comparator was

      19   relatively modest.

      20             So, I’m interested in this target attainment

      21   for the strains encountered for the comparator drug as

      22   a possible explanation as to why one might see a --

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       1   though the numbers were the low, the total number

       2   encountered low for the differences in performance of

       3   these two agents.

       4             DR. RICCOBENE:    Excuse me.    We didn't

       5   specifically look at ceftriaxone target attainment in

       6   our Phase 3 studies.    We didn’t measure ceftriaxone

       7   levels, but I can show you some recent work that was

       8   done by Dr. Ambrose's group where they used a

       9   population PK model to simulate target attainment for

      10   different doses of ceftriaxone and compare that to

      11   recent surveillance data both in the U.S. and in

      12   Europe.

      13             DR. RELLER:    May we see it?

      14             DR. RICCOBENE:    It's coming.    So, this is a

      15   target attainment plot again for different doses of

      16   ceftriaxone; 1 gram every 12 hours, 1 gram every 24

      17   hours, and 2 grams every 24 hours, and it’s versus

      18   MIC, and then the MIC distributions for Europe and the

      19   U.S. are overlaid.   And you can see for the 1 gram

      20   every 24 hours, you have adequate target attainment

      21   greater than 90 percent up to an MIC of 1, which is

      22   the current breakpoint for ceftriaxone.     So, we

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       1   believe that the dose that was used in our studies is

       2   adequate to cover the MICs that would be encountered

       3   in our trials.   And I can ask Dr. Ambrose to provide

       4   additional details if you have further questions on

       5   that analysis.

       6             DR. RELLER:    If one superimposed these data

       7   with the ceftaroline, it would be a considerable shift

       8   in terms of the probability of target attainment with

       9   the strains encountered in the upper MIC range.

      10             DR. MOORE:    Thank you, Dr. Reller.

      11   Actually, Mr. Mullins, if your question is quick,

      12   perhaps, we can squeeze it in before we move on.

      13             MR. MULLINS:    Yes, I can make it quick.    My

      14   concern or my question is about the patient profile in

      15   the summary of death in the Phase 3 CAP studies, and I

      16   wanted to know if there has been any adjudication or

      17   profile of potential at-risk patients for ceftaroline.

      18   And my concern is just from a consumer standpoint,

      19   trying to understand is there a patient population

      20   that is more at-risk than another patient population

      21   because you don’t specify a profile for the patients

      22   that experience morbidity.   I want to know is there

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       1   further adjudication on the profile of the patients

       2   that did die?

       3                DR. FRIEDLAND:   So, we did adjudicate each

       4   case.   we looked at it very carefully, and I think FDA

       5   have done the same analysis on their side, and we did

       6   not identify a patient population specifically that

       7   would be at risk for receiving ceftaroline compared to

       8   any other drug.    Of course, when you looked in the

       9   Community-Acquired Pneumonia Program, the majority of

      10   the deaths, which is what you’d expect, occurred in

      11   the subjects that were PORT Risk Class IV versus Risk

      12   Class III.    So, the more elderly, the sicker subjects,

      13   they were more likely to die, which is what you’d

      14   expect, but in equal numbers between the two treatment

      15   groups.

      16                So, there was no increased risk on

      17   ceftaroline over the comparator agents, and I just

      18   wanted to just show the slide, and this was in answer

      19   to a question earlier on, as well, which I forget to

      20   show, is when you look at the timing of the deaths,

      21   you can see when we look at 7-day mortality, they were

      22   actually fewer deaths on ceftaroline than there were

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       1   on the comparators, and when you look at 14, 21, and

       2   30-day mortality, the numbers are equal between the

       3   two treatment groups.

       4                And it’s only when you get past study day 30

       5   that you see a 3-patient higher number on ceftaroline,

       6   but then, as I mentioned in my core presentation, when

       7   you go even past that, then there’s another 4 deaths

       8   on ceftriaxone versus 1 one on ceftaroline.      So, for a

       9   total number of mortality in the CABP Program was 16

      10   versus 16.

      11                So, when you look at the numbers, when you

      12   look at the timing, when you look at the cause, when

      13   you look at the investigator or whether our review or

      14   the FDA’s review, there was no difference between the

      15   two treatment groups.     There’s no evidence of any

      16   increased risk of mortality on ceftaroline compared to

      17   ceftriaxone.

      18                DR. MOORE:   Thank you.   We’re going to have

      19   to stop there and move on with the FDA presentations.

      20   We’ll start with Dr. Goodwin.



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       1                        FDA Presentations:

       2        Ceftaroline "MRSA-active cephalosporin" with

       3                      Gram-negative Activity

       4             DR. GOODWIN:    Good morning.     My name is

       5   Avery Goodwin, and, today, I will be discussing the

       6   microbiology of ceftaroline.

       7             First of all, ceftaroline is a

       8   cephalosporin, and is a member of the ß-lactam class

       9   of antimicrobials.    Both in vitro and in vivo data

      10   suggests that ceftaroline has adequate activity

      11   against some gram-positive bacteria, including MRSA,

      12   as well as gram-negative bacteria, including those

      13   from the family.

      14             Now, this slide shows a mechanism of action.

      15   The antimicrobial activity of ceftaroline is similar

      16   to that of other ß-lactams.    Ceftaroline binds

      17   conveniently to Penicillin-Binding Protein, and this

      18   binding interferes with cell wall biosynthesis.

      19   Basically, it inhibits the peptoglycin function, and

      20   the affect of this is inhibition of growth of the

      21   bacterial cell, and, ultimately, the bacteria dies.

      22             Now, alteration in PBPs are a mechanism for

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       1   ß-lactam resistance.   Within Staphylococcus aureus,

       2   there are four PBPs, and ceftaroline is capable of

       3   binding to all.   However, it binds with high affinity

       4   to a PBP 2.   This is the product of the mecA gene.

       5   And PBP 2 is associated with methicillin resistance in

       6   Staphylococcus aureus.

       7             Now, it should be noted that there are

       8   differences in affinity for PBP 2 among ß-lactams, and

       9   this slide shows IC50 of ceftaroline in comparison

      10   with full ß-lactam comparators.   The IC50 is a

      11   concentration of inhibitor at which 50 percent enzyme

      12   inhibition is observed, and, as you can see here from

      13   the sponsors of applicant’s data, ceftaroline

      14   demonstrated the lowest IC50 in comparison to the

      15   highs, which is ceftriaxone, which is over 4,000 times

      16   higher.

      17             Ceftaroline is also capable of binding to

      18   other PBPs, or Penicillin-Binding Proteins, that are

      19   identified in Streptococcus pneumoniae, as well as

      20   those identified in Enterobacteriaceae, and that

      21   affect, again, is the inhibition of growth and

      22   ultimate demise of the cell.

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       1               In terms of in vivo activity, ceftaroline

       2   demonstrates a time-dependent Enterobacterial affect,

       3   and by that I mean bacterial killing is dependent on

       4   the percent of time during a dosing interval that the

       5   drug concentration is above the MIC, and this is

       6   usually abbreviated by %T>MIC.

       7               This slide shows a summary of surveillance

       8   data of spectrum activity of ceftaroline against

       9   selected gram-positive organisms, and this is

      10   basically rehashing the applicant I showed you

      11   previously.   I want to draw your attention to pvl

      12   genes.    The presence of pvl appear to have no affect

      13   on clinical efficacy and in vitro efficacy.

      14               This slide shows a spectrum of activity

      15   against selected gram-negative bacteria, and, again,

      16   it was from surveillance data that was submitted by

      17   the applicant, and you can see here that for

      18   Haemophilus influenzae, MIC 90 is .015 micrograms per

      19   ml.   No measurable activity against Pseudomonas

      20   aeruginosa, MIC values were greater than 32 micrograms

      21   per ml.

      22               Now, in terms of Enterobacteriaceae, MIC 90

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       1   values range from 1 to as high as over 60 micrograms

       2   per ml, and ceftaroline demonstrated a significantly

       3   decreased activity ESBL extended spectrum ß-lactamase

       4   positive organisms.

       5             Now, ESBL enzymes that are usually encoded

       6   by plasmids, and these enzymes are capable of

       7   hydrolyzing and inactivating ceftaroline.   Other such

       8   enzymes as the applicant alluded to is AmpC.    These

       9   are usually encoded by chromosomes, however, they’ve

      10   been found in plasmids, and these enzymes can also

      11   inactivate ceftaroline.   And as has been suggested,

      12   it’s a weak inducer of AmpC in Enterobacteriaceae.

      13   So, gram-negative isolates produce, and these enzymes

      14   would be expected to demonstrate higher ceftaroline

      15   MIC values.

      16             Now, this slide shows the clinical

      17   microbiology assessment that the FDA conducted, and in

      18   terms of their CABP assessment, most of the efficacy

      19   was based around the presence of methicillin-

      20   susceptible Staphylococcus aureus since there were no

      21   MRSA isolates within the clinical studies in the

      22   microbiologically-valuable population.

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       1             For Streptococcus pneumoniae, efficacy was

       2   based around this organism, however, limited data

       3   existed for penicillin-resistant isolates.     And in

       4   terms of the Enterobacteriaceae, the majority of the

       5   clinical efficacy experienced were with E. coli and

       6   Klebsiella pneumoniae.

       7             Now, in the Complicated Skin Study, efficacy

       8   was based on MSSA, MRSA, Streptococcus pyogenes,

       9   agalactiae, and for the Enterobacteriaceae, the

      10   majority of the experiences were based on E. Coli,

      11   Klebsiella pneumoniae, and Klebsiella oxytoca.

      12             Now, in terms of breakpoints, the FDA

      13   proposed breakpoints I establish using three

      14   parameters, and these are ceftaroline in vitro

      15   susceptibility data that we obtained from the

      16   applicant, PK-PD analysis of the data, and clinical

      17   success in microbiological eradication rate.

      18             The term breakpoints are MICs that define

      19   infections as susceptible, intermediate, or resistant

      20   to certain antimicrobials.   And the FDA breakpoints

      21   are proposed by indication, complicated skin or skin

      22   structure infection, and Community-Acquired Bacterial

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       1   Pneumonia.

       2                This slide shows the proposed breakpoints

       3   for CABP, and you can see here for Staphylococcus

       4   aureus, MSSA in CABP, the proposed breakpoints are

       5   less than 0.5 micrograms per ml, and for

       6   Streptococcus, proposed breakpoints are less than

       7   0.008, and these are the proposed breakpoints for

       8   Enterobacteriaceae.

       9                Now, our breakpoints are proposed again by

      10   clinical experience and what we see with the data, and

      11   we make an assessment of that data to propose these

      12   breakpoints.

      13                Now, for the Complicated Skin Study, these

      14   are the proposed breakpoints.    As you remember, I

      15   alluded that they were MRSA isolates and MSSA isolates

      16   present in this study, so adequate data was available

      17   for us to propose a breakpoint for Staphylococcus

      18   aureus.   In terms of Streptococcus pyogenes, a

      19   proposed breakpoint less that equals to 0.04

      20   micrograms per ml, and for Streptococcus agalactiae,

      21   the proposed breakpoints are less than equals to 0.015

      22   micrograms per ml.    And again, these are the

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       1   breakpoints for Enterobacteriaceae.

       2             For the skin study, these breakpoints are

       3   based E. coli, Klebsiella pneumoniae, and Klebsiella

       4   oxytoca because insufficient experience exists for

       5   thePother members of this family.

       6             So, in summary, ceftaroline demonstrated

       7   adequate gram-positive activity, especially against

       8   staphylococci.   This is because it does bind and

       9   inhibit PBP2a and MRSA isolates.    It had good activity

      10   against streptococci.   In terms of gram-negative

      11   activity, it demonstrated activity against selected

      12   isolates of this family, and, in addition, it has

      13   decreased activity against ESBL-positive isolates.

      14   And as I mentioned earlier, it’s a weak inducer of

      15   AmpC Enterobacteriaceae.   Moreover, insignificant in

      16   vitro activity was detected against non-fermenters,

      17   such as Pseudomonas aeruginosa.     Thank you.

      18             DR. MOORE:    Thank you, Dr. Goodwin.   Let’s

      19   move with Dr. Rubin.

      20      Efficacy Assessment for Ceftaroline:     Community-

      21                Acquired Bacterial Pneumonia

      22             DR. RUBIN:    Good morning.   My name is Dan

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       1   Rubin.   I’ll be speaking about our efficacy assessment

       2   for the pneumonia indication.

       3               When the application arrived, we saw that

       4   pre-specified, non-inferiority goals were met in both

       5   studies.   Our main issue in this review has been

       6   concern about the adequacy of non-inferiority trials

       7   that used clinical response endpoint at the test of

       8   cure.    We, therefore, conducted several additional

       9   analyses thinking that if we could come up with an

      10   endpoint in population for which we were more

      11   comfortable in the non-inferiority setting, and the

      12   drug still seemed efficacious, that would provide

      13   support for the application.

      14               The nine subjects that were excluded who

      15   have already been mentioned, who are not used in my

      16   results here, also, I think a few of the slides in the

      17   handout may have been in a different order from these

      18   slides I’ll present here.

      19               Let me first provide some background on

      20   endpoints used in pneumonia studies.   To establish

      21   efficacy in a non-inferiority trial, it’s necessary to

      22   quantify the treatment effect of the comparator drug

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       1   relative to placebo.    Yet, antibiotics were developed

       2   before placebo-controlled trials become common, and

       3   placebo controls are now considered unethical for this

       4   pneumonia indication.

       5             When reviewing the historical literature

       6   that does exist on subjects given serum or no therapy,

       7   we found that the strongest evidence for an antibiotic

       8   treatment effect was for an affect on mortality, but,

       9   as I’ll show in the next two slides, mortality rates

      10   were too low in these ceftaroline studies under review

      11   to draw any meaningful efficacy inferences.

      12             Mortality rates over the two studies and two

      13   treatment arms were generally in the neighborhood of 1

      14   or 2 percent.   These are 30-day all-cause mortality

      15   rates in the applicants’ MITTE population containing

      16   all randomized subjects in PORT Risk Class III or IV

      17   who received any amount of study drug.

      18             This slide shows mortality rates in the two

      19   pooled pneumonia studies within certain subgroups.

      20   For example, you can see that on the next to last row

      21   that among subjects who were bacteremic at baseline,

      22   there were no deaths.   There just was not a lot of

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       1   mortality in these studies, even though we had

       2   recommended using a PORT III to IV population to

       3   enrich for subjects at greater risk.

       4               In our next presentation, Dr. Porcalla will

       5   go into more detail on mortality from a safety

       6   perspective.

       7               Along with mortality, the historical

       8   literature may also support an antibiotic treatment

       9   effect for clinical response, which usually refers to

      10   resolution of signs and symptoms of the disease.    The

      11   historical literature here is based on a cross-study

      12   comparison, and it was discussed by this committee in

      13   December.   Our review found that the evidence that

      14   exists may support an antibiotic treatment effect

      15   relatively early in the course of therapy, and

      16   particularly from days three to five.

      17               The next segment of the presentation will

      18   concern the responder analysis that we conducted in

      19   light of this consideration that the evidence for a

      20   antibiotic treatment effect is early in the treatment

      21   course.

      22               And in line with this committee's vote last

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       1   December, our responder analysis with an early

       2   endpoint was conducted in the population with

       3   microbiologically-confirmed pneumonia.

       4              Now, the evidence that exists is for an

       5   early treatment effect, but in these two ceftaroline

       6   studies, there was no overall investigator assessment

       7   of clinical response at an early time.    The earliest

       8   assessment was at the end of therapy, which, for most

       9   subjects, was on day seven.   We consequently defined

      10   an earlier endpoint at day four.   Our endpoint was

      11   based on two main criteria; the first involved vital

      12   signs, and the second, which has grown out of

      13   discussions currently being conducted by the FNIH

      14   Biomarkers Consortium involves symptoms of the

      15   disease.

