First Novel Clinical Candidate for SMA by vqx13199


									  DRUG DISCOVERY                                                                                SPRING 2007

FA M I L I E S          OF       S P I N A L M U S C U L A R AT R O P H Y

  A Publication Dedicated To Research Updates

  First Novel Clinical Candidate for SMA
  By Mark Gurney, PhD, MBA, Senior VP Drug Discovery and Development
  deCODE Chemistry

         SMA has had the vision to         medicinal chemistry team began          Having passed those tests, and with
         pursue drug discovery for         improving the drug-like properties      the demonstration of therapeutic
         spinal muscular atrophy. We       of the original compound in 2003.       benefit of the lead compound in
  now are beginning to see the             Every drug discovery project has its    the SMA mouse model, the next
  outcome of that leadership vision.       own unique challenges. In the case      goal of the FSMA-deCODE project
  The goal of the FSMA-deCODE              of the project undertaken for           is to show that the compound is
  drug discovery effort has been to        FSMA, very potent compounds             safe for use in human clinical trials.
  find chemicals that increase the         were synthesized within the first       To date, only small amounts of the
  amount of full-length SMN protein        year of work. These initial com-        lead compound have been pro-
  produced from the SMN2 gene.             pounds were promising as they           duced. The project now needs to
  Excitingly, the FSMA-deCODE              increased activity of the SMN2          transfer to a manufacturing team
  drug discovery effort has identified     gene leading to an increase in full-    to produce larger quantities of the
  drug-like compounds that act on          length SMN protein in cells             compound for further animal
  SMA patient cells in culture to          exposed to the compounds.               studies and then for human clinical
  increase SMN2 gene activity and          However, toxicity was observed at       trials. Generally, safety evaluation
  thereby the amount of functional,        higher concentrations due to off-       and manufacturing require 9-12
  SMN protein. The same com-               target activity on an enzyme            months. Results of safety testing in
  pounds also have now demon-              unrelated to SMN activity.              cells and mice have been positive to
  strated therapeutic benefit in a         Through the efforts of the chem-        date, but there is the real possibility
  mouse model of a severe form of          istry team, the undesired off-target    that unexpected safety issues could
  SMA. The FSMA compounds have             activity was removed while              still be identified as more compre-
  been shown to improve lifespan in        maintaining SMN2 promoter               hensive tests are performed.
  the SMA mice and to improve their        activity. While this was possible, it   This next phase of the FSMA-
  movement and bodyweight. It has          was not a simple challenge.             deCODE project will determine if
  not been an easy task to reach this      Also challenging was the task of        the lead compound has adequate
  point. Having shown potential            optimizing compounds for the            safety to allow entry into clinical
  therapeutic benefit, the goal for the    ability to cross the blood-brain-       trials. It has been a long road, but
  FSMA-deCODE collaboration now            barrier. Unlike blood vessels           within one year our lead com-
  is to evaluate the potential safety of   elsewhere in the body, blood vessels    pound will enter human clinical
  the lead compound in animal tests        in the brain have a unique seal to      trials, if adequate safety is estab-
  prior to beginning human clinical        prevent the free movement of small      lished.
  trials.                                  chemicals from the blood into the
  In 1999 this project began at            brain. The focus of the deCODE
  Aurora Biosciences where a large         chemistry effort over the last year
  SMA screening campaign was               has been to identify and develop a
  completed. An initial compound           lead compound that satisfies these
  was identified. At deCODE a              many criteria.
First Round of Lead Optimization Successful in Development
for SMA Treatment at Paratek Pharmaceuticals
By Joel A. Berniac, Ph.D., M.B.A., Principal Scientist and SMA Project Leader
Paratek Pharmaceuticals

