Pipeline_ Airway Surface Liquid Modulation - North American Cystic

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					   Pipeline:
Airway Surface
    Liquid
 Modulation

           Eric J. Sorscher, M.D.
     University of Alabama at Birmingham
                 Baltimore, MD
               October 21, 2010
            We Will Address:

1. Formation of airway surface liquid (ASL) and
   the mechanisms underlying mucus transport
   in human airways.
2. Key molecular defects in cystic fibrosis,
   including abnormalities of ASL and mucus
   clearance.
3. Emerging cystic fibrosis therapies designed
   to overcome defects in CFTR and enhance
   pathways that regulate ASL.
Histopathology of Human CF Airways
 Airway lumen                White blood cell



                                        Mucus layer
                                        (gel)


                                        Airway surface
                                        (sol) liquid layer




  Goblet cell   Submucosal
                 Glandular
                   duct




                                                             Courtesy of Steven Rowe
Airway Mucus in a 2-month-old CFTR-/- Pig




                            Courtesy of David Stoltz & Mike Welsh
Lung Disease in 8-month-old CF Ferret
                      Tenacious
                        Mucus




  WT




   CF


                              Courtesy of John Engelhardt
Courtesy of Jeff Wine & Mauri Krouse
  Cystic Fibrosis




WT (Control)




  WT (VX-770)




                    Courtesy of Steven Rowe and Gary Tearney
X   X
Courtesy of S. Aller
Courtesy of S. Aller
CaCC
       ENaC
              CFTR
HTS Robotics
Opening a CFTR Portal
That is “Locked Shut”
    (e.g., G551D)
          Phase 2a VX-770 Study Design for
                  G551D Mutation
Part 1                                                         Part 2
Mixed cross-over and parallel design                           Parallel design with low N
Statistically modeled analyses based on LS mean                Statistical analyses based on median

                     VX-770                      VX-770
                                                                                      VX-770 150 mg q12h
                   25 mg q12h                  25 mg q12h                                    (n = 8)
Group A (n = 10)     VX-770                      VX-770
                                                             Randomization            VX-770 250 mg q12h
Randomization      75 mg q12h                  75 mg q12h                                   (n = 7)
(2:2:1)                                                      (n = 19) (2:2:1)
                    Placebo                     Placebo                                     Placebo
                                                                                             (n = 4)

                     VX-770                      VX-770                                 Treatment (28 days)
                   75 mg q12h                  75 mg q12h

Group B (n = 10)     VX-770                      VX-770
Randomization      150 mg q12h                 150 mg q12h
(2:2:1)
                     Placebo                     Placebo
                                                                      Accurso FJ, Rowe SM, Clancy JP et al. Effect
                                                                       of VX-770 in persons with cystic fibrosis &
                    Treatment     Washout       Treatment
                    (14 days)    (7-28 days)    (14 days)               the G551D-CFTR mutation. N Engl J Med
                                                                                        2010;363(21):1991-2003.
                       Sweat Chloride Change from Baseline
                                     Individual subject response with population mean/median
                      Part 1                                                                                                               Part 2
                      Day 14 means (modeled)                                                                                               Day 28 medians

                                     20                                                                                                    20

                                                  +4.4                                                                                                 +5.0
 Change in sweat chloride (mmol/L)




                                                                                                       Change in sweat chloride (mmol/L)
                                     10                                                                                                    10

                                      0                                                                                                     0

                                     -10                                                                                                   -10

                                     -20                                                                                                   -20

                                     -30                                                                                                   -30
                                                                                                                                                                                         -38.0 †
                                     -40                        -32.3*                                                                     -40
                                                                                 -40.4*
                                     -50                                                      -42.3*                                       -50
                                                                                                                                                                       -59.5†
                                     -60                                                                                                   -60

                                     -70                                                                                                   -70
                                             Placebo     VX-770 25 mg    VX-770 75 mg VX-770 150 mg                                              Placebo      VX-770 150 mg     VX-770 250 mg