      16              To be a responder in our sensitivity

      17   analysis, the subject first had to be clinically-

      18   stable according to treatment guidelines of the

      19   Infectious Diseases Society of America and American

      20   Thoracic Society.   This definition was based on vital

      21   signs such as temperature, heart rate, or respiratory

      22   rate.

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       1               Second, to be a responder in our analysis, a

       2   subject also had to meet criteria involving four

       3   symptoms:   cough, dyspnea, chest pain, and sputum

       4   production.    By day four, our responder needed to have

       5   improved upon the baseline value on at least one of

       6   these four symptoms, and could not have worsened on

       7   any of the four symptoms.   Aside from sputum, these

       8   were categorized by the investigator as absent, mild,

       9   moderate, or severe.

      10               Now, I’ve noted that our responder analysis

      11   was conducted in a population with

      12   microbiologically-diagnosed pneumonia that our main

      13   differences between our population, which we called

      14   the FDA-mITT population and the applicant’s pre-

      15   specified microbiological populations dealt with

      16   whether Haemophilus parainfluenzae should be

      17   considered a primary pathogen, whether Legionella

      18   could be a co-pathogen, and adequacy criteria for

      19   sputum specimens.

      20               The sample sizes in our responder analysis

      21   were very small with less than 100 subjects per arm in

      22   each study, requiring microbiological confirmation

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       1   dramatically reduce the sample size relative to the

       2   applicant’s pre-specified populations.     Also, I should

       3   note that of the non-excluded subjects, only one of

       4   them would have made it into a micropopulation.

       5                The next few slides will quickly go through

       6   baseline characteristics of our analysis population.

       7   For these slides, the bars on the left are for Study

       8   08.   The bars on the right are Study 09.    Blue is

       9   ceftaroline, and maroon is ceftriaxone.     This slide

      10   just shows that a fair proportion of subjects were 65

      11   or older.

      12               Almost all subjects were in PORT Risk Class

      13   III to IV, and the results I’ll present don’t

      14   qualitatively change if the other subjects are

      15   excluded.   Over the two studies, between 10 and 20

      16   percent of subjects had bacteremia at baseline.        Also,

      17   most subjects were from Eastern Europe.

      18               This slide shows rates at which different

      19   vital signs were abnormal at baseline according to the

      20   clinical stability criteria we used.   Only 5 percent

      21   of subjects were clinically-stable at baseline, and,

      22   again, the results don’t change if they’re removed.

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       1   And you can see here that most subjects were abnormal

       2   on either temperature or respiratory rate.

       3             This slide shows rates at which the symptoms

       4   of cough, dyspnea, chest pain, and sputum production

       5   were reported as being present at baseline.    Virtually

       6   all subjects had multiple symptoms present.

       7             Okay, the next slide will show the results

       8   of our responder analysis in microbiological

       9   population using day four signs and symptoms endpoint.

      10   At day four, response rates were higher for

      11   ceftaroline than ceftriaxone in both treatment arms.

      12   About 70 percent to 58 percent in Study 08 and 68

      13   percent to 61 percent in Study 09.   The difference in

      14   response rates was 11 percent in Study 08 and 6

      15   percent in Study 09, and lower confidence limits for

      16   these treatment differences were negative 4.6 percent

      17   and negative 8.1 percent.

      18             To anchor these numbers in response rates

      19   that you may be more familiar with interpreting, also

      20   show clinical response rates at the end of therapy, as

      21   assessed by the investigator for our analysis

      22   population.

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       1              At the end of therapy, response rates were

       2   higher for ceftaroline than ceftriaxone in Study 08,

       3   whereas in Study 09, the rates were approximately

       4   equal.

       5              This slide shows point estimates for the

       6   ceftaroline, ceftriaxone difference, as well as

       7   confidence intervals about these differences.    In

       8   Study 08, the lower confidence limit actually exceeded

       9   zero, which favors ceftaroline.    In Study 09, the

      10   lower confidence limit for the treatment difference at

      11   the end of therapy barely exceeded negative 10

      12   percent.

      13               We looked at subjects who were classified

      14   at different ways when using our day four signs and

      15   symptoms endpoint and using the investigator’s

      16   assessment at the end of therapy.    The early endpoint

      17   was predictive of later clinical response, but, but no

      18   means was a perfect correlate.    Among those who we

      19   called Day Four Responders, 88 percent went on to

      20   become later clinical successes at the end of therapy

      21   versus only 65 percent among those who we did not call

      22   Day Four Responders.

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       1              The next slide will show results on our day

       2   four signs and symptoms endpoint for subjects with

       3   different baseline pathogens.   If I could direct your

       4   attention to the bottom row in this table, where

       5   response rates at day four were higher for ceftaroline

       6   than ceftriaxone in both studies among subjects with

       7   Streptococcus pneumoniae.    For the other pathogens, we

       8   found that the numbers were really too small to make

       9   any meaningful observations.

      10             The next slide will show results for our day

      11   four signs and symptoms endpoint, broken out by prior

      12   antibiotic use.   Subjects in these studies were

      13   restricted to at most one dose of a short-acting

      14   systemic antimicrobial, and the 96 hours before

      15   randomization.    And in Study 08, this was on top of

      16   two doses of adjunctive clarithromycin.

      17             If you could look at the bottom rows, these

      18   are results for subjects in our microbiological

      19   population without prior therapy.   Now, I think this

      20   really is the cleanest group of subjects to look at in

      21   a non-inferiority study, however, these trials clearly

      22   were not powered in any way to look at this enriched

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       1   subgroup.   These results here by themselves probably

       2   could not support efficacy.    The lower limit in Study

       3   09 for the treatment difference goes down to negative

       4   17 percent, although, the sample sizes become very

       5   small when requiring both no prior antibiotics and

       6   microbiological diagnoses.    I’m going to come back to

       7   prior antibiotics a little later in the presentation.

       8               Now, our responder analysis involved making

       9   several choices that were not necessarily

      10   straightforward.    We also examined how robust the

      11   findings were to different choices that could have

      12   been made in terms of the endpoint definition, the

      13   timing of the assessment, or the analysis population.

      14               This slide shows results separately when

      15   first on the left most bars, only looking at the

      16   symptoms endpoint defined by cough, dyspnea, sputum,

      17   and chest pain.    On the next bars over, you can see

      18   response rates when only looking at clinical stability

      19   definition determined by vital signs such as

      20   temperature or heart rate.    And also, you can see

      21   results that have already been shown when the signs

      22   and symptoms are put together.    For these different

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       1   endpoint definitions in terms of signs and symptoms,

       2   the ceftaroline rates are always slighter higher than

       3   the ceftriaxone rates.

       4              Here are confidence intervals for the

       5   treatment differences between ceftaroline and

       6   ceftriaxone using the different endpoint definitions

       7   in terms of signs and symptoms.   I’m not going to go

       8   through all six of them, but you can see that for the

       9   different configurations, the lower confidence limit

      10   is always somewhere between zero and negative 10

      11   percent.

      12              One thing we noticed about the symptoms

      13   endpoint was that it may not have been very sensitive

      14   because it did not appear terribly difficult to be

      15   called a responder by improving on at least one of the

      16   four symptoms, and another idea that I believe came

      17   out of the FNIH meetings was to define a more

      18   stringent symptoms endpoint by requiring that at least

      19   two of the four symptoms improve upon their baseline

      20   value while still requiring that none of the symptoms

      21   could worsen.

      22              This slide shows day four response rates in

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       1   our microbiological analysis population with the more

       2   stringent symptoms endpoint both by itself and then

       3   again put together with the vital signs.   Again, with

       4   this more stringent definition, ceftaroline is leading

       5   to slightly higher rates than ceftriaxone.   And again,

       6   with the more stringent symptoms endpoint definition,

       7   the lower confidence limits are always somewhere

       8   between zero and negative 10 percent.

       9              We had several discussions about when the

      10   early endpoint should be assessed.   This slide shows

      11   our signs and symptoms endpoint at different times,

      12   specifically day three, day four, and the end of

      13   therapy.   In Study 08, ceftaroline is leading to

      14   higher rates than ceftriaxone over time.

      15              In Study 09, as you move across time, the

      16   response rates look roughly equal between the two

      17   study drugs.   Now, if we had defined our endpoint at

      18   day three or the end of therapy instead of at day

      19   four, the lower confidence limits for the treatment

      20   differences between ceftaroline and ceftriaxone

      21   actually would have dropped below negative 10 percent

      22   in Study 09.

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       1             Finally, we considered our day four signs

       2   and symptoms endpoint in different analysis

       3   populations.   We recognized that requiring

       4   microbiological diagnoses can lead to some false

       5   negatives, and ignoring information from subjects who

       6   do indeed have bacterial pneumonia, we therefore

       7   looked at our endpoint and the applicant’s pre-

       8   specified analysis populations, and we also looked at

       9   results in their microbiological population to assess

      10   robustness with respect to how we handled the criteria

      11   involving pathogens and sputum samples.

      12             I’m not going to go through the three

      13   analysis populations in each study, but you can see

      14   that over the different populations, the response

      15   rates are relatively constant and slightly favor

      16   ceftaroline relative to ceftriaxone.

      17             And again, over the different populations,

      18   the lower confidence limits are always somewhere

      19   between zero and negative 10 percent.      The confidence

      20   intervals are wider for the mMITT population because

      21   this is a microbiological analysis population with

      22   fewer subjects.

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       1             Now, we’re not 100 percent sure that this

       2   day four signs and symptoms endpoint is the absolute

       3   ideal one to use for non-inferiority studies.     We’re

       4   really hoping the committee will weigh in on

       5   endpoints, but I’ve shown a lot of analyses and we’ve

       6   done many more as part of the review, and there's

       7   definitely a consistency of results supportive of

       8   ceftaroline when you cut the data in different ways in

       9   terms of the endpoint definition, in terms of signs

      10   and symptoms, the timing of assessment, or the

      11   analysis population.

      12             However, there are also important

      13   limitations to keep in mind here.   Our responder

      14   analysis was post-hoc and not part of a protocol or

      15   statistical analysis plan.   The sample sizes were

      16   small, in our microbiological population, so, there

      17   was a lot of uncertainty about the treatment

      18   differences.   Also, the sign and symptom measurements

      19   were not standardized in terms of how they were

      20   assessed or when they were assessed, which is not

      21   ideal in a non-inferiority setting.

      22             Further, virtually all of the sign and

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       1   symptom components can be manipulated

       2   pharmacologically, and almost all subjects in the two

       3   studies were given some degree of non-antimicrobial

       4   concomitant therapy.

       5             Additionally, because we saw that it was not

       6   terribly difficult to be a responder on the symptoms

       7   endpoint, that meant that the results were largely

       8   being driven by vital signs, and these might not

       9   really be telling the whole story because they might

      10   not be capturing how the patient is feeling or

      11   functioning.   We also recognized that, aside from

      12   mortality, no algorithmic combination of these signs

      13   and symptoms would precisely correspond to the overall

      14   clinical responses assessed in historical studies.

      15             And the constancy assumption was a little

      16   questionable here because, as I’ve noted, there was

      17   not a lot of death, and subjects in historical studies

      18   were at much greater risk.   Finally, we’re responsible

      19   for patients in the United States, and there were only

      20   five American subjects in our analysis population.

      21             That concludes the presentation of our day

      22   four signs and symptoms responder analysis.   As

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       1   another part of the review, we reexamined the non-

       2   inferiority margin for the applicants’ pre-specified

       3   analysis.    As you know, there's been a tension between

       4   empiricism and judgment in the non-inferiority margin

       5   discussions, and we tried to see how far we could get

       6   with the statistical approach.

       7                In the pre-specified ceftaroline analysis,

       8   enrolled subjects had radiographically-confirmed

       9   pneumonia.    It was not necessarily microbiologically-

      10   confirmed.    Subjects in the co-primary analysis

      11   population were in PORT Risk Class III to IV and were

      12   restricted to, at most, 1 dose of a prior

      13   antimicrobial in the 96 hours before entry.    The

      14   primary endpoint was investigator-assessed clinical

      15   response 8 to 15 days after the end of therapy.

      16                To examine the effect of the comparator drug

      17   ceftriaxone, we looked at two pneumonia studies

      18   comparing ceftriaxone to Daptomycin.    Daptomycin was

      19   later found to have been partially deactivated in the

      20   lung, so, a treatment effect for ceftriaxone over

      21   Daptomycin could be taken to be conservative for an

      22   effect over placebo, which is what you need for a

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       1   margin.    And the first thing we did with these

       2   Daptomycin studies was classify prior therapy as long-

       3   acting or short-acting based on what was allowed in

       4   the ceftaroline studies.

       5                Last December, this committee voted to

       6   restrict “prior effective therapy,” but we may need

       7   more input on what’s meant by “effective,” and, in

       8   particular, if Strep pneumo is so fragile that one

       9   does of, say, ampicillin should be grounds for

      10   exclusion.

      11                Now, the two studies of ceftriaxone and

      12   Daptomycin were similar in design to the ceftaroline

      13   studies.   The biggest differences were that there were

      14   more PORT I and II subjects -- there was more long-

      15   acting therapy allowed, and, often, concurrent

      16   aztreonam was given.

      17                This slide shows results for ceftriaxone and

      18   Daptomycin and the ITT population, and the two pooled

      19   studies.   If you could look at the second-to-last row,

      20   these are results for subjects in PORT Risk Class III

      21   to IV with no long-acting prior therapy, which is

      22   where we think we need a margin to interpret the

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       1   applicant studies.     Here, there’s a 12 percent

       2   difference between ceftriaxone and Daptomycin, with a

       3   confidence interval of 3 percent to 21 percent.

       4              Meta-analysis of the two studies also gives

       5   a statistical margin of 3 percent, and a rule of thumb

       6   is to cut this in half, and whether you do that or

       7   not, it’s very small, but we asked whether it provided

       8   enough of a buffer to help interpret the ceftaroline

       9   results.

      10              Here are the results for ceftaroline and

      11   ceftriaxone, and the applicants’ pre-specified co-

      12   primary MITTE population.     The lower confidence limits

      13   for the treatment differences of clinical response is

      14   that the test of cure.    At worst, negative 1 percent,

      15   which are within the margins that we derived for the

      16   Daptomycin data.    And for the other co-primary

      17   population, the clinically-evaluable population, and

      18   if you go through the same exercise applying the non-

      19   inferiority machinery to the Daptomycin studies, you

      20   also fall within the derived margin in both

      21   ceftaroline studies.

      22              Here are the results for the applicants’ co-

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       1   primary population by prior antibiotic use, and let me

       2   go back a few slides.   If you look at the bottom row

       3   here in the Daptomycin studies, you see that there may

       4   also be some evidence of treatment effect for the

       5   ceftriaxone comparator among subjects given no priory

       6   therapy at all.   And in the ceftaroline studies among

       7   the subgroup with no prior antibiotic therapy, again,

       8   the lower confidence limits for the treatment

       9   differences are very small, at worse seeming to be

      10   negative 1 percent.

      11              The strengths of this margin justification

      12   were that the Daptomycin studies were relatively

      13   recent and randomized, whereas other studies that have

      14   been brought up in the non-inferiority discussions are

      15   more dated and more observational.   Also, the

      16   Daptomycin may have still had some effect, even if it

      17   was partially deactivated.