       aratek Pharmaceuticals’ interest in                            SMA Drug Pipeline: Novel Preclinical Development
       developing a small molecule drug dis-
       covery program in the Spinal Muscular
Atrophy (SMA) therapeutic area started back
in 2002 when a portion of Paratek’s library of
over 2,000 modified Tetracycline (TC) deriv-
atives were screened in an SMA relevant in
vitro assay. The initial concept of screening
tetracycline (TC) derivatives for SMA came
                                                       Stages of Novel SMA Projects:                                   Pharmaceutical Industry Averages:
from their structural similarity with Aclaru-
bicin A (see Figure 1). This chemotherapeutic            Early Discovery                Novel Pre-Clinical             • 10 to 15 years to reach registration
drug was reported in 2001 to be active in cel-           Assay Dev         ~6         Le ad         Pre-Cl inica l     • Costs $800 million for drug development
                                                         Screening.    p ro grams Optimization         S afe ty
                                                                                                                         (includes cost of failures in price)
lular assays relevant to SMA:                              Hit to
                                                            Le ad
                                                                                    Paratek*         deCODE*
                                                                                    NINDS                              • High Risk venture: For every 100 discovery
  (1) it enhanced the inclusion of exon 7 in           *Funded by Families of SMA                                        approaches 1 to 2 drugs approved
  the splicing of SMN2 pre-messenger RNA                                                                               • Less than 10% approval after reaching IND
  (pre-mRNA); and                                     Drug Development Process: 1. Targets for drug screening are identified through basic research in
                                                      academic labs. 2. These targets become the basis of drug-identification assays, which are used to screen
  (2) it restored normal SMN protein levels           large numbers of potential drug compounds. 3. Compounds found during screening are called “hits”. 4.
  in an SMA patient-derived cell line.                “Hits” then undergo further testing to verify they have the desired bioactivity in cell culture models of
                                                      disease. These compounds are potential leads for pre-clinical drug development. 5. Lead optimization is a
However, Aclarubicin is toxic and not suitable        reiterative process whereby compounds are further modified until the greatest bioactivity is obtained,
for clinical development. Paratek surmised            toxicities and off-target activities are reduced, and drug-like properties are maximized. 6. At the
that nontoxic TC derivatives could potentially        completion of the lead optimization process, a Clinical Candidate is selected with the desired specifica-
increase full-length mRNA production and              tions, and an extensive series of preclinical safety studies are completed on the clinical candidate for an
SMN protein synthesis from the SMN2 gene.             Investigational New Drug Application (IND) to the FDA. 7. If the FDA accepts an IND application, first-
                                                      in-human (FIH) testing can begin with Phase I safety studies, typically in healthy volunteers. This begins
The discovery of a nontoxic TC derivative             the clinical development process of Phase I, II, and III clinical trials.
would be an important finding leading to a
potential treatment for SMA.
                                                   SMN protein and consequently in decreased                         promising results in that assay with an
SMN2 fails to compensate for the SMN1              motor functions in SMA patients. Therefore                        increase of SMN protein levels in a Type I
mutation, and thus to protect from develop-        the SMN2 gene is an ideal target for drug                         SMA patient fibroblast cell line of 8.3-fold
ment of SMA, because its mRNA undergoes            intervention to induce the synthesis of nor-                      increase. In addition, PTK-SMA1 again

SMN protein, known as Δ7SMN. After tran-
alternative splicing to encode for an unstable     mal SMN protein in SMA patients.                                  increased SMN protein levels in the same
                                                                                                                     fibroblast patient cell line when visualized by
scription of a gene into its corresponding pre-    Therapies that specifically increase inclusion                    Western Blot analysis instead of gems count.
messenger RNA (pre-mRNA), the nuclear              of exon 7 into the SMN2 mRNA are likely to
splicing machinery is responsible for process-     be effective treatments for even severe SMA                       While further in vivo evaluation of PTK-
ing that pre-mRNA into its corresponding           type I patients. With the support of Families                     SMA1 is currently underway in an animal
messenger RNA (mRNA) by eliminating                of SMA and in collaboration with Professor                        model of SMA with adult heterozygote trans-
introns (bits of pre-mRNA unnecessary for          Adrian Krainer’s team at Cold Spring Harbor                       genic mice expressing the human SMN2 gene,
protein synthesis) and joining together exons      Laboratory (CSHL) in NY for in vitro screen-                      Paratek’s medicinal chemists were able to syn-
(bits of pre-mRNA coding for protein syn-          ing, several TC derivatives from Paratek’s                        thesize more than 30 derivatives, 13 of which