                                           * P < 0.001 within-group and vs. placebo
                                           † P < 0.05 within-group and vs. placebo



Accurso FJ, Rowe SM, Clancy JP et al. Effect of VX-770 in persons with cystic fibrosis & the G551D-CFTR mutation.
N Engl J Med 2010;363(21):1991-2003.
                                                Relative Change in FEV1 % pred (%)
                                                Individual subject response with population mean/median
                                           Part 1                                                                                                           Part 2
                                           Day 14 means (modeled)                                                                                           Day 14 and Day 28 medians

                                          40
                                                                                                                                                      40
Relative change in %predicted FEV 1 (%)




                                                                                                             Relative change in %predicted FEV1 (%)
                                          30                                                                                                          30



                                          20                                                                                                          20                               12.4†
                                                                                                                                                                            9.2*
                                                                                                                                                                                                                   8.7*
                                                                                      10.0*          10.5*
                                          10                                                                                                                                                         7.3
                                                                                                                                                      10
                                                                     4.9
                                                                                                                                                               3.1                                                                 4.4†
                                                       0.7
                                           0                                                                                                           0



                                          -10                                                                                                         -10

                                                  Placebo    VX-770 25 mg   VX-770 75 mg   VX-770 150 mg                                                     Placebo   VX-770 150 mgVX-770 250 mg   Placebo   VX-770 150 mgVX-770 250 mg

                                                                                                                                                                          Day 14                                 Day 28
                                                *P < 0.01 within-subject
                                                †P < 0.05 within-subject



Accurso FJ, Rowe SM, Clancy JP et al. Effect of VX-770 in persons with cystic fibrosis & the G551D-CFTR mutation.
N Engl J Med 2010;363(21):1991-2003.
                                                         NPD Change from Baseline
                                        Change in zero chloride plus isoproterenol response
                                        Individual subject response with population mean/median

                                        Part 1                                                                                                         Part 2
                                        Day 14 means (modeled)                                                                                         Day 28 medians
                                         8
                                                                                                                                                  8
Change from baseline in zero chloride




                                                                                                         Change from baseline in zero chloride
                                         4
  plus isoproterenol response (mV)




                                                                                                                                                  4




                                                                                                           plus isoproterenol response (mV)
                                         0                                                                                                        0
                                         -4          -1.7           -1.6                                                                          -4
                                                                                                                                                                 -0.4
                                                                                                                                                                                   -3.5 †
                                         -8                                        -4.7*         -5.4*                                            -8                                                  -5.5 †
                                        -12                                                                                                      -12
                                        -16                                                                                                      -16
                                        -20                                                                                                      -20
                                        -24                                                                                                      -24
                                        -28                                                                                                      -28
                                        -32                                                                                                      -32
                                               Placebo      VX-770 25 mg   VX-770 75 mg VX-770 150 mg                                                      Placebo      VX-770 150 mg       VX-770 250 mg


                                              * P < 0.01 within-subject
                                              † P < 0.05 within-subject


      Accurso FJ, Rowe SM, Clancy JP et al. Effect of VX-770 in persons with cystic fibrosis & the G551D-CFTR mutation.
      N Engl J Med 2010;363(21):1991-2003.
   VX-770 Registration Program in CF



         Orphan Drug and Fast-Track Designation
Three separate registration studies:

                   • Primary trial to enroll ages 12+ with G551D mutation
                         • Enrollment complete
                   • Patients aged 6 to 11 with G551D mutation
                         • Enrollment complete
                   • Phase 2 study of CF patients homozygous for the F508del
                     mutation
                         • Enrollment complete

              Vextex press release Oct. 25, 2010 http://investors.vrtx.com/releasedetail.cfm?ReleaseID=522615
Correcting the F508del
CFTR Processing Defect
                           VX-809 Study Design
                                            Placebo qd (n = 17)

                                        VX-809 25 mg qd (n = 18)
    Enrolled and
    randomized                          VX-809 50 mg qd (n = 18)          Follow-up
      (n = 89)
                                       VX-809 100 mg qd (n = 17)