      18              However, there are significant limitations

      19   here.   Again, this was after the fact, and there's

      20   another statistical issue I have to bring up.    The

      21   applicant tested their primary and secondary and

      22   tertiary non-inferiority hypothesis with a sequential

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       1   gate-keeping strategy, and in that context, there’s no

       2   multiplicity adjustment for first meeting your 10

       3   percent margin, and then using your lower confidence

       4   limit to test for a smaller margin, even if it’s

       5   justified.

       6                That's another way of saying that there’s

       7   not really any alpha control with this post-hoc

       8   looking that we’re doing.

       9                Regarding the margin justification, it was

      10   motivated by a published post-hoc subgroup analysis,

      11   and these are probably best considered exploratory,

      12   and also, that 3 percent margin that resulted, the

      13   statistical margin was very small, and large margins

      14   would be more robust to uncertainties in the

      15   justification process.

      16                On balance, we concluded that the

      17   limitations did not allow rigorous, empirical margin

      18   justification for clinical response at the test of

      19   cure.   However, as an exploratory analysis, the

      20   Daptomycin study seemed to be suggesting at least some

      21   small treatment effect for the ceftriaxone comparator

      22   on clinical response, and ceftaroline does not seem to

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       1   lose much, if any, of this effect.   I don’t think that

       2   argument can meet our substantial evidence standard,

       3   but we considered this analysis to provide support of

       4   any direct evidence of advocacy.

       5             There were several other issues that we

       6   examined as part of the review, and I don’t have time

       7   to go into detail, but can provide more information,

       8   if requested.   To mention only one, adjunctive

       9   clarithromycin was given in two doses to subjects in

      10   Study 08, and this was an issue because clarithromycin

      11   has activity against cap pathogens, such as Strep

      12   pneumo or H. flu.   That being said, when looking at

      13   the two studies together, which had otherwise

      14   identical protocols, we certainly didn’t see any

      15   evidence that the biocin was masking this inferiority.

      16             To summarize the efficacy assessment, the

      17   applicant met pre-specified, non-inferiority results,

      18   but there were a lot of uncertainties and concerns

      19   about using a clinical response endpoint all the way

      20   out at the test of cure.   We conducted a day four

      21   responder analysis with signs and symptoms and

      22   microbiological analysis population.   It continued

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       1   pointing towards efficacy, but we recognized that

       2   there are multiple limitations.    And we also attempted

       3   an empirical determination of a margin for the pre-

       4   specified analysis.

       5              Again, there were limitations, but we

       6   concluded that these could provide indirect support of

       7   evidence of efficacy.

       8              Thank you.

       9              DR. MOORE:   Thank you, Dr. Rubin.

      10              We’ll move forward now with Dr. Porcalla.

      11               Review of Safety for Ceftaroline

      12              DR. PORCALLA:   Good morning.   I am Dr. Ariel

      13   Porcalla, and I’m a Medical Officer with the Division

      14   of Anti-Infective and Ophthalmology Products, and I’m

      15   here to present the safety review for ceftaroline.

      16              My presentation will be based on the

      17   following outline.    I will initially talk about the

      18   safety population and adequacy of exposure to study

      19   drug.   Next, I will talk about non-clinical studies

      20   and the demographics of the Phase 3 population.    Then,

      21   I will describe the major safety parameters, such as

      22   overall adverse events, deaths, Serious Adverse

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       1   Events, or SAEs, reasons for premature drug

       2   discontinuation and study withdrawal, Adverse Drug

       3   Reactions, or ADRs, cardiac evaluation, AEs relevant

       4   to cephalosporins, and finally, my conclusions and

       5   recommendation.

       6             The safety population of the Ceftaroline

       7   Drug Development Program consists of subjects given

       8   intravenous and intramuscular ceftaroline in clinical

       9   pharmacology studies and of subjects enrolled in an

      10   adolescent study to Phase 2 complicated skin trails

      11   and for Phase 3 trials for the indications of

      12   complicated skin and skin structure infections and

      13   Community-Acquired Bacterial Pneumonia.    In all, there

      14   were 1,740 subjects given ceftaroline, of whole 1,441

      15   subjects were given the proposed dose, compared to

      16   1,458 subjects who were treated at the comparator

      17   regimens or placebo.

      18             In this tally, we have excluded subjects

      19   enrolled by investigators in India.

      20             With the proposed treatment duration of 5 to

      21   14 days for skin infections and 5 to 7 days for

      22   pneumonia, the main treatment duration and the median

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       1   number of treatment days for ceftaroline were similar

       2   for ceftaroline in the comparator arms

       3   for both indications.    In short, it appears that the

       4   pooled Phase 3 population received adequate exposure

       5   to the study drug so that 95.3 percent of subjects

       6   receive the proposed dose of 600 mg IV q12 hours or

       7   the proposed dose for patients with moderate and

       8   severe renal impairment.

       9             Prior to the clinical trials, non-clinical

      10   studies in animal models were performed to determine

      11   possible toxicities that may be experienced in

      12   clinical trials.    Rats and monkeys given high

      13   exposures of ceftaroline experienced seizures.       This

      14   was consistent with experience involving the central

      15   nervous system in rats given cephalosporins.

      16             For the cardiovascular system, no evidence

      17   of QT prolongation was noted in conscious monkeys.

      18   There was no evidence hepatic toxicity.     And in

      19   rabbits who were given intravenous and intramuscular

      20   ceftaroline, they tolerated the administration.

      21             As for the renal system, rats and monkeys

      22   given ceftaroline developed cloudy urine, increased

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       1   kidney weights.   Laboratory changes with kidney

       2   function tests were noted in animals given short-term

       3   high doses of ceftaroline.    Microscopic renal changes

       4   were seen so that in the 13 week studies of rats given

       5   270 mg/kg/day, which is a high dose, granular

       6   formation with foreign material was noted in the

       7   renal-collecting tubulars, while in rats given a lower

       8   dose of 90 mg/kg/day, which is equivalent to 1 times

       9   the human AUC concentrations, rats showed minimal

      10   vacuolation which resolved during recovery.   No

      11   development toxicity was noted in rats.

      12             Next, the demographics of the Phase 3 safety

      13   population and the overall incidents of adverse events

      14   will be discussed.

      15             In general, subjects who were enrolled in

      16   the Phase 3 clinical trials were predominantly male,

      17   White, non-Hispanic, with a main body mass index of 27

      18   kilograms per square meter, main age of 54 years, and

      19   with normal renal function.   The demographic and

      20   baseline characteristics of the population of the skin

      21   trials and the pneumonia trials were similar in terms

      22   of gender, height, weight, and body mass index, while

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       1   they were different in terms of age, ethnicity, race,

       2   and creatinine clearance, as you will see later.

       3             Within trials for each indication, the

       4   demographic and baseline characteristics were similar

       5   between the patients treated with ceftaroline and the

       6   population treated with a comparator regimen.   The

       7   population subsets of interest were relatively well-

       8   represented in the Phase 3 trials.    In particular, 31

       9   percent of the Pooled Phase 3 safety population was

      10   65-years-of-age or older, 14 percent were older than

      11   75-years-of-age.

      12             In terms of weight, subjects who were

      13   overweight comprised 32.2 percent, and morbidly obese

      14   patients comprised 4.4 percnt of the populations.

      15             In terms of renal insufficiency subjects

      16   with mild renal impairment comprised 22.4 percent of

      17   the population, while those with moderate renal

      18   impairment comprise 8.5 percent of the safety

      19   population.

      20             In the pneumonia trials, subjects were

      21   generally older.    Specifically, a greater proportion

      22   of subjects in the complicated skin trials were

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       1   enrolled in the U.S., while a greater proportion of

       2   subjects in the pneumonia trials were enrolled from

       3   Eastern Europe.    More subjects in the pneumonia trials

       4   had mild to moderate renal impairment.

       5              For the Phase 3 Skin trials, the overall

       6   incidents of TEAEs and SAEs were comparable between

       7   the ceftaroline-treated group and the Vancomycin and

       8   Aztreonam group.    There appears to be a slightly

       9   higher incidence of TEAEs causing discontinuations and

      10   study withdrawal in the Vancomycin and Aztreonam

      11   group.   There were three deaths observed in the

      12   ceftaroline arm compared to none in the Vancomycin

      13   arm.

      14              As for the pneumonia trials, the overall

      15   incidents of SAEs, TEAEs, and TAEs that led to

      16   premature discontinuation of the study group or

      17   premature study withdrawal were comparable with the

      18   group treated with ceftaroline and the group treated

      19   with ceftriaxone.    These incident rates exclude data

      20   from the three India sites, as mentioned previously.

      21   As far as mortalities are concerned, the overall

      22   mortality rates in the ceftaroline-treated group was

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       1   around 2.4 percent, and it was 2 percent in the

       2   ceftriaxone group.

       3                Now, we move on to a discussion of the

       4   deaths.

       5                During the clinical pharmacology trials,

       6   there were no deaths reported.    In the Phase 3

       7   clinical trials, before the late follow-up visit, a

       8   total of 30 deaths were reported.    Three were in the

       9   ceftaroline arm in the skin trials, as I’ve said, 15

      10   were treated with ceftaroline in the pneumonia trials,

      11   and 12 were treated with ceftriaxone in the pneumonia

      12   trial.    Additionally, nine subjects consisting of four

      13   subjects in the skin trials and five subjects in the

      14   pneumonia trials died after the late follow-up visit.

      15                This is a breakdown of the reported deaths

      16   in the skin trials prior to and after the late follow-

      17   up visit.    Subject 1 is a treatment failure.     He died

      18   of respiratory failure with an overall picture of

      19   sepsis from a gangrene skin lesion and a concomitant

      20   urosepsis.

      21                Multiple comorbidities, such as diabetes,

      22   hypertension, severe arterial insufficiency, skin

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       1   cardiomyopathy, and heart failure for the case can

       2   make it difficult to associate the death as

       3   ceftriaxone, ceftaroline use.   Hence, none of the

       4   deaths reported in the ceftaroline group in the skin

       5   trials may possibly be attributed to ceftaroline use.

       6             Next.   This slide lists and describes the

       7   deaths from ceftaroline arm in the Pneumonia Study 08.

       8   Of the six mortalities reported, one case of sudden

       9   death, Subject 2, may be associated with ceftaroline

      10   use, and will be discussed later.

      11             Noteworthy is patient five, who was

      12   classified as a treatment failure on day four, and

      13   then the patient grew coagulase negative

      14   Staphylococcus and Pseudomonas on day 22, and

      15   cefuroxime was added to his therapy.   But because of

      16   the remoteness of ceftaroline administration from the

      17   day of death and the fact that this may be nosocomial,

      18   it is unlikely that this death is associated with

      19   ceftaroline use and treatment failure.

      20             On the other hand, Subject 6 died on day 16

      21   from respiratory failure, and this is probably from

      22   progression of pneumonia.   This patient was judged as

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       1   treatment failure on day four and antibiotic therapy

       2   was changed to antibiotics such as Moxifloxacin,

       3   Piperacillin, and Levofloxacin.

       4             Autopsies showed that this patient died from

       5   acute respiratory distress syndrome, most probably

       6   from progression of pneumonia, so this mortality may

       7   have resulted from the failure of ceftaroline to treat

       8   the infection.

       9             In ceftriaxone arm of Study 08, one death

      10   may be possibly associated with ceftriaxone use.     This

      11   is Subject 4 who died of multi-organ failure, and he

      12   was 60-years-old and a history of smoking,

      13   hypertension, and a questionable history of

      14   alcoholism, who developed alcoholism who developed

      15   initially hepatic failure, then developed renal

      16   failure, and subsequent multi-organ failure and died.

      17   No autopsy was performed.   But no other etiology to

      18   which the subject’s death can be attributed to this

      19   death, and may be possibly associated with ceftriaxone

      20   use.

      21             The other mortality worth mentioning is

      22   Subject 2.   A treatment failure after two days of

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       1   treatment was changed to piperacillintazo bactam.     He

       2   initially improved, but worsened and died after 23

       3   days, and because of a history of COPD and the

       4   remoteness of study drug administration from the day

       5   of death, this mortality is probably not associated

       6   with the failure of the study drug.

       7             In Pneumonia Study 09, there were nine

       8   deaths reported.    One of the reported deaths, Subject

       9   9, is from the site in India that is being excluded,

      10   and this is a case of a 57-year-old male with a

      11   history of smoking, diabetes, and pulmonary

      12   tuberculosis, who failed treatment with the

      13   ceftaroline by day 5, despite the change of therapy to

      14   Vancomycin and Aztreonam, he died from

      15   Nosocomial pneumonia and COPD and asthma, and Subject

      16   5, a case of respiratory failure classified as a

      17   treatment failure on day six, but then experienced

      18   COPD exacerbation, which ultimately led to his death.

      19   The rest of the report, mortalities with respective

      20   causes of death are most probably unrelated to

      21   ceftaroline use.

      22             The next slide describes the six deaths

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       1   reported in ceftriaxone arm.    One’s death, Subject 4,

       2   with COPD and diabetes was classified as a treatment

       3   failure and died on study day six from respiratory

       4   failure, probably from the primary infection and the

       5   COPD exacerbation.    The rest of the reported deaths

       6   were probably not associated with a study drug.

       7             This slide summarizes the deaths reported to

       8   occur after the late follow-up visit.       Because of the

       9   causes of death, such as pancreatic malignancy,

      10   mayopathy, and hospital-acquired infection from

      11   Pseudomonas and Stentorophomonas, and the remoteness

      12   of the deaths from the study drug administration

      13   association between the deaths and the study drug are

      14   highly unlikely.

      15             All in all, for the overall pooled safety

      16   population, the mortality rate was low and comparable

      17   between the ceftaroline-treated group and the

      18   comparator-treated group.    Only one death was possibly

      19   associated with ceftaroline, and this is a case of a

      20   73-year-old Hispanic woman who died suddenly on day

      21   three, while being treated with ceftaroline for a

      22   right middle lobe pneumonia with no identified

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       1   pathogen.   Based on evaluation of significant for

       2   fever, tachycardia, and premature atrial complexes.

       3               On study day three, she was found dead and

       4   unresponsive with no rashes noted, and with no

       5   difficulty experiencing intubation.    Unfortunately, an

       6   autopsy was not performed, so, the cause of death was

       7   not certain.   And because the death occurred while the

       8   patient was on ceftaroline and there was no other

       9   possible explanation for her death, this cause of

      10   sudden death may possibly be associated with

      11   ceftaroline use.

      12               Deaths reported during the Phase 3 trials

      13   were mostly classified under cardiac disorders,

      14   respiratory and thoracic disorders, and neoplasms.

      15   And that is illustrated in this table.

      16               In summary, based on the discussion and

      17   analysis of the reported deaths, it is unlikely that

      18   ceftaroline use is associated with an increased risk

      19   of death.

      20               Now, I will discuss serious adverse events

      21   DAE is leading to premature study discontinuation or

      22   study drug discontinuation and common adverse drug

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       1   reactions.

       2                The overall incidents of SAEs in the

       3   complicated skin infection trials was slightly lower

       4   than the incidents of SAEs in the pneumonia trials.

       5   For each indication, the incidents of SAEs were

       6   similar between the ceftaroline-treated group and the

       7   comparator-treated group.     Seven point four percent of

       8   population reported at least one SAE compared to seven

       9   point seven percent of comparator-treated subjects

      10   reported at least one SAE.    SAEs were mostly

      11   classified under infections, respiratory and thoracic

      12   disorders, and cardiac disorders.

      13                This slide illustrates the different SAEs

      14   categorized under each system organ class.    Most of

      15   the SAEs reported would appear to be complications of

      16   the primary disease for which patients were enrolled

      17   in, such as the development of pyrothorax, cellulitis,

      18   lung abscess, and pleural effusion. SAES also appear to

      19   come from the chronic comorbidities of the subjects,

      20   such as COPD exacerbation and cardiopulmonary failure.