cated Δ7SMN is due to exon 7 being skipped
thesis). The aberrant production of the trun-      compound library were screened. Among sev-                        showed activities similar to PTK-SMA1’s in
                                                   eral “hit compounds”, PTK-SMA1 emerged as                         the exon 7 splicing assay. Paratek Pharmaceu-
during splicing of the SMN2 pre-mRNA,              the most promising. When incubated in                             ticals, armed with its expertise and intellec-
resulting in insufficient amounts of full length   nuclear extracts from HeLa cells, PTK-SMA1                        tual property coverage in chemical
                                                   showed an increase in the percentage of exon                      modifications of the Tetracycline class of mol-
                                                   7 inclusion during mRNA splicing of SMN2                          ecules, is perfectly positioned to implement a
                                                   by 2.6-fold.                                                      drug discovery project for the treatment of
                                                                                                                     SMA. In addition to demonstrating sufficient
                                                   The same screening compounds were evalu-                          increase of SMN protein levels in an in vivo
                                                   ated collaboration with Professor Arthur                          model of SMA, Paratek’s objectives also
                                                   Burghes at Ohio State University in a whole                       include the optimization of the pharmacoki-
                                                   cell “Gems” assay which looks at the concen-                      netic profile and of all other drug-like prop-
                                                   tration of full length SMN protein in nuclear                     erties of the selected lead compound in order
                   Figure 1                        studies called “Gems.” PTK-SMA1 showed                            to develop a small molecule candidate for the
                                                                                                                     treatment of SMA within the next few years.
                                                       Compass 2007                 2
                                                           R E S E A R C H D I R E C TO R U P DAT E
                                                                                                                                           SPRING 2007

     Dear Families and Friends,
           ince 2000 FSMA has invested substantial funds in SMA therapeu-             supplying them with resources such as research tools, scientific expert-
           tics development. The ultimate goal of our investment in pre-clin-         ise, and established clinical networks. The costs of drug development
           ical drug development is to find an effective treatment for SMA.           increase substantially as we are successful and reach later stages. For
     One strategy we have actively pursued to reach this goal is to encourage         example, a late-stage clinical development project for SMA, consisting
     biotech and pharmaceutical partners to engage in pre-clinical SMA drug           of a full set of Phase I, II, and III trials, can cost between $25M to $50M
     research by providing direct funding. Traditionally, it has been difficult       over 5 years.
     to attract companies to conduct research in orphan disease therapeutic
                                   areas, such as SMA that have small patient         One extremely important aspect of our research strategy for SMA drug
                                   populations. Therefore, our best option            discovery is to build a therapeutic pipeline, which will increase our
The goal of the deCODE col-                                                           chances of successfully developing a SMA therapy. In order to build a
laboration was to generate a       has been to provide financial incentive for
                                   companies to pursue early stage SMA                broader therapeutic pipeline, FSMA plans to invest in additional drug
final optimized compound                                                              discovery programs. In March 2006 we began funding a program at
with the required properties       drug discovery, as well as providing the
                                   tools, academic expertise, and SMA advi-           Paratek Pharmaceuticals that involves assessing the ability of Tetracy-
of an effective SMA drug,                                                             cline compounds to correct SMN2 splicing. This is a different approach
called a “Clinical Candidate”.     sors to help make these projects successful.
                                                                                      from our Quinazoline program to increasing SMN levels. We recently
Now in May of 2007 this goal     Our first venture in drug discovery began            renewed this collaboration for a second year – please see attached WSJ
has been met. As will be         in 2000 as a collaboration with Aurora               article.
reported at the upcoming         Biosciences, since acquired by Vertex
11th Annual International        Pharmaceuticals. The goal of that collab-            Additional new drug discovery programs will be added to our portfolio
SMA Group Meeting (spon-         oration was to develop screening tools to            over the next few years. We need to build a pipeline of candidates for
sored by FSMA), our com-         search for chemical compounds that                   treatment of SMA for a number of reasons:
pounds prolong survival in       could increase SMN levels specifically               • Individual patients may react differently to a drug, and so we must
mouse models of SMA and          from the SMN2 gene. Several compounds                  aim to have multiple treatment options available.
are very effective at crossing   with the capability of doing this were dis-
the blood brain barrier to       covered, and one of these compound                   • A chronic treatment approach may require shifting between drugs
reach motor neurons in the       classes (called Quinazolines) has since                over time to limit side-effects.
spinal cord.                     been chemically modified at deCODE                   • The potential exists that two or more drugs could be used as a
                                 Chemistry to optimize and generate                     therapeutic cocktail to increase SMA levels even further than either
                                 drug-like properties. FSMA is now enter-               one alone could.
     ing into a new agreement with deCODE to generate the data package
     for an “Investigational New Drug” application to the FDA, which is               • It is important that multiple approaches be taken as drug develop-
     required to initiate human testing. This package of data will require              ment is a very high risk venture for each individual program.
     approximately one year to generate and cost $2.5M.                               This is an exciting time in the SMA community. On multiple fronts, our
     Our ultimate goal for this project is to find an industrial partner to           basic research investments have allowed us to design rational therapeu-
     progress this compound through human clinical testing and develop-               tic strategies for SMA. We are now beginning to see early results from the
     ment. Therefore, FSMA hopes to advance the project with our own                  translational drug discovery programs that we and other groups have
     funding to the point where the risk to industrial partners is effectively        invested in.
     reduced to allow their own financial investment in the program. Over-            Jill Jarecki, Ph.D.,
     all, we are trying to provide incentives to industry partners to enter the       Research Director, Families of SMA
     SMA drug development arena, by reducing risks and simultaneously