                                       VX-809 200 mg qd (n = 19)


                         Day 0              7            14     21   28          +7
                   • Subjects recruited in 2 Groups:
                      – Group A (placebo, VX-809 25 mg, VX-809 50 mg)
                      – Group B (placebo, VX-809 100 mg, VX-809 200 mg)
                   • Safety evaluation was done after enrollment of Group A

Clancy JP, Spencer-Green G. J Cyst Fibros 2010;9(Suppl 1):S20
http://www.clinicaltrials.gov (NCT00865904)
            CFTR-Mediated Cl– Transport:
               Sweat Cl– Biomarker
                                                                                    Treatment effect at Day 28
                                                                              +0.10              - 4.61           - 6.13*        - 8.21†
                                                                             (n=16)             (n=16)            (n=15)        (n=16)
                                                                    8
                                                                    6




                               Change in sweat chloride (mmol/L)
                                                                    4
                                                                    2
                                                                    0




                                        (mean [95% CI])
                                                                    -2
            Direction of
                                                                    -4
             increased
                                                                    -6
                CFTR
               activity                                             -8
                                                                   -10
                                                                   -12
                                                                   -14
                                                                   -16
                                                                          VX-809 25 mg      VX-809 50 mg VX-809 100 mg VX-809 200 mg

                                                                         * P<0.05 vs placebo and within-treatment group
                                                                         † P<0.01 vs placebo and within-treatment group
                                                                         Linear trend test for dose-response: P=0.0013

Sweat Cl– responder analysis at Day 28                                                                    VX-809
                                 Placebo*                                                    100 mg                  200 mg
                                  (n=17)                                                     (n=15)                  (n=16)
Response ≥10 mmol/L
reduction from baseline,            0                                                        6 (40%)                 6 (38%)‡
n (%)
*Combined groups A & B; ‡P=0.02 vs placebo
                                                    Clancy JP, Spencer-Green G. J Cyst Fibros 2010;9(Suppl 1):S20
               Vertex press release February 3, 2010 (http://investors.vrtx.com/releasedetail.cfm?ReleaseID=442429
                          Phase 2
• Randomized, double-blind, placebo-controlled study
• VX-770 150 mg q12h for 16-week treatment duration
• Patient population:
  • Homozygous for the F508del mutation
  • Aged ≥ 12 years
• Primary endpoints
  • Safety
  • Absolute change from baseline in % predicted
    FEV1 through Week 16
• Estimated enrollment: 140
• Study sites in USA
                                        http://www.clinicaltrials.gov (NCT00953706)
                          Synergy of F508del CFTR Correction
                             1 + 1 Is Much Greater Than 2
            100             vehicle control
                            10 mM Corrector A
                80          10 mM Corrector B                                               80

                            10 mM Corr A/10mM Corr B
                                                                                            60




                                                                            DIsc [mA/cm ]
                                                                            2
                60
DIsc [mA/cm ]
2




                                                                                            40
                40
                                                                                            20

                20
                                                                                            0
                                                                                                   Corr A    Corr B   Corr A + Corr B
                 0
                                                                                                             Bar graph
                -20                    Fsk       IBMX       Genistein   CFTRinh-172                          illustrates
                                       10 mM     100mM      20 mM       20 mM                                synergy of
                      0        500        1000           1500      2000                     2500            end currents
                                               time[s]
                  Current traces from FRT cell Ussing chamber recordings

                                                                                                        Courtesy of Martin Mense
                CF Consortia
 Sharing of ideas and interdisciplinary collaboration
  to accelerate development of F508del correctors

• How and why does F508del CFTR misfold?
• How can CFTR misfolding be overcome?