      21                 This slide shows SAEs categorized under the

      22   immune system, the nervous system, and the renal

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       1   system.   Specifically, one case of non-fatal

       2   anaphylactic shock in the ceftaroline group was a

       3   patient with facial and labial swelling with

       4   bronchospasm pallar and cyanosis.     The patient was

       5   treated with epinephrines, steroids, and beta-

       6   agonists, and the patient recovered.

       7              Two subjects reported seizures, and these

       8   two patients were given ceftaroline.    One subject was

       9   a 75-year-old male with no history of prior

      10   convulsions, who experienced seizures three days after

      11   end of therapy with ceftaroline.    The other case was a

      12   65-year-old male with diabetes, hypothyroidism, HIV,

      13   and Hepatitis C infection, who developed seizures five

      14   days after ceftaroline therapy.     Because of pre-

      15   existing cerebral infarcts, cerebral vascular

      16   accident, and prior syncopal episodes, later diagnosed

      17   as seizures, both of these cases were probably not

      18   associated with ceftaroline intake.

      19              Lastly, the incidences of SAEs classified

      20   under the renal disorders in the safety population is

      21   slow.

      22              Moving on, the number of patients who

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       1   prematurely discontinued the study drug or withdrew

       2   from the study because of an adverse event is slow;

       3   3.7 in the ceftaroline group and 4.5 percent in the

       4   comparator group.   More specifically, the causes of

       5   study withdrawal from the trials are as follows:

       6   Around 2 percent of subjects enrolled in the

       7   ceftaroline and the comparator groups withdrew their

       8   consent to participate, and 4.1 percent of patients in

       9   the ceftaroline group and 3.8 percent in the

      10   comparator group were lost to follow-up.

      11             Disorders of skin and subcutaneous tissues

      12   appear to be the most common adverse events, causing

      13   discontinuation and study withdrawal.

      14   Hypersensitivity appears to be the most common

      15   treatment emergent adverse event that was reported as

      16   the reason for primary discontinuation of the study

      17   drug or study withdrawal, with an incidence of 0.3

      18   percent in the ceftaroline group and 0.5 percent in

      19   the comparator group.

      20             From this slide, adverse events causing

      21   premature discontinuation from the study drug or study

      22   withdrawal were typically classified under the skin

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       1   and subcutaneous tissue disorders, infections, and

       2   respiratory and thoracic disorders.

       3              Moving on, the next point of discussion are

       4   on the common adverse drug reactions, which are a

       5   subset of TEAEs that are possibly related to the study

       6   drug.   As can be seen in the next slide, the most

       7   common ADRs attributed to ceftaroline are diarrhea and

       8   nausea, classified under “gastrointestinal

       9   complaints,” and headache classified under “nervous

      10   system complaints.”

      11              The incidences of ADRs appear to be low and

      12   similar between the two treatment groups.    All in all,

      13   adverse drug reactions experienced by subjects in the

      14   ceftaroline drug development program appear to be

      15   consistent with the adverse drug reactions expected in

      16   the cephalosporin class of antibacterials.   Here is a

      17   table that illustrates the most common adverse drug

      18   reactions in the Phase 3 trials.

      19              Moving forward to the review, the last three

      20   bullet points will be discussed.   The potential for

      21   ceftaroline to cause cardiac problems was evaluated.

      22              In the Phase 3 clinical trials,   there was

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       1   no evidence of increased risk of cardiac toxicity as

       2   seen in the ceftaroline-treated group relative to the

       3   comparator group.   The thorough QT study, which was

       4   reviewed by the Interdisciplinary Review Team, is a

       5   crossover study of 54 subjects who were given 1,500

       6   milligrams of ceftaroline, moxifloxacin, and placebo.

       7   No significant prolongation of the QT interval was

       8   seen compared to moxifloxacin, with a mean QT duration

       9   being 1.6 milliseconds in ceftaroline-treated subjects

      10   compared to 19.2 milliseconds for moxifloxacin.

      11             Guided by non-clinical studies and prior

      12   experience with cephalosporins, the following relevant

      13   adverse events are noteworthy to mention.   The

      14   incidents of renal events in the clinical trials is

      15   slow, with an incidence of 1.5 percent in the

      16   ceftaroline arm and 0.8 percent in the ceftaroline

      17   comparator arm.

      18             As previously mentioned, two cases of

      19   seizures were reported in the ceftaroline arm and one

      20   case was reported as a non-serious, adverse event in

      21   the ceftriaxone arm, all of whom were probably

      22   unrelated to the study drug.

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       1                As far as the incidents of Coombs’ test

       2   seroconversion, more subjects in the ceftaroline

       3   group, around 10.7 percent, experienced seroconversion

       4   compared to 4.4 percent in the comparator group.

       5   However, since the incidents of anemia was low and

       6   similar between the ceftaroline and comparator arms,

       7   and since there were no cases of clinical hemolytic

       8   anemia reported in both arms, the clinical

       9   significance of the difference in the Coombs’ test

      10   seroconversion is unknown.

      11                As for AEs that represent potential allergic

      12   reactions, their incidents was lower in the

      13   ceftaroline group.    Lastly, the incidents of

      14   antibiotic associated diarrhea was simlair between the

      15   two groups.    Only two cases of C. diff colitis was

      16   reported in the ceftaroline arm compared to one case

      17   in the Vancomycin Aztreonam arm.

      18                All in all, to summarize the review of

      19   safety for ceftaroline, it appears that use of

      20   ceftaroline is not associated with a higher risk of

      21   mortality.    Of equal importance is the observation

      22   that ceftaroline has a safety profile comparable to

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       1   the active comparators used in the clinical trials,

       2   particularly the Vancomycin with Aztreonam and

       3   ceftriaxone.   It also has a safety profile comparable

       4   to the safety profile of existing cephalosporins.

       5              In this slide, similar to other

       6   cephalosporins, clinical practitioners need to be

       7   aware of ceftaroline’s potential to be associated with

       8   the following:    gastrointestinal complaints and

       9   headaches, Coombs’ test seroconversion, allergic

      10   reactions, and antibiotic-associated diarrhea.

      11              Thank you for your attention.

      12              DR. MOORE:   Thank you, Dr. Porcalla.

      13              In the interest of time, I’m going to

      14   exercise my authority as the chair to change the

      15   agenda.   We’re going to go now to the 15-minute break,

      16   and then we’ll come back and do questions and

      17   clarifications.

      18              So, with that, committee members, please

      19   remember that there should be no discussion of the

      20   meeting topic during the break amongst yourselves or

      21   with any member of the audience.    We will resume at

      22   11:00.

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       1             (Whereupon, a recess was taken.)

       2             DR. MOORE:    Okay, if I can get everyone to

       3   take their seats now.    As I say, we’re on a bit of a

       4   tight schedule today.    Why don’t we do this?

       5   Dr. Thye from Cerexa has some information that was

       6   requested earlier from Dr. Kaplan regarding

       7   Enterococci and ceftaroline.

       8             DR. THYE:     Yes, I just want to follow-up on

       9   that question regarding the incidents of UTIs due to

      10   Enterococcus seen in the studies.      We reviewed the

      11   data listings and identified with respect to UTIs

      12   specifically 11 cases of UTI on ceftaroline versus 9

      13   on ceftriaxone.   We don’t have the microbiology data

      14   associated with those cases.

      15             DR. MOORE:    Thank you.

      16             With that, we’ll now go to questions and

      17   clarifications from the committee.

      18             Yes, Dr. Camardo?

      19                Questions and Clarifications

      20             DR. CAMARDO:    Thank you.    It continues to

      21   get the attention of the industry when you develop

      22   antibiotics, how the breakpoints are set, and it is an

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       1   industry-wide question, I think, but I have to ask it

       2   sort of specifically with this one product.   It’s

       3   striking to me how concordant are the safety and

       4   efficacy evaluations by FDA, and the issue, I think,

       5   is that sometimes when you set the breakpoints, you

       6   actually eliminate from sort of common use organisms

       7   that contributed to the efficacy of the trial.     So,

       8   they do have an endpoint, so I really have two

       9   questions, but I’m not sure whether to ask the FDA or

      10   whether to ask the sponsor.

      11             There’s a difference between the

      12   interpretative criteria that was set, but I can’t see

      13   how using the same data you got that difference, and I

      14   wonder if maybe I could ask the FDA first is there

      15   something that's missing that was done to get there or

      16   is there some concern theoretical or otherwise that is

      17   sort of restricting the breakpoints to these most

      18   sensitive organisms?   I guess that's really the

      19   question, and it does have impact because I know, I

      20   mean, I checked before I came in here.   It’s still

      21   something that's going on in industry that we watch

      22   how these things are done and what impact they do

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       1   have.

       2              DR. MOORE:   I think that's fine.   Would the

       3   sponsor care to address that or the FDA?    Let me just

       4   say actually before we get into that, there are two

       5   things I want to try to avoid wading into with the

       6   charge put before the committee.   The FDA hasn’t had

       7   the opportunity, as I understand it, to discuss or

       8   provide any background regarding the amendment the

       9   sponsor has submitted regarding differences in

      10   susceptibility breakpoints.   That's something the

      11   committee won't be able -- we can discuss it, but I

      12   don’t want to spend too much time on it.

      13              DR. CAMARDO:   No, okay, I understand that.

      14              DR. MOORE:   It’s not going to be part of our

      15   vote.   The other is that, we’ll talk about it later,

      16   the change in the moving goal post, if you will, that

      17   is going to become or seems to be becoming part of the

      18   new pneumonia endpoint considerations.     As many of you

      19   were involved in the discussion with this committee

      20   before, those changes in endpoints took place after

      21   these drug trials were initiated, and so, that's going

      22   to cover some of the discussion we have later with the

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       1   charge to the committee.

       2             Sorry about that dissertation.   Let’s go

       3   with the sponsor.

       4             DR. CRITCHLEY:   Okay, well, I guess we could

       5   start with really I think everybody’s aware of the

       6   fact that there are differences in the interpretative

       7   criteria that were proposed by ourselves and by our

       8   colleagues at the FDA, and if we look at Streptococcus

       9   pneumoniae.

      10             I think we proposed a susceptible breakpoint

      11   of equal to or less than 0.05 micrograms per ml, and I

      12   know that we’ve provided additional information on the

      13   criteria that we used to assign our proposed

      14   breakpoints not only for Streptococcus pneumoniae, but

      15   also for Staph aureus in the addendum to the briefing

      16   book, and we did use a variety of criteria to

      17   determine our breakpoints and, of course, the clinical

      18   efficacy data is a component of that, but it’s not the

      19   sole factor that was considered in the breakpoints

      20   that were assigned by us I think in the core

      21   presentation this morning for Streptococcus

      22   pneumoniae.

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       1             We had an opportunity to share how we came

       2   up with the target attainment work to show and justify

       3   that the dosing regime that was studied in Phase 3 was

       4   appropriate for Streptococcus pneumoniae, and, also,

       5   this afternoon, we were going to share the data on

       6   Staph aureus, but maybe it might be good to cover that

       7   topic in one fell swoop.

       8             What I would like to do though is our

       9   strategy was to integrate not only the clinical data,

      10   but also the other components, and what I’d like to do

      11   is invite Dr. Paul Ambrose from ICPD to come in and

      12   maybe just walk through so that you can understand a

      13   little more closely how we came with that.

      14             But maybe just before I do that, what I’d

      15   like to is just show you one of the issues associated

      16   with assigning the breakpoint for Streptococcus

      17   pneumoniae.   These are the 36 isolates that were

      18   procured in the Phase 3 Program.   There were

      19   additional subjects with Streptococcus pneumoniae, but

      20   they were identified by urine antigens.   So, it was

      21   impossible to get the supporting susceptibility data

      22   for the assignment of breakpoints.

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       1              And if you quickly just look at the MIC

       2   distributions, I mean, they range from equal to or

       3   less than 0.004 micrograms per ml, up to a maximum MIC

       4   of 0.25.   Most of the organisms are down at the lower

       5   end, and I guess there’s just one point to be made

       6   here; when you’re trying to procure clinical isolates

       7   in clinical studies where there’s a certain proportion

       8   of subjects that have not had prior antimicrobial

       9   therapy, that makes it more challenging to find and

      10   identify these higher MIC isolates in clinical

      11   studies, and sometimes when you look at the higher

      12   end, this is where you do see a disconnect with what

      13   you find in clinical trials versus those of what you

      14   do in surveillance.

      15              So, to kind of help us assign what we felt

      16   was an appropriate breakpoint for Streptococcus

      17   pneumoniae, we actually integrated the MIC data with

      18   the exposure data, and maybe that's where I could hand

      19   it over to Dr. Ambrose, who will walk you through what

      20   we did certainly for Streptococcus pneumoniae, and if

      21   you feel this time we could do Staph aureus.

      22              DR. AMBROSE:   Thank you, Dr. Critchley.

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       1              My name is Paul Ambrose, and before I get

       2   started, I want to make the committee aware of two

       3   important conflicts of interest to keep in mind as I

       4   speak.   The first is I’m a temporary member or

       5   sometimes member of the same committee that you’re

       6   sitting on, and earlier this year, I participated in a

       7   meeting like this.   And secondly, our group in Albany

       8   was responsible for the Pharmacokinetic and Dynamic

       9   Analysis and Breakpoint Justification Reports that

      10   were submitted by Cerexa as part of the NDA.    In both

      11   instances, I received enumeration.   In fact, I’m being

      12   paid to be here today.

      13              So, what we want to do when we set

      14   breakpoints is integrate, as Dr. Critchley said, three

      15   types of data and start at the top of that hierarchy

      16   is clinical data followed by PK-PD data, and then MIC

      17   distribution data.   Dr. Critchley showed you a table

      18   with outcome by MIC for the strains of pneumoccus with

      19   which they had MIC values, and you can see no clear

      20   decrease in drug performance as the MIC increased.

      21              So, what can we then learn from PK-PD, the

      22   second tier?   These are data from the neutropenic

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       1   murine thigh infection model.    These analyses were

       2   conducted by David Andes and Bill Craig in Wisconsin,

       3   and what you’re looking at is the change in log CFU on

       4   the Y axis versus free drug time above MIC.    Zero

       5   represents net baceteriostasis in the thighs of these

       6   neutropenic mice.    Positive numbers are bacteria

       7   growing.   Negative numbers are bacteria dieing.     Like

       8   for all ß-lactams, you can clearly see time above MIC

       9   predicts response to therapy.

      10              There are there important points I want you

      11   to take from this slide.    First, the blue symbols are

      12   penicillin-susceptible strains, while the red are

      13   penicillin-resistant strains.    Note it takes the same

      14   time above MIC to get a given level of drug effect.

      15   So, it’s not the presence or absence of penicillin-

      16   resistance that predicts efficacy for ceftaroline.

      17   The question is:    Can you get enough time above MIC?

      18   That's the first point I’d like you to remember.

      19              The second point is that baceteriostasis is

      20   associated with the time above MIC of about 35 percent

      21   at a one log kill or 90 percent reduction in the

      22   bacteria, and the numbers of bacteria in the thighs

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       1   are mice is associated with a 44 percent probability

       2   of time above MIC.    That's the second point.

       3             The third point, why focus on stasis or a

       4   log kill in this animal model?    And that's because

       5   other PK-PD analyses of clinical trial datasets that

       6   were part of NDAs, when you look back at the

       7   relationships found in the clinical data and say what

       8   corresponded with those relationships in the animal

       9   data, it was stasis to a one log kill in this animal

      10   infection model.

      11             So, when you look at ceftaroline’s     clinical

      12   data and you say what was the time above MIC that they

      13   achieved in patients, well, 91 percent of all subjects

      14   in the ME population had a free drug time above MIC

      15   value that exceeded 90 percent of the dosing interval.

      16   And when you look at the patients that had pneumonia

      17   that were associated with pneumoccus, every single one

      18   of them had 100 percent time above MIC.

      19             So, now let’s integrate the PK-PD targets

      20   from the animal data with patient population of

      21   pharmacokinetics patients actually with disease using

      22   a tool called Monte Carlo simulation, and what you’re

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       1   looking at here on the Y axis is the probability of P

       2   K-PD target attainment on this axis.    And these lines

       3   represent either stasis, 35 percent time over MIC, a

       4   one log kill, or a two log reduction in thighs in

       5   mice.   I urge you to pay attention to this stasis and

       6   one log kill targets.   This is overlaid the MIC

       7   distribution for Streptococcus pneumoniae.     And you

       8   can see you get about 90 percent target attainment in

       9   either one of these P K-PD thresholds all the way up

      10   to and including an MIC value of one.     The sponsor has

      11   asked for a susceptibility breakpoint of 0.5.

      12              Now, let’s look at MIC distribution data and

      13   see what this tells us.

      14              These are data from 6,500 isolates from JMI

      15   Laboratories in Iowa.   And the data is split up by

      16   green as U.S., EU is orange, is the of the E.U., and

      17   it’s also yellow, is penicillin-susceptible, and red

      18   is penicillin-non-susceptible, and you can clearly see

      19   two modes for ceftaroline; one down low around less

      20   than or equal to 0.008, and another up higher.     The

      21   FDA breakpoint in the briefing book is 0.008.

      22              So, the question the committee has to think

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       1   about:    Is there evidence to suggest the ceftaroline

       2   can treat these higher MICs, and, remember,

       3   penicillin-non-susceptible strains start showing up

       4   here.    Ceftriaxone, less susceptible strains also

       5   start showing up in the region.    Typically, the

       6   ceftriaxone MICs in this region would be somewhere

       7   around 0.5 all the way up to 8 micrograms per ml.

       8               So, I shared with you earlier it wasn’t

       9   really penicillin-susceptibility that was important

      10   for ceftaroline; it was really time above MIC.      I also

      11   showed you patient population pharmacokinetics and

      12   associated simulations to show they get adequate

      13   target attainment with ceftaroline using this dosage

      14   regimen all the way up to MIC values up to one.     So, I

      15   believe these data can support a breakpoint much

      16   higher than 0.008 anywhere up to an MIC value of 1.

      17               With that, Dr. Critchley?

      18               DR. CRITCHLEY:   While we're discussing this

      19   topic, I think Staph aureus is such a key pathogen for

      20   this drug, and, also, as are the methicillin-resistant

      21   strains, and there was also a notable difference here.

      22   We were actually using very much the same models and

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       1   tools to propose a susceptible breakpoint of 2

       2   micrograms per ml.    Again, we used very much the same

       3   criteria, but what I’d like to do is show you next the

       4   outcome by MIC for Staphylococcus aureus in the same

       5   way that we just showed you for Streptococcus

       6   pneumoniae.    And this was for all isolates of Staph

       7   aureus, and here we have a good end, a good number of

       8   isolates.

       9               We had 362 isolates per cure.   This is in

      10   the ME population, and in both Phase 3 studies

      11   combined, you can see the MICs ranged from 0.06 to 2

      12   micrograms per ml.   We did have 11 isolates with MICs

      13   of 1, and, there, we had a pretty good clinical

      14   response rate with all 11 subjects with those

      15   isolates, with those MICs being successfully treated.

      16   We did get a handful at two, but the response rate

      17   there was two out of four.

      18               But when we looked carefully at those two

      19   failures, and as Dr. Ambrose has mentioned, we also

      20   had PK-PD information on these two subjects that

      21   failed, and in both subjects, the failure was not due

      22   to a lack of exposure.   Both those subjects had

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       1   sufficient percent time above MIC that was greater

       2   than 50 percent.

       3                And in fact, both subjects were showing

       4   signs of clinical improvement in the primary

       5   infection, but one patient had therapy discontinued

       6   because of a treatment limiting adverse event due to

       7   the onset of Clostridium difficle diarrhea occurring

       8   on day 10.    And the other patient was a subject that

       9   required amputation to address a pre-existing

      10   necrosis.

      11                So, we have integrated this data along with

      12   the PK-PD target attainment, and I’ll ask Dr. Ambrose

      13   to walk you through that.

      14                DR. AMBROSE:   And I’ll move quickly through

      15   this, as it’s much of the same sort of information

      16   that I shared with you with regard to the

      17   pneumococcus, except these data are specific to Staph

      18   aureus.     It’s the neutropenic murine thigh infection

      19   model.    Again, note MSSA and MRSA perform identically

      20   in this model; that is, it’s not the resistance

      21   determinant that's important; it’s attaining enough

      22   time above MIC.

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       1               For Staph, like for all ß-lactams, Staph

       2   tends to require a little less time above MIC than

       3   does Streptococcus pneumoniae.    And here, you can see

       4   the median time above MIC of 27 percent and a one log

       5   kill associated with 36 percent time above MIC.      So

       6   the targets are a little bit less.

       7               Again, stasis to a one log kill has also in

       8   clinical analyses of other NDA data also seems to

       9   march back to being an appropriate target for us to

      10   use for dose justification or for setting

      11   susceptibility breakpoints.

      12               How much time above MIC for Staph aureus did

      13   we see in these clinical data?   Everybody had more

      14   time above MIC than the one log kill target.   You can

      15   see virtually everybody was at 40 percent, around 40

      16   percent, was the lowest, but the vast majority of

      17   patients up at 90 or 100 percent time above MIC.

      18               Same sort of plot is before the blue, it’s

      19   an MIC distribution with a target attainment plot

      20   overlaid.   MSSA here is in blue, and red is MRSA.

      21   There are two lines; one for the stasis target and one

      22   for the one log kill target.   You can see target

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       1   attainment is essentially 100 percent all the way up

       2   to an MIC value of 1 for either target.

       3              At an MIC value of two, if you use the

       4   stasis target, we’re still getting very high target

       5   attainment and performance to grades a little bit when

       6   we use a one log kill target.     So, these data would

       7   support either a one log -- a one log target would

       8   support a breakpoint of one, a stasis target would

       9   support an MIC breakpoint of two.

      10              If you look at the MIC distribution data

      11   again, the FDA breakpoint that they were suggesting in

      12   the package was 0.5, which would capture the MSSA

      13   distribution, but not the vast majority of the MRSA

      14   distribution.   So, the question you have to think

      15   about:   Are they data sufficient for you to believe

      16   that we have enough drug exposure here in order to

      17   cover this MRSA distribution.     I shared with you

      18   earlier it’s about time over MIC, not whether the

      19   strain is MRSA or MSSA.     And I also showed you very

      20   high target attainment up to MIC values of one or two.

      21              DR. CRITCHLEY:    Thank you, and that was the

      22   basis of the criteria that we used for the

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       1   interpretative criteria that we proposed in our NDA.

       2             DR. MOORE:   Thank you.

       3             My protestations not withstanding, we’ve now

       4   gone onto this topic, which I wanted to try to avoid

       5   going into too much in depth.   We’ve chewed up a bit

       6   of time, and I apologize.   I want to thank the

       7   gentleman for that information, that those data are

       8   compelling and important, but unfortunately, outside

       9   the discussion of our panel today.

      10             So, if there are any questions or

      11   clarifications for the committee, I would like to

      12   solicit them now exclusive of this topic.

      13             Yes, Dr. Goetz?

      14             DR. GOETZ:   I have one question regarding

      15   the MRSA distributions showing a similarity of

      16   exposure data predicting outcome in neutropenic mice.

      17   In looking at those MRSA strains, we recognize there’s

      18   diversity in toxin production by MRSA strains which

      19   may lead to differences in clinical response rates.

      20             Can you comment at all as to how many of

      21   those are so-called community-acquired MRSA strains

      22   versus hospital-associated MRSA strains?

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       1               DR. CRITCHLEY:   Yes, what we can do is we

       2   could show you, actually, in the Phase 3 studies, we

       3   did look at the PVL status, and we also looked at the

       4   pulse field status, and I think we can have data that

       5   we can show you, response rates.      Certainly, we did

       6   look at the PVL production among all the isolates, and

       7   you can see there was a good collection of both PVL-

       8   positive and negative isolates.

       9               And the susceptibility profile, and I think

      10   Dr. Goodwin mentioned this in his presentation earlier

      11   today was fairly similar.     These are the cure rates

      12   looking at MRSA, PVL-negative and PVL-positive

      13   isolates, and what you see is regardless of the PVL

      14   status.   The clinical response rates are fairly

      15   identical, as were the susceptibility of both

      16   phenotypes to ceftaroline.

      17               DR. MOORE:   Thank you.   Dr. Goetz, did that

      18   answer --

      19               DR. GOETZ:   That's very interesting and

      20   important information, but I was more referring to the

      21   slide that Dr. Ambrose showed, looking at the

      22   similarity in response in the neutropenic model as to

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       1   whether the isolates --

       2             DR. CRITCHLEY:    Yes, we didn't have data on

       3   community-associated versus the traditional hospital-

       4   associated.

       5             DR. MOORE:   Thank you.

       6             Dr. Fleming?

       7             DR. FLEMING:    I’d like to pose one question

       8   to Dr. Rubin on slide 13.   While that slide’s coming

       9   up, I’d like to take one minute just to put some

      10   context on the question and refer back to the NIH

      11   Foundation discussions that had been occurring since

      12   our committee met here on December 9.

      13             These have been an ongoing collaboration

      14   involving dozens of scientists from industry,

      15   academia, and government, including the FDA, to

      16   address exactly what we’re thinking about today.    What

      17   are the proper endpoints in CABP and SSSI?

      18             And regarding issues of clinical cure, this

      19   committee has recognized, as FDA has indicated in

      20   their briefing document, several problematic issues,

      21   timing matters to be assessing one to two weeks after

      22   the end of treatment is problematic.

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       1             We need validated instruments, and very

       2   importantly, the clinical cure endpoint is a

       3   combination of signs and symptoms, and the committee

       4   carefully discussed the IOM, Institute of Medicine's

       5   recently-released document on rigors that are

       6   necessary if one is going to use biomarkers as

       7   surrogate endpoints.   And these biomarkers that

       8   include signs, that include temperature, heart rate,

       9   respiratory rate, et cetera, according to the IoM

      10   document, have to undergo significant, rigorous

      11   validation with a framework of analytical,

      12   quantitative, and utilization phases, and these have

      13   not occurred for the signs in the CABP or SSSI

      14   setting, and, hence, the focus, according to IoM, as

      15   the NIH Foundation Committee also recognized, then

      16   should be on clinical endpoints measures that directly

      17   reflect how a patient functions, feels, and survives.

      18             Those could be mortality or exactly these

      19   symptoms that are here on slide 13.

      20             And so, in essence, the NIH Foundation’s

      21   recommendation was, in the future, in CABP, we should

      22   be looking at mortality or a properly-validated

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       1   symptom-based measure that will take time to validate.

       2   Signs are useful, but only in supportive manner, and

       3   so, their recommendation was exactly what on this

       4   slide the FDA has presented, and that is to focus on

       5   analyses that are based on symptoms over this

       6   timeframe of 72 to 96 hours focusing on patients that

       7   had not received prior antibiotics and PORT Score III,

       8   IV, and patients that had confirmed bacteriology.

       9             So, I want to thank the agency for

      10   presenting this specific analysis, which is exactly

      11   the essence of what the NIH Foundation focused on as

      12   its proposed endpoint to be using in CABP.   And if we

      13   go real quickly to slide 33 then for my question, the

      14   results here that we see on the left in each case

      15   reflect favorable results.

      16             So, in essence, if one looks at resolution

      17   of symptoms in the three to four-day timeframe, for

      18   both studies, results are quite favorable.   The next

      19   slide also shows a lower limit of confidence intervals

      20   that indicate near superiority or at least in the

      21   second trial, likely positivity for a margin.

      22             My one question for Dr. Rubin is there’s an

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       1   indication that those whose EOT occurred by Day four

       2   being called “failure.”    And that's the one

       3   inconsistency with what the foundation was talking

       4   about.   It’s not clear why that's being done, but at

       5   least as a reassurance, can you tell us how many

       6   patients per arm were called “failure” based on that

       7   criteria in this key analysis?

       8              DR. RUBIN:    I do not have that information

       9   at my disposal.   We have certainly looked at it.    We

      10   were calling them failures because they were all

      11   classified by the investigator as failures, and I

      12   think a handful of indeterminates, but no, I don’t

      13   have that information.

      14              DR. FLEMING:    So, your sense is, because the

      15   principal measure here is, as you have it, improvement

      16   in one domain are not worsening in others, or, as

      17   you’ve also pointed out, we’ve also discussed maybe

      18   improvement in two.     The point is your sense is likely

      19   that criterion would not have been met, although, we

      20   would have preferred you assess it, but that was your

      21   rationale for calling them failures?

      22              DR. RUBIN:    Yes.

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       1             DR. FLEMING:    But, just in closing, this is

       2   a very important analysis that reflects exactly what

       3   the foundation had endorsed doing, and give certainly

       4   encouraging evidence.

       5             DR. MOORE:    Agreed.

       6             Dr. Calhoun, did you have a question?

       7             DR. CALHOUN:    I did.   Just a quick,

       8   technical question.

       9             I noticed on the FDA’s slide 26 that

      10   pyrothorax was seen essentially exclusively in

      11   ceftaroline patients, whereas pleural effusion was

      12   seen evenly distributed between the groups.    And that

      13   then raises the question for me as to whether

      14   ceftaroline is penetrating into serous fluids.

      15             So the question is actually to the sponsor

      16   is whether there are any data on the penetration of

      17   ceftaroline vis-à-vis serum concentrations into serous

      18   fluids like the pleural space, the peritoneal space,

      19   and potentially even into lung?

      20             DR. THYE:     We don't have any clinical data

      21   that would be informative in that regard.     We haven't

      22   done any pharmacokinetic studies to evaluate drug

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       1   concentrations in those fluids.

       2               DR. MOORE:   Thank you.

       3               Dr. Brittain, yes?

       4               DR. BRITTAIN:   Yes, I wanted to ask the

       5   question as a FDA statistician, and I really like the

       6   analysis you presented.     However, you’re looking at

       7   things as a whole bunch of binary endpoints, at day

       8   four, at test of cure, et cetera, and I’m wondering if

       9   you’ve ever looked at it in another way, which is that

      10   sort of an ordered, categorical endpoint where the

      11   best category would be someone who’s doing well at day

      12   four and however you want to define that and at every

      13   subsequent visit.   And the worst outcome on the other

      14   end of the spectrum would be mortality.

      15               And I wondered if you ever looked at it in

      16   that kind of ordered way side by side because you said

      17   you looked at the data in a variety of ways.

      18               DR. RUBIN:   This is Dr. Rubin.   No, we have

      19   not used in ordered, categorical endpoint to look at

      20   the data.   The feeling was that responder rates would

      21   be easier to interpret for a non-inferiority study.         I

      22   could imagine in a superiority study having that kind

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       1   of scale, but I think it would just be a little harder

       2   to interpret those responder rates.

       3              And I want to clarify one aspect of my

       4   response to Dr. Fleming, something I remembered.        A

       5   couple of those people who we were calling failures

       6   because their EOT was earlier than day four was

       7   because it was on day two or three they stopped the

       8   therapy, so we didn’t have the symptom information on

       9   day four, and we were calling those people failures.