• Which interventions restore surface
  localization of F508del CFTR?
• How can the mutant protein be activated to
  replete the airway surface liquid?
Overcoming Premature
 Truncation Mutations
(e.g., G542X, W1282X)
Phase 2 Studies Have Demonstrated Ataluren Activity
    in Nonsense-Mutation-Mediated CF (nmCF)




   • Increased CFTR at the epithelial cell surface (as measured by immunofluorescence)
     in nmCF patients receiving ataluren for 2 weeks1
   • Increased CFTR chloride channel activity (as measured by nasal transepithelial
     potential difference) in nmCF patients receiving ataluren
     for 2 weeks1
   • Reduced cough (as measured by the VivoMetrics LifeShirt) in nmCF
     patients receiving ataluren for 12 weeks2
   • Trends in improvement in pulmonary function (as measured
     by spirometry) in nmCF patients receiving ataluren for 12 weeks2

1Sermet   et al, AJRCCM 2010                                    2Wilschanski   et al, ERJ [in press]
    An International Registration-Directed
Phase 3 Study in Patients with nmCF is Ongoing
                                               Double-blind                     Open-label
                                            Placebo-controlled                  Extension
Key Eligibility Criteria:                         Study                           Study
• Nonsense mutation CF
• Age  6 years                                     Ataluren
• FEV1  40% and  90%                          10, 10, 20 mg/kg
  predicted                                                                            Ataluren
                                        N~104                                          10, 10, 20
                                                                                        mg/kg
Outcome Measures:      R/S
• FEV1
• Exacerbation rate                                  Placebo
• HRQOL
• Cough rate                            N~104
• NPD & Sweat Chloride                              48 Weeks
• Lung CT

 • Enrollment (target = 208 subjects) is on track
 • Data available first half 2012
                                                                                  www.clinicaltrials.gov
                                                               Illustration courtesy of PTC Therapeutics
CaCC
       ENaC
              CFTR
Denufosol is a Novel Ion Channel Regulator Under
Development for the Treatment of CF Lung Disease
Denufosol’s Mechanism of Action
  • Increase of chloride secretion via calcium-activated chloride channels (CaCCs)
  • Inhibition of sodium absorption via epithelial Na+ channels (ENaCs)
  • Stimulation of ciliary beat frequency

  Chloride Secretion in Normal and CF Epithelia                   ENaC Inhibition in Airway Epithelium                                                           Stimulation of Ciliary Beat Frequency
                                                                                                                                                                 1.0
More chloride                                                 More sodium
                                                                                              14
                  12                                                                                                     pre-Denufosol
 transport                                                     absorption                     12
                                                                                                                         Pre-Denufosol
                                                                                                                         Post-Denufosol
                                                                                                                         post-Denufosol




                                                                                                                                          Cilia Beat Frequency
                  10




                                                                                                                                            (relative to UTP)
                                                                                              10


                                                                            DISC (mAmp/cm )
                                                                            2
                   8                                                                                                                                             0.5
                                                                                              8

                   6                                                                          6

                   4                                                                          4
                                                                                                                                                                 0.0
                   2                                                                          2

                   0                                                                          0                                                                           -7       -6           -5   -4   -3
Less chloride                                                 Less sodium                                 -D Amiloride

  transport                                                    absorption                                  (ENaC)
                                                                                                                                                                               log [denufosol], M
                          Normal +      CF +        CF +
                          Forskolin   Forskolin   Denufosol                                   Human Bronchial Epithelial Cells                                         Human Airway Epithelial Cells
                       Human Airway Epithelial Cells




Yerxa et al., JPET 302:871-880, 2002
Courtesy of Jack Stutts, PhD, UNC at Chapel Hill, manuscript in preparation
                                      Mean Change From Baseline FEV1
                                                       Mean (SE) Change From Baseline FEV1 (mL)*
     Mean (SE) Change From Baseline


                                          140
                                                               Denufosol
                                          120                  Placebo
                                                               Placebo switched to denufosol        Denufosol only, open-label phase
                                          100
                                               80
                                      FEV1 (ml)*




                                               60
                                               40
                                               20
                                                   0
                                            -20
                                            -40
                                                       0   4             12                    24      28         36               48
                                                                                   Treatment Week
       ITT population
       *Values displayed are mean observed values at each time point
       without adjustment for discontinuations or covariates.