      10              DR. MOORE:    Yes, go ahead.

      11              DR. BRITTAIN:    Yes, I just wanted to add

      12   that I didn’t mean it as a primary analysis, I mean

      13   more as a sensitivity descriptive comparison.    Say

      14   that you can see all the information, because it’s a

      15   wide range of outcome.

      16              DR. RUBIN:    That's certainly a very good

      17   idea.   I guess we really hadn’t thought about how to

      18   weigh the symptoms absent, mild, moderate, or severe,

      19   how to come up with a scale when the responses are in

      20   that format, but it’s certainly something we can look

      21   into.

      22              DR. MOORE:    Mr. Mullins, you had a question?

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       1             MR. MULLINS:    Yes, I had a question from a

       2   public health standpoint.      It seems the data is rather

       3   homogenous.   The patient population demographics of

       4   the Phase 3 trials is rather homogenous, and my

       5   concern is the type of approval that Cerexa is

       6   seeking, and it seems to be approval for treatment of

       7   this CAP community.    Well, children are heavily

       8   affected by pneumonia, so, my concern from a public

       9   health standpoint with data so constricted, so

      10   constrained, are you seeking age exclusions because

      11   the occurrence of CAP in children is quite different

      12   than adults is my first question.

      13             Secondly, I want to know what pathogens were

      14   ceftaroline-resistant?

      15             Thank you.

      16             DR. THYE:    Sure.    I’ll address the first

      17   question, and then I can ask Dr. Critchley to address

      18   your second question about ceftaroline-resistant

      19   pathogens, but you make a very important point about

      20   the pediatric population.      Certainly, that's a

      21   population in desperate need of new antimicrobial

      22   therapies in a population that is of great interest to

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       1   us.

       2             When we deigned development programs, we

       3   always start with adults first because children are

       4   such a vulnerable population, but we have performed

       5   one initial study, pharmacokinetic study in

       6   pediatrics, and we have an extensive pediatric program

       7   planned with six additional studies, which includes

       8   efficacy studies, and these two indications that we’re

       9   seeking today in addition to other important diseases

      10   in pediatrics, such as neo-natal sepsis.

      11             MR. MULLINS:    So, just for clarification,

      12   this therapy has not been proven to be efficacious

      13   with children, correct?

      14             DR. THYE:   That's correct.   We haven't

      15   performed efficacy studies in children yet.   As I

      16   mentioned, we always start with the adult population

      17   first.

      18             MR. MULLINS:    Okay.

      19             DR. THYE:   And I can ask Dr. Critchley to

      20   address your --

      21             MR. MULLINS:    So, are you suggesting that we

      22   should have exclusions with this therapy?

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       1               DR. THYE:    We’re not seeking approval for

       2   the pediatric population.       Only for the adult

       3   population.

       4               MR. MULLINS:     Okay.   I wanted to make sure.

       5               DR. THYE:    Yes.

       6               MR. MULLINS:    Okay.    I just wanted to

       7   clarify that.   Okay.

       8               DR. CRITCHLEY:      And with respect ceftaroline

       9   resistance, the only mechanism of resistance would be

      10   among the gram-negative organisms due to ESBL-

      11   producing strains, and those were very low in the

      12   Community-Acquired Pneumonia.        I believe there was

      13   only one isolate that was in ESBL, and that was in the

      14   ceftriaxone arm.

      15               So, it looks like the prevalence of ESBL

      16   producing organisms in pneumonia is relatively low,

      17   and of course we’d have interpretive criteria that

      18   would exclude the use of those, and ceftaroline, in

      19   common with other cephalosporins, would not be active

      20   against the ESBL-producing strains.

      21               DR. MOORE:    Dr. Reller, did you have a

      22   question?

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       1                DR. RELLER:    Actually, I wanted to ask Dr.

       2   Fleming or someone from the agency about the clinical

       3   endpoints.    It’s not intuitive, at least for me, that

       4   subjective symptoms would be more robust than signs.

       5   Is that because the signs are not as specific as the

       6   symptoms when one talks about the indication?      For

       7   example, pneumonia, that the symptoms are related to

       8   pneumonia whereas the signs could be with other

       9   infections in addition to pneumonia?

      10                DR. FLEMING:   Well, signs are certainly

      11   typically very specific.      So, the issue, and I think

      12   it’s well-articulated in the Institute of Medicine

      13   submitted a 75-page document that was released this

      14   spring, makes the same distinction that has been

      15   frequently made before, and that is

      16   Biomarkers are typically capturing the biological

      17   process through which we hope to achieve true clinical

      18   benefit, and caregivers will appropriately be

      19   influenced by effects on signs and symptoms as they

      20   manage patients.

      21                But, ultimately, the effect of an

      22   intervention should be based as the Institute of

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       1   Medicine document and indicates and many before have

       2   indicated on direct measures of how a patient

       3   functions, feels, and survives, unless those signs

       4   have been rigorously validated, and the document goes

       5   through the rigorous steps and encourages FDA to

       6   ensure that if any biomarkers are used as surrogates,

       7   that that rigorous validation occurs.

       8             So, the bottom line for the NIH Foundation

       9   focus and the Institute of Medicine document before it

      10   and many before them is not that signs aren't

      11   objective measures, but they typically haven't been

      12   validated to ensure that an effect on a sign truly,

      13   reliably predicts an effect on a direct measure of a

      14   patient’s functions, feeling, and surviving, which is

      15   what the patient most directly cares about.

      16             DR. MOORE:   Dr. Neely?

      17             DR. NEELY:   I have one quick question for

      18   Dr. Rubin and a couple of quick ones for the sponsor.

      19             For the clinical endpoints, did the patients

      20   for you to say that there was a clinical response have

      21   to meet all of the criteria for IDSA or some or?

      22             DR. RUBIN:   Yes, they had to meet all of the

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       1   clinical stability criteria.       Well, there’s one

       2   caveat.   So, the IDSA criteria had, I think, one item,

       3   which was ability for oral intake, and we didn’t have

       4   that one case report forms, but all of the criteria

       5   that I listed, temperature, oxygen saturation,

       6   respiratory rate, they had to meet all of those

       7   criteria.

       8               DR. NEELY:   Thanks.    And for the sponsor,

       9   there’s a lot of weight put on target attainment, so,

      10   I have two, quick questions.

      11               First, for the simulations, the Monte Carlo

      12   simulations, I’ve only seen data for healthy subject

      13   PK.

      14               Did you use healthy subject or patient, and,

      15   if so, how different are they?

      16               And then the third question is:     Is there

      17   actual data that you have for exposure in individual

      18   patients and outcome?

      19               MR. MULLINS:   I'd like to ask Dr. Ambrose

      20   and Dr. Riccobene to answer the question.

      21               DR. RICCOBENE:   So, in terms of the target

      22   attainment information that was shown to the

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       1   committee, that was simulations based on patients with

       2   normal renal function.    That's the groups that we were

       3   showing.   We did, of course, look at the difference

       4   between the PK in healthy subjects versus patients.

       5   There was a small difference, but in doing all of our

       6   target attainment analysis, we would, of course,

       7   assume that we were predicting for patients because

       8   that would be the relevant population to look at.

       9              And I’m sorry, what was the second question?

      10              DR. NEELY:   Do you have any actual data from

      11   the exposure achieved in patients correlated with

      12   their individual outcome?

      13              DR. RUBIN:   Yes, so, we took sparse PK

      14   samples in our Phase 3 Program.    Only a relatively

      15   small population had PK samples collected, but we did

      16   have a robust PK model that we could use to predict

      17   exposures in those subjects who didn’t have PK samples

      18   collected, and we did predict exposures in all of the

      19   subjects in our microbiologically evaluable

      20   populations.

      21              As Dr. Ambrose alluded to, the vast majority

      22   of those had very high time above MICs and had

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       1   favorable, that they did do some PK-PD analyses for

       2   both the Skin and the CABP programs.      For CABP, it was

       3   eliminate because nearly everybody was 100 percent

       4   time above MIC, so, you couldn’t really correlate that

       5   with a response.    For skin, there was some lower time

       6   above MICs, but, for the most part, they were greater

       7   than 40 percent, and the response rate was very high,

       8   as well, so, it was difficult to find a good

       9   correlation in that analysis, as well.

      10               DR. MOORE:    Thank you.   Let me move on to

      11   Dr. Shyr.

      12               DR. SHYR:    Yes, I have a question for Dr.

      13   Rubin.   When you did the sensitivity analysis, have

      14   you considered all your comments about non-compliant

      15   rate, the missing data, or the loss of follow-up?

      16               DR. RUBIN:    So, for the missing data,

      17   primarily, this was because subjects were stopped

      18   before day four, and these were primarily called

      19   failures.   There were two exceptions.      Both subjects

      20   given ceftaroline and were successes.       So, it was

      21   conservative to include them.

      22               For the non-compliance, we didn’t look at an

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       1   ME population because those post-baseline exclusions

       2   mean that randomization no longer protects you from

       3   confounding, but one thing that we did was exclude

       4   anyone who had a baseline violation, such as not

       5   meeting the diagnostic criteria, and, again, the

       6   confidence limits were the same as they were in all

       7   the other analyses between zero and negative 10

       8   percent.

       9              About the evaluability, one thing we

      10   noticed, as you go up to higher times, the

      11   evaluability becomes more of a problem.   So, there’s a

      12   fair number of people who have missing data at the TOC

      13   or have a window violation there, but, as you move up

      14   earlier in time to the end of therapy or to day four,

      15   the missing data becomes much less of a problem.

      16              DR. MOORE:   Thank you.

      17              Dr. Cappelletty?

      18              DR. CAPPELLETTY:   Yes, also for Dr. Rubin,

      19   on slide 20, you indicated that in your baseline vital

      20   signs, systolic blood pressure changes or differences

      21   between the groups, and, if I’m reading it correctly,

      22   greater systolic blood pressure changes or drops in

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       1   the ceftriaxone arm versus the ceftaroline arm, and I

       2   was wondering if that influences given the smaller end

       3   in this analysis at day four, if that had an impact on

       4   how you might interpret the clinical outcomes or the

       5   trends between the two groups?

       6             DR. RUBIN:    So, systolic blood pressure,

       7   this slide on page 20, is giving the baseline values,

       8   and of all these signs, systolic blood pressure did

       9   not seem to have much of an impact.   If we completely

      10   removed it from the definition, the results, I

      11   believe, only changed for one or two subjects, at

      12   most.

      13             We also did some covariate-adjusted

      14    Analyses for these baseline signs and symptoms, which

      15   tended to agree with the other results.

      16             Again, I have the information at my disposal

      17   for this specific sign here, but systolic blood

      18   pressure by day four seemed to have normalized for

      19   basically everyone.    I’m not sure if this cutoff of 90

      20   is necessarily the greatest one, but it did not seem

      21   to be playing any type of role in the endpoint.

      22             DR. MOORE:    Thank you.

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       1              Dr. Follmann?

       2              DR. FOLLMANN:    This is a comment for Dr.

       3   Rubin.   To echo what Tom said, I appreciate the

       4   analysis that you did, and I looked at focus on the

       5   Daptomycin trials, which I thought were quite helpful,

       6   and I thought you did a very nice analysis.

       7              My comment really is I think you were kind

       8   of conservative in coming up with the margin based on

       9   that, and the reason I think that is because, first of

      10   all, you assume Daptomycin is as useless as a placebo.

      11   So, that's one thing.    The next thing is to take the

      12   lower bound at the 95 percent confidence interval.      I

      13   know that's commonly done, but that's also a

      14   conservative maneuver.     And then to take 50 percent of

      15   data on top of these other things, as well.

      16              So I thought, perhaps, you were doing this

      17   because, at the end of the day, even when you do all

      18   these conservative maneuvers, you end up showing that

      19   the non-inferiority margin of 1.5 percent is still

      20   met.

      21              And so, my comment, I guess, is just that I

      22   thought that Daptomycin trial results and the analysis

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       1   you did were very helpful and supportive.

       2              DR. MOORE:    Dr. Sepkowitz?

       3              DR. SEPKOWITZ:    I have a very simple, I

       4   think, question of the FDA, but it’s data in the

       5   yellow book.   Do you have the yellow book that you

       6   provided us with?   I think it’s just a typo, but I

       7   want to make sure that it’s just a typo.     Does anybody

       8   have a yellow book?

       9              All right, it’s page 24 in our hymnals.

      10   Okay.   Page 24, there’s a row that is a typical sole

      11   pathogen or Legionella, and ceftriaxone in the 0309 is

      12   wildly -- it’s a 77, and the others in the 30s.       I

      13   assume that's a typo.    If it’s not a typo, it creates

      14   all sorts of problems.

      15              DR. RUBIN:    Yes, it’s a typo.

      16              DR. SEPKOWITZ:    Typo.   Thank you.

      17              DR. RUBIN:    Ceftaroline --

      18              DR. SEPKOWITZ:    Done.

      19              DR. RUBIN:    The ceftriaxone, this last

      20   column here should be the two studies put together,

      21   which is why it’s larger, and we apologize for that.

      22              DR. SEPKOWITZ:    I got you.   Okay.

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       1              DR. RUBIN:    Right.

       2              DR. SEPKOWITZ:    Otherwise, I thought someone

       3   had a big outbreak that was messing things up.        Thank

       4   you.

       5              DR. MOORE:    Okay.    Amen.

       6              I have one question for the sponsor.       What I

       7   find interesting is that the use of clarithromycin in

       8   the 08 study, one assumes, if anything, should have

       9   ameliorated or blunted the effect of the difference

      10   between the outcomes between ceftaroline and

      11   ceftriaxone.   My question really is:     Would the

      12   sponsor like to offer any speculation or any early

      13   analysis or anything that would explain why

      14   ceftaroline seemed to perform better in the 08 study

      15   versus the 09 study, even though in 08 study, the

      16   clarithromycin was given as a pre-drug or co-drug?        I

      17   mean, is there any evidence of synergy or added effect

      18   of these drugs?

      19              DR. THYE:    No, I don't think we see any

      20   particular strong evidence.       Certainly, in vitro,

      21   there is no obvious hypothetical mechanism for

      22   synergy.   I think what we’re seeing between the two

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       1   studies is difficult to attribute specifically to the

       2   clarithromycin because they’re two different trails,

       3   but what we do see is that the treatment difference

       4   between treatments is relatively consistent between

       5   trials.

       6                I think when we look at the data more

       7   carefully, we don’t see an obvious effect of the

       8   clarithromycin.    It doesn’t appear to be contributing

       9   a great deal, and in fact, a recent analysis has shown

      10   that about half of the pathogens procured in the

      11   subject were actually resistant to clarithromycin.

      12                DR. MOORE:   Interesting.   Thank you, Dr.

      13   Thye.

      14                        Open Public Hearing

      15                Let’s move forward.   We do have one speaker.

      16   Initially, we had no one booked for the open public

      17   hearing, but we do have one speaker from the American

      18   Thoracic Society.    I’d like to invite that speaker to

      19   come forward.    But, before I do, I have to read this

      20   statement.

      21                Both the Food and Drug Administration and

      22   the public believe in a transparent process for

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       1   information-gathering and decision-making.    To ensure

       2   such transparency at the open public hearing session

       3   of the Advisory Committee Meeting, the FDA believes

       4   that it is important to understand the context of an

       5   individual’s presentation.   For this reason, the FDA

       6   encourages you, the open public hearing speaker, at

       7   the beginning of your written or oral statement to

       8   advise the committee of any financial relationship you

       9   may have with the sponsor, its product, and, if known,

      10   its direct competitors.

      11             For example, this financial information may

      12   include the sponsor’s payment of your travel, lodging,

      13   or other expenses in connection with your attendance

      14   at the meeting.   Likewise, the FDA encourages you at

      15   the beginning of your statement to advise the

      16   committee if you do not have such financial

      17   relationships.

      18             If you choose not to address this issue of

      19   financial relationships at the beginning of your

      20   statement, it will not preclude you from speaking.

      21   The FDA and this committee place great importance on

      22   the open public hearing process.   The insights and

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       1   comments provided can help the agency and this

       2   committee in their consideration of the issues before

       3   them.    That said, in many instances and for many

       4   topics, there will be a variety of opinions.

       5           One of our goals today is for this open public

       6   hearing to be conducted in a fair and open way where

       7   every participant is listened to carefully and treated

       8   with dignity, courtesy, and respect.       Therefore,

       9   please speak only when recognized by the chair.

      10                Thank you for your cooperation.      I think

      11   actually that statement is longer than I believe

      12   you’re going to be speaking.      So, go ahead.

      13                (Laughter.)

      14                MR. EWART:    You stole my punch line.

      15                (Laughter.)

      16                MR. EWART:    Thank you.   I’m Gary Ewart,

      17   director of Government Relations for the American

      18   Thoracic Society.    I have no conflict of interest to

      19   disclose to the committee.      The American Thoracic

      20   Society appreciates the opportunity to testify in the

      21   open comment hearing on the sponsor’s drug application

      22   for ceftaroline.

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       1             The American Thoracic Society is a medical

       2   professional organization of over 15,000 clinicians

       3   who diagnose, treat, research for cures for

       4   respiratory, critical care, and sleep disorders.     As

       5   such, we are keenly interested in new drugs that can

       6   be used to treat Community-Acquired Pneumonia and

       7   Hospital-Acquired Pneumonia.

       8             The American Thoracic Society is pleased

       9   that industry is continuing to develop new drugs to

      10   treat Community-Acquired Pneumonia and Hospital-

      11   Acquired Pneumonia, and urge the FDA to be supportive

      12   and this Advisory Committee to be supportive of

      13   industry efforts to develop new therapies.    We

      14   strongly encourage the continued pursuit of novel

      15   compounds to treat Community-Acquired Pneumonia and

      16   Hospital-Acquired Pneumonia, and are particularly

      17   interested to see the Advisory Panel and FDA support

      18   drugs that are effective against gram-resistant gram-

      19   positive bacteria and allowing these to enter the

      20   market.

      21             The American Thoracic Society hopes that the

      22   Advisory Panel and FDA will keep the need for such

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       1   products in mind as it considers the sponsor’s

       2   application for ceftaroline.     Thank you very much.

       3                DR. MOORE:   Thank you.   Okay, the open

       4   public hearing portion of this session of the meeting

       5   is now concluded, and we will no longer take comments

       6   from the audience.

       7                The Committee will now its attention to

       8   address the task at hand.     The careful consideration

       9   of the data before the Committee, as well as the

      10   public comments.

      11                Dr. Laessig is now going to charge the

      12   Committee.

      13                      Charge to the Committee

      14                DR. LAESSIG:   Thank you, Dr. Moore.   As you

      15   said, we’ll now turn to the task at hand for this

      16   morning’s session of this Advisory Committee, which is

      17   to answer the lone question.     You’ve heard a lot of

      18   information this morning about the safety and

      19   efficacy, both the pre-specified analyses, as well as

      20   many sensitivity analyses.     You also heard information

      21   about the clinical microbiology.       And so, now we are

      22   asking you to synthesize all of that and answer the

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       1   following question, which is:    Has the applicant

       2   demonstrated the safety and efficacy of ceftaroline

       3   for the requested indication of Community-Acquired

       4   Bacterial Pneumonia?     In your response, please discuss

       5   the strengths and weaknesses of the FDA Sensitivity

       6   Analyses.

       7               So, as you know, you will first vote on your

       8   handy-dandy microphone, and then we will go around

       9   individually, and you will explain why you voted the

      10   way you did.    So, if you vote yes, we ask that you

      11   please address if there are any specific issues that

      12   you want addressed in the labeling or that you

      13   recommend to be addressed in the labeling, and if you

      14   vote no, please discuss what additional data are

      15   needed.

      16               Thank you.

      17                Committee Discussion of Questions

      18               DR. MOORE:   Thank you.   All right, so, we’ll

      19   be using the electronic voting system for this

      20   meeting.    Each of you have three voting buttons on

      21   your microphone.    As you can see before you, they are

      22   yes, no, and abstain.    Once we begin the vote, please

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       1   press the button that corresponds to your vote.     The

       2   vote will then be displayed on the screen.      I will

       3   read the vote from the screen into the record.     And

       4   then, next, we’ll go around the room and each

       5   individual, as Dr. Laessig said, who voted, will state

       6   their name and vote into the record, as well as the

       7   reason why they voted as they did.

       8              If there is no further discussion on the

       9   question at hand, then we’ll now begin the voting

      10   process.   Does anybody have any questions about the

      11   question, any clarifications before we -- no?      Okay,

      12   good.

      13              Please press the button on your microphone

      14   that corresponds to your vote.      Do we need to have the

      15   question read into the record specifically, or --

      16              MS. DOAN:    I think she --

      17              DR. MOORE:   Okay.   I wasn’t sure if we have

      18   to do it again.   Again, so, let’s move forward then

      19   with the vote.    Press yes, no, or abstain, depending

      20   on your vote.

      21                              Voting

      22              DR. MOORE:   Okay, the voting is now

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       1   complete, and the results are 21 yes, no votes for no,

       2   and no abstentions.

       3               We’ll now go around the room and have

       4   everyone explain how they voted.    We’ll start with

       5   you, Dr. Calhoun.

       6                         Voting Discussion

       7               DR. CALHOUN:   Yes, Calhoun.   I voted yes.

       8   So, the safety and efficacy question has two pieces;

       9   the safety and the efficacy, and vis-à-vis, the safety

      10   side, the safety profile really looks to me to be

      11   quite comparable to that of other cephalosporins which

      12   have proven to be acceptably safe in clinical

      13   practice.

      14               I think the only question about safety that

      15   has risen for me is this increased frequency of

      16   Coombs’ positivity, but even that higher rate is vis-

      17   à-vis ceftriaxone, which has lower incidents in

      18   inducing Coombs’ positivity, and the higher rate is

      19   within the spectrum of Coombs’ positivity that we see.

      20   So, that was really the principle safety issue for me.

      21               Vis-à-vis the efficacy, there are two

      22   studies in which the primary endpoint, pre-specified

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       1   endpoint was met.   At the very worst, as Dr. Rubin, I

       2   think, has very elegantly articulated, ceftaroline is

       3   equivalent to ceftriaxone, and as Dr. Follmann

       4   mentioned, those were very conservative assumptions,

       5   and so, the likelihood is that this drug and some of

       6   your drug sensitivity analyses, both yours and by the

       7   sponsor, there were some evidence of superiority.

       8               So, I thought that the efficacy data in the

       9   spectrum of Community-Acquired Bacterial Pneumonia was

      10   actually fairly strong.    The multiple cuts, the

      11   multiple views, the multiple approaches to analyzing

      12   the data done partly by the sponsor, but largely by

      13   Dr. Rubin, are all consistent with, again, at very

      14   worst, non-inferiority, and the point estimates are

      15   positive.   So, I thought there was, again, in the

      16   context of CABP efficacy data, that they were strong.

      17   And so, the safety to efficacy looks positive for me.

      18               DR. MOORE:   Dr. Fleming?

      19               DR. FLEMING:   Fleming.   I voted yes.   And in

      20   essence, the mortality effects through a non-

      21   inferiority analysis have not been established, but

      22   there is adequate evidence, in my view, of symptomatic

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       1   benefit, and in this regard, I think the analyses that

       2   were done by the FDA are extremely important in the

       3   spirit of the NIH Foundation Working Group consensus,

       4   my sense is that the clinical response at test of cure

       5   is really supportive evidence because it’s heavily

       6   influenced by the biomarkers that are specifically

       7   signs, but the data on the symptoms is very

       8   encouraging, and I don’t think we should be

       9   grandfathering, even though there has been a

      10   substantial evolution of understanding of what the

      11   endpoint should be, I think we need to have direct

      12   evidence of clinical benefit here until we have

      13   validated surrogates.    I’d feel a little more flexible

      14   on the irregularities.

      15             I recognize the FDA analyses were done as

      16   best possible in a trial design that hadn’t been

      17   specifically targeting looking at these symptoms at

      18   day three or day four, and there are some issues of

      19   missing data. Hopefully, in the future, as these

      20   measures are used, those irregularities would be less.

      21             My sense is, overall, efficacy is

      22   established, but not superiority, and I would argue

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       1   not superiority either overall or in any subgroups, as

       2   someone might propose, such as Strep pneu patients.

       3              And finally, it would be useful if there

       4   would be creative ways post marketing to get enhanced

       5   understanding about mortality effects overall, and,

       6   specifically, in some of these domains, such as

       7   neoplasm and respiratory failure.

       8              DR. MOORE:    Dr. Bennett?

       9              DR. BENNETT:    I want to congratulate the

      10   sponsors on a well-designed, carefully-conducted, and

      11   conservatively-analyzed study.        I was impressed by the

      12   quality of the data.

      13              My only concern about the studies are the

      14   generalized ability of this Eastern European

      15   population who seems to be less sick than PORT III and

      16   PORT IV patients in this country.       However,

      17   apparently, it’s impossible to conduct these kind of

      18   studies.   The United States, I believe they tried, but

      19   I’m not completely assured that we could extrapolate

      20   those results to our patients.

      21              DR. MOORE:    Thank you.

      22              Dr. Tunkel?

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       1               DR. TUNKEL:    Yes, I would agree with what

       2   the first three people said regarding safety and

       3   efficacy.   I guess the question I would raise is that

       4   there really have not been patients studied who’ve had

       5   pneumonia caused by methicillin-resistant Staph

       6   aureus, and this will be a very important part of the

       7   labeling because I believe it probably will be used to

       8   treat methicillin-resistant Staph aureus pneumonia,

       9   and I think it has to be very clear that there are no

      10   data to make that recommendation.

      11               DR. MOORE:    Thank you.

      12               Dr. Neely?

      13               DR. NEELY:    Neely, and I voted yes.

      14   Similarly, I think it’s interesting that ceftriaxone

      15   is the comparator drug for Staph aureus, including

      16   Staph aureus pneumonia, and this drug is seeking a

      17   Staph aureus indication.      But I do think that the PK-

      18   PD analysis supports an indication of treatment for

      19   Staph aureus pneumonia, and even regarding the MRSA

      20   issue, I agree, there’s obviously no experience in

      21   these trials, since that was an exclusion in criteria.

      22               But I think the data that Dr. Ambrose showed

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       1   us, that really, the MRSA may not be relevant.    It’s

       2   the MIC that counts and the exposure over the MIC.

       3   So, I do think that they’ve done a good job with their

       4   PK-PD analysis.

       5             I think, also, supporting efficacy and non-

       6   inferiority of the multiple cuts of data that have

       7   been done by both the sponsor and the FDA, and I

       8   thought those were good analyses.    And I don’t have

       9   anything additional to add regarding safety to what’s

      10   already been said.

      11             DR. MOORE:    Thank you.

      12             Dr. Reller?

      13             DR. RELLER:    Although the discussion of

      14   breakpoints was off the table or at least limited in

      15   this presentation, I think it is an important question

      16   looking ahead for multiple reasons.    One is how this

      17   drug looks on hospitals anti-biograms will be affected

      18   by these breakpoints.   More importantly, of getting

      19   the breakpoints correct and with some measure of

      20   comparability or equity vis-à-vis other agents that

      21   would be similarly used.

      22             For example, if one considers the extent

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       1   breakpoints for Streptococcus pneumoniae,

       2   Staphylococcus aureus, both MRSA and MSSA, and

       3   Enterobacteriaceae, they are much closer to what the

       4   sponsor recommended than what the agency has put

       5   forth.   So that this sisue of breaking populations is

       6   an important one.

       7               Now, having said that, given that most

       8   therapy is empirical and if that patient is doing

       9   well, they’re not going to change, even if they have

      10   MRSA, it’s a potential opportunity, and what I’d

      11   really like to see are two studies that may not be

      12   done, but would be very instructive.   And one is to

      13   see a ceftaroline with or without Vancomycin for

      14   MRSA or some other comparable drug that's used

      15   empirically, regardless of the susceptibility upfront

      16   for MRSA.

      17               And the other that may help address the

      18   reservation that Dr. Bennett expressed, namely the

      19   paucity of patients enrolled in the United States and

      20   Canada, and that is given what we’ve seen so far, I’d

      21   like to see a ceftaroline with or without a macrolide

      22   study going forward.   Maybe it’s not necessary to have

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       1   the macrolide in the IDSA-ATS guidelines depending on

       2   the agent with which it is coupled.

       3             DR. MOORE:   Thank you.

       4             Dr. Brittain?

       5             DR. BRITTAIN:   Yes, I wish all non-

       6   inferiority trials were this easy to interpret.     I

       7   mean, I guess I was very impressed that there were all

       8   sorts of hints at superiority just all over the place,

       9   and while it’s not absolutely superior, I think that

      10   its hints were really important.    And I also really

      11   like the FDA’s sensitivity analysis, even though in

      12   their presentation, they seemed to be kind of critical

      13   of what they did, I felt very comforted by using the

      14   Daptomycin trial results to justify the margin and all

      15   the various sensitivity analyses that were done.    So,

      16   like I said, I wish it were always this easy.

      17             DR. MOORE:   Thank you.

      18             Dr. Steckelberg?

      19             DR. STECKELBERG:    Steckelberg.   Yes, and I

      20   don’t have too much to add.   I agree with the comments

      21   that have been previously made, and I would especially

      22   underscore my agreement with the breakpoint comments,

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       1   very important, and from the best interest of the

       2   patient perspective, it’s equally problematic for me

       3   to withhold a drug which is likely effective and may

       4   have advantages over other drugs because the

       5   breakpoints are too low, as it is an ultra-

       6   conservative approach to where the breakpoints should

       7   be, based on pharmacokinetic data.

       8               And then I would also agree with the

       9   Staphylococcus aureus issues in pneumonia for

      10   labeling.

      11               DR. MOORE:   Thank you.

      12               Dr. Patterson?

      13               DR. PATTERSON:   I voted yes, and I found the

      14   FDA’s sensitivity analysis very helpful, and, in the

      15   future, of course, would be very helpful to

      16   incorporate prospectively in the design.

      17               Also, I think mortality rate, as we’re seen

      18   from this and other recent studies is not going to be

      19   very helpful as an endpoint, and so, studies designed

      20   to look at early evaluation on symptoms and validation

      21   of signs would be very helpful in the future, as well.

      22               For the label, the increased incidents of

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       1   indirect Coombs, although, at least in this study, did

       2   not prove to be clinically-significant, but should be

       3   addressed in the labeling, as well as the lack of data

       4   on MRSA, unfortunately, because that is a very common

       5   problem, and hopefully, maybe that can be addressed in

       6   the future.

       7             And I also share some concerns about

       8   generalized ability, but, having said that, I realize

       9   the lack of feasibility of this kind of study without

      10   combination therapy in the United States, and, also,

      11   with the length of intravenous therapy, I don’t think

      12   we treat our Community-Acquired Pneumonia patients

      13   nearly that long with intravenous therapy these days

      14   in the United States.

      15             And then, finally, I agree that the

      16   breakpoint issue is going to be very key.