RB Moss, RD Anbar, RW Wilmott, M Barnes, AE Schaberg, TA Durham, FJ Accurso. Phase 3 study of denufosol
tetrasodium for the treatment of cystic fibrosis. Am J Respir Crit Care Med 2009; 179: A1189.
TIGER-2 Phase 3 Clinical Trial (08-110)
 Planned Trial Size: 450            R
                                                                                Primary Endpoint
                                    A
   Key Exclusion Criteria
                                    N                                       • Change in FEV1 in liters at
                                                     Denufosol
  • FEV1 ≥75% and ≤110%             D                                         48-week endpoint
                                                       60 mg
    predicted normal for age,       O                   TID
    gender and height                                 N = 225
                                    M
  • Age 5 or older                  I                                        Secondary Endpoints
                                    Z
                                    A                 Placebo               • Other pulmonary
   Key Exclusion Criteria                               TID                   function tests, pulmonary
                                    T                 N = 225                 exacerbation, antibiotic
  • Participated in TIGER-1         I                                         use, incidence of
  • Standard CF meds                O                                         hospitalization/ER visits,
    allowed, except hypertonic                                                health resource utilization,
                                    N                                         quality of life
    saline

                                     48-week Treatment Period             4-week Follow-up Period
● Based on TIGER-1, made three modifications to enhance
  TIGER-2 – extended trial length; added upper limit on lung
  function entry criteria; and increased number of patients enrolled
● Patients who complete TIGER-2 are eligible for three-year
  open-label, denufosol trial


                            www.clinicaltrials.gov (NCT00625612) Illustration courtesy of Inspire Pharmaceuticals
Newborn Screening
 Continuing Clinical Studies of Hypertonic
Saline Aerosolization ISIS Trial: Some Firsts
• First clinical trial of chronic
 maintenance therapy in
 infants
  • Opportunity to intervene early in
   CF especially with NBS
• First multi-center trial using
 pulmonary exacerbation and
 infant PFTs as endpoints in
 this age group
  • Model for subsequent trials
   assessing other early intervention
   strategies
                                        Courtesy of Stephanie Davis & Margaret Rosenfeld
      ISIS 001: Pilot Data
      2-week Safety Trial
         20 infants enrolled
          5 with pre-post HS PFTs


                                       1 withdrew after <1 min


 1 of 19 (5%) intolerant of test dose
              (95% CI 0, 26%)

                                      1 not evaluable due to acute
                                          respiratory infection

None of 17 intolerant of repeated doses
            (95% CI 0, 20%)

                                Courtesy of Stephanie Davis & Margaret Rosenfeld
ISIS 001: Current Recruitment Status




                     Courtesy of Stephanie Davis & Margaret Rosenfeld
                      Summary
 Powerful new capabilities have positioned the field to
 address questions about clinical CF in ways that were
 not possible even 12 months ago.
 Novel CFTR modulators, animal models, and other
 advances in basic CF science will allow us to discern
 mechanistic features of airway surface liquid generation,
 pulmonary ion transport, infection, and inflammation.
 New human clinical trials will address the magnitude of
 CFTR correction necessary to improve the surface liquid
 and overcome pulmonary injury; including the potential
 for ameliorating structural lung damage.
                    Conclusion
 The CF field is benefiting from a tremendous wealth
  of new capabilities. These will provide an even
  better understanding of airway surface liquid and
  pathobiology in the disease.
 Numerous interventions to restore airway surface
  liquid and mucus clearance in cystic fibrosis are
  rapidly advancing through the clinical testing
  phase, and the pipeline for the future is robust.
 What has made all of this possible is a spirit of
  collaboration, sharing of ideas, working together,
  and sincere concern about a cause so important to
  all of us.
      International Collaboration


• CF Colleagues Worldwide
• CFF Therapeutics Development Network
• Patients and their Families
Rosey, age 19 months

				
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