      17             DR. MOORE:    Thank you.

      18             Dr. Alston?

      19             DR. ALSTON:    When, at the beginning of all

      20   this, when we heard about the clinical need, it was

      21   portrayed as being MRSA and drug-resistant Strep

      22   pneumo, and I think it’s just interesting that MRSA

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       1   wasn’t included because the comparator was

       2   ceftriaxone, and then there were only a small handful

       3   of drug-resistant Strep pneumos.

       4              So, ceftaroline still looked really good in

       5   a setting of essentially drug-sensitive Strep pneumo

       6   and MSSA, which is interesting, and I think lends

       7   credibility that those lower MICS and the

       8   pharmacokinetics we saw might actually really have

       9   clinical relevance, which gets back to that breakpoint

      10   issue.   And in fact, if you kind of turn the data

      11   over, had this been a non-inferiority trial for

      12   ceftriaxone, it would have failed, of course.     And so,

      13   I think that's important to keep in mind.

      14              And I just wanted to make a comment about

      15   the prior antibiotic thing.   I think given all the

      16   weaknesses we’ve heard about non-inferiority designs

      17   over the years, the prior antibiotics, when you’re

      18   studying an antibiotic, always really bothers me, and

      19   in the overall data that the sponsor showed us, the

      20   prior antibiotic group, of course, were precisely

      21   equivalent.   It absolutely muddied the waters, as you

      22   would expect.

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       1             And so, I’ve been thinking all along that I

       2   think the real push in doing these studies is to

       3   eliminate people with prior antibiotic exposure, and I

       4   know that's very, very difficult, especially in this

       5   country, and I think we need to have expedited

       6   enrollments so that patients can be enrolled quickly

       7   because, obviously, in the elderly with high PORT

       8   scores, you don’t want them waiting hours and hours

       9   for their study enrollment so that they’re free of

      10   antibiotic, because that would obviously be harmful.

      11             And I wonder about some look at time to

      12   presentation to time of first dose as really a

      13   comorbidity, and maybe an important comorbidity, and

      14   that will influence what countries the studies are

      15   done and the whole health care delivery system.

      16             And then I was interested in the FDA’s

      17   analysis that that prior antibiotic thing totally

      18   flipped around.   And then the patients with

      19   antibiotics really did better.   And I don't know what

      20   explains how looking at that small subgroup that fell

      21   apart, but I was just interested in that.

      22             And then I was also interested in the

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       1   macrolide issue, and that at least with high PORT

       2   scores, macrolides weren't important, and I think

       3   that's just important clinical information separate

       4   from the study.

       5             Thanks.

       6             DR. MOORE:    Thank you.

       7             Dr. Follmann?

       8             DR. FOLLMANN:    Yes, I voted yes.    I guess

       9   for a lot of the reasons that Dr. Brittain mentioned.

      10   I thought this is a relatively easy decision to make.

      11   I thought that hints toward superiority were

      12   comforting.   The consistency of the analyses that the

      13   sponsor did along with the FDA.      I thought that

      14   sensitivity analyses that Dr. Rubin did, looking at

      15   day four endpoints and also the Daptomycin trial

      16   results were very important, and I ended up thinking

      17   this was not a very difficult decision to make.

      18             I wanted to talk a little bit about

      19   breakpoints, and something I wanted to mention earlier

      20   before it was off limits, and I’ll mention it now, I

      21   guess, and to me the key issue about breakpoints is

      22   clinical data.    So, some of the graphs that the

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       1   sponsor showed were based on the mouse model, and then

       2   how much drug a human would have in him, but there was

       3   very little and it’s of necessity, there’s not much

       4   clinical data on people who have isolates with high

       5   MICs.   And so, I think that's the fundamental problem

       6   with a breakpoint construction.

       7              I don’t really trust anything unless it’s

       8   based on a clinical data, and we have very little

       9   clinical data there, and I think that's probably the

      10   reason for the difference in the FDA and the sponsor’s

      11   choice of breakpoints, which are very different.       I

      12   think the FDA is saying if I don’t have clinical data,

      13   I don’t want to make the leap, and the sponsor has a

      14   different view.

      15              So, I guess when you’re wrestling with that,

      16   if you could analyze more data, and with a focus on

      17   the breakpoints and their effect on clinical outcomes,

      18   that would be the best way to try and deal with it.

      19              DR. MOORE:   Thanks.   This is Dr. Moore.   I

      20   also voted yes, obviously, and it was a very easy

      21   decision to make.   I think the non-inferiority margin

      22   seemed to be preserved and exceeded in many instances.

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       1   In fact, it seemed at some points that ceftaroline was

       2   strong enough to, perhaps, star in its own Old Spice

       3   commercial.

       4              (Laughter.)

       5              DR. MOORE:    Look at your drug, now look at

       6   me.   But, having said that, I think in terms of the

       7   FDA analysis by Dr. Rubin, I thought that was very

       8   helpful, and particularly as Dean said, the Daptomycin

       9   data, which I thought was contemporary and relevant.

      10   All those endpoints analyzing signs and symptoms, as

      11   well, although, very difficult to do in light of the

      12   previous discussions with this committee were done, I

      13   think, very well, and underscored the conclusions that

      14   were made by other data.

      15              I think the proof is in the pudding though,

      16   ultimately, applying those analyses to subsequent

      17   drugs that are, perhaps, less effective is going to be

      18   the real challenge, but I thought you did a superior

      19   job, and it was an obvious decision to make, obvious

      20   vote to make.

      21              Dr. Kaplan?

      22              DR. KAPLAN:   I voted yes for all the reasons

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       1   that have already been stated.        I thought the multiple

       2   analyses were quite helpful.    I do think that we

       3   certainly need more information on an

       4   MRSA.   This is going to be a real issue for both the

       5   adult population and pediatric population, especially

       6   if you use a drug like this in a patient with

       7   ultimately prove MRSA, pneumonia, they’re getting

       8   better on this agent.    What are you going to do after

       9   that?   So, we definitely need more information.

      10              I’m really looking forward to the pediatric

      11   studies.   I think this is a really potentially

      12   fabulous drug for pediatric patients, one that would

      13   be very helpful to us.    I hope that we’ll have much

      14   more information on penetration into CSF because

      15   that's always a concern in patients who have

      16   pneumococcal bacteremia in particular.       So, I want to

      17   thank you for coming forward with this drug.

      18              DR. MOORE:    Thank you.

      19              Dr. Sepkowitz?

      20              DR. SEPKOWITZ:    I also voted yes, and I have

      21   absolutely no comments about the breakpoint.

      22              (Laughter.)

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       1              DR. SEPKOWITZ:   But the issue of the

       2   remarkable homogeneity of the study population is

       3   concerning less to me about efficacy than about safety

       4   since there are many examples of drugs or side effects

       5   are seen in certain populations that were not

       6   anticipated because that certain population was not

       7   studied.   So, I would implore the maker of the drug to

       8   be sure to do thorough evaluations of side effects in

       9   other populations other than Caucasians.

      10              The second thing is that I think that we’ve

      11   gotten too comfortable with cephalosporins as a class.

      12   I think we kind of give it a free pass.    We’re

      13   comparing it to ceftriaxone and et cetera.    I was sort

      14   of startled to see absolutely nothing about

      15   coagulation issues.   That's only one generation ago

      16   that that was the bête noire of all cephalosporins,

      17   and yet, there was no evaluation here at all.      So,

      18   probably not with this drug, but one of these days,

      19   we’re going to end up passing through a cephalosporin,

      20   and we’re going to get burnt, I suspect.

      21              And finally, because we’re not sufficiently

      22   broad in our evaluation of potential toxicities, a

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       1   final comment on MRSA.     I worry a great deal, as

       2   everyone has, that depending on what this afternoon’s

       3   discussion is, that this drug will be perceived as a

       4   “MRSA drug,” and it will leak accidentally on purpose

       5   onto use for community pneumonias where MRSA is a

       6   pathogen.   So, I would hope that the label would

       7   specifically state that it is not active in pneumonia

       8   for MRSA and should not be used as such.

       9               DR. MOORE:    Thank you.

      10               Dr. Katona?

      11               DR. KATONA:    I voted yes.   I think the

      12   sponsor did an excellent job at presenting its case.

      13   But I have two provisos that concern me a little bit.

      14               One is the dosing of ceftriaxone.     This was

      15   the lower end of the dosing schedule that we don’t

      16   normally use, and I wondered whether that might have

      17   skewed things slightly.

      18               And the other concern is that since this is

      19   a drug touted for MRSA and resistant pneumococci,

      20   those are, unfortunately, the two things that really

      21   weren't adequately evaluated by the drug, one, because

      22   of design, and the other because of lack of numbers.

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       1   And so, that bothers me some, especially since the

       2   drug is really touted for that purpose.

       3             DR. MOORE:   Thank you.

       4             Dr. Goetz?

       5             DR. GOETZ:   Yes, I voted yes, as well.    The

       6   safety and efficacy I think were well-demonstrated.

       7   There’s a minor concern in my mind about the increased

       8   rates of Coombs’ positivity.   I’m relieved by the fact

       9   that there was no obvious evidence of anemia.    Further

      10   clinical experience hopefully will bear that out, and

      11   that warrants monitoring.   The FDA’s rigorous

      12   assessment of the effectiveness of the drug linked

      13   with the response rates both clinically as well as by

      14   signs of infection at day four I found to be very

      15   reassuring, as was the Daptomycin data, which were

      16   presented, as well.

      17             The big issue in regards to, I think,

      18   breakpoints in MRSA. I think that we need more data to

      19   be absolutely certain that the pharmacodynamic data

      20   rely equally to MSSA and MRSA, particularly with the

      21   diversity of pathogenicity factors seen in the

      22   Community-Acquired MRSA.

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       1               I’m not altogether certain that we can

       2   extrapolate the hospital-associated strain results to

       3   community-associated strains.     Clearly, it we’d be on

       4   much firmer ground in setting breakpoints which needed

       5   to be in the package insert, will have the dramatic

       6   effects and our biograms and how physicians use the

       7   drug, where we’d be certain that really drug

       8   exposures, all that matters, and that the MRSA

       9   diversity doesn’t make any difference, and we can

      10   treat MRSA as MSSA if we have the appropriate drug

      11   exposure.   But I don’t think we’re quite there yet.

      12               DR. MOORE:   Thank you.

      13               Mr. Mullins?

      14               MR. MULLINS:   I voted yes, and I think from

      15   a public health standpoint, my concerns were that the

      16   data did not represent the public, and I hope that in

      17   the future, I’m very interesting in the post-marketing

      18   studies because I think that the indications of how

      19   this drug will perform based on the hybridization of

      20   CAP, based on the way the illness performs, behaves in

      21   different populations concerns me because I think the

      22   jury’s still out, but I think based on the information

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       1   and the data we were presented, safety and efficacy

       2   were proven, but I think that my issues lie in the

       3   fact that I think that the constraint and the

       4   homogeneity of the patient population severe to

       5   moderate, just the constraints, I think there could

       6   have been a lot more inclusion of various issues, even

       7   addressing the MRSA, because that was my concern, and

       8   I was excited because I thought there would be more

       9   data relevant to MRSA.

      10             So, I think that the efficacy was very

      11   similar to ceftriaxone.    I think that there were times

      12   when I thought they were very similar.    So, but I

      13   think based on the data, I was able to vote that it

      14   was effective and safe, but I do have some concerns.

      15             Thank you.

      16             DR. MOORE:     Thank you.

      17             Dr. Shyr?

      18             DR. SHYR:    This is really an easy case from

      19   a statistical point of view.    The data from both

      20   sponsors and FDA success convince me just that it’s a

      21   good application.   So, especially, I would like to

      22   thank Dr. Rubin thoroughly in sensitivity analysis

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       1   that answer almost all the questions that I have.     I

       2   think overall, no matter it’s a design issues or the

       3   non-inferiority marginal issues, all of them that were

       4   justified, and the only things were just I’d like to

       5   comment in the future is just if we can have a

       6   thorough missing data analysis or other part will even

       7   strengthen the final data analysis.     But overall, I

       8   just vote yes.

       9              DR. MOORE:    Thank you.

      10              Dr. Cappelletty?

      11              DR. CAPPELLETTY:    Yes.   Again, I also voted

      12   yes, and I think the efficacy data was clearly

      13   demonstrated, safety data looks very good for me, as

      14   well.   And I echo what my colleagues have said in that

      15   my cautions are with the MRSAs, especially an MRSA

      16   pneumonia, which can be necrotizing pneumonia and

      17   result in an ICU stay.     And since we don’t have an ICU

      18   population, I would also caution that in the labeling

      19   for the product.

      20              DR. MOORE:    Thank you.

      21              Dr. Wiedermann?

      22              DR. WIEDERMANN:    Bud Wiedermann.   I voted

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       1   yes, and I won't repeat excellent comments that others

       2   have made.    Certainly, Dr. Rubin’s analysis was very

       3   helpful to me.    And I hope that will be sort of a

       4   prototype for future analyses, but we also have to

       5   remember that a lot of this is post-hoc subgroup

       6   analyses, and there are a lot of pitfalls for that,

       7   so, if it comes down the pike on the next drug-disease

       8   combination, it may detract from supporting the drug’s

       9   indication.    Again, we have to take that with a grain

      10   of salt.

      11                And I would also point out I think in terms

      12   of the percent time above MIC or Monte Carlo analyses,

      13   these are sort of like biomarkers or surrogate

      14   outcomes, and we still need enough patience with the

      15   clinical entity that's being modeled to know what to

      16   make with that.    Because, otherwise, we don’t know how

      17   tight that link is to that particular indication.

      18                DR. MOORE:   Thank you.

      19                Dr. Roberts?

      20                DR. ROBERTS:   Yes, thank you.   I voted yes.

      21   Excellent presentations from both groups.

      22                I would echo my colleagues’ comments,

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       1   especially Dr. Reller, with which I agree with most of

       2   what he says.   My concerns with the marketing, and,

       3   perhaps, the labeling issues would be for empiric

       4   therapy.   The bulk of patients we see are going to be

       5   treated empirically, and the bulk of those are going

       6   to be culture-negative.      I think there is compelling

       7   data that macrolide addition does result in an

       8   improved outcome in patients who have evidence of

       9   septic shock, and I would suggest that labeling be

      10   worded in such a way as to preclude monotherapy for

      11   this drug in patients with evidence of sepsis.

      12              Thank you.

      13              DR. MOORE:     Thank you, everyone.

      14              Sorry.    Dr. Fleming, you had a comment?

      15              DR. FLEMING:    Yes, at the beginning of the

      16   comments, I had been understanding the breakpoint

      17   issue wasn’t as much on the table as it obviously is,

      18   so, I just wanted to add my comments, and they’re very

      19   much in line with Dr. Follmann's, and that is the lab-

      20   based modeling is being used and should be used to

      21   propose clinical cut points, but this hypothesis

      22   generation, and we need the actual clinical data in

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       1   order to be able to adequately informed.       So, for

       2   MRSA, I definitely endorse what Dr. Follmann

       3   indicated.

       4                That is, we need the data in order to be

       5   able to understand what the efficacy is in that

       6   setting from the clinical setting.

       7                               Adjourn

       8                DR. MOORE:   All right.   Thank you.   We’re

       9   going to have to make that the final word.      I hope

      10   nobody objects.

      11                We’ll now break for lunch.    We’ll reconvene

      12   again in this room in one hour from now at let’s make

      13   it 1:15.   Please take any personal belongings you may

      14   want with you at this time.

      15                Committee Members, please remember that

      16   there should be no discussion of the meeting during

      17   lunch amongst yourselves, with the press, or with any

      18   member of the audience.

      19                Thank you.

      20                (Whereupon, at 12:18 p.m., the meeting on

      21   Community-Acquire Bacterial Pneumonia was concluded.)


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