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                                                             Compass 2007         3
     SMA Drug Discovery Program Reaches Stage of Clinical Candidate

     Dear Supporters,
                e are pleased to announce a major result     will require funding of $2.5M and take about 12
                for the SMA community in this Compass.       months to complete. If we are successful in this             The Patient Advocacy
                Our general topic for this edition is Drug   next stage we would then look to start phase I clin-         Group, consisting of
     Discovery. This is the area of research where we take   ical trials.                                                 representatives from
     basic results and attempt to turn them into practi-
                                                             Families of SMA has always focused the majority of           FightSMA, MDA, SMA
     cal drugs. If successful in these programs we can
     then move into clinical trials.                         our efforts and funds towards research to find a             Foundation and Families of
                                                             treatment and cure for this disease.                         SMA is organizing and
     The lead compounds in our program with
                                                             • We invested $4.6M in research in our fiscal year           funding a “SMA Summit on
     deCODE have shown the ability to extend survival
     in a mouse model of SMA. Due to this successful           2006.                                                      Drug Development” to
     result we have now been able to select a Clinical       • We expect to fund over $5M over the next year.             be held in September in
     Candidate. This is the first time a novel compound                                                                   Washington, DC.
     specifically designed to treat SMA has reached this     Our long term goal is to build a therapeutic pipeline
     stage in drug development.                              for SMA that contains a number of drug candidates.           In anticipation of major drug
     Families of SMA has been funding and directing this     Thank you for your support which has enabled us to           efficacy trials for SMA, the
     particular program for the last 7 years. Our total      reach this point. Your backing has provided hope to          mission of this meeting is to
     investment to date in this program alone is over        many patients and families. Your help over the next          identify and reduce or
     $10M. The collaboration has involved many part-         few years will allow us to move forward to clinical
                                                                                                                          eliminate barriers to
     ners: starting with Aurora/Vertex, then transition-     trials with this particular program, and also to build
                                                             the essential pipeline of treatments for SMA.                successful drug develop-
     ing to deCODE, with assistance along the way from
     Ohio State University and Cold Spring Harbor Lab-                                                                    ment.
     oratory. So far we have been successful.
     Selecting a Clinical Candidate means that we are
     now preparing to run the safety tests required to       Kenneth Hobby
     apply to the FDA to begin clinical trials. This work    Executive Director, FSMA

                                                                            to the FDA which is needed to begin clinical trials.

                                                                                                                                                          Design: Evan Hill Design, Inc. Printing: AIM Business Printers
                                                                          • FSMA is beginning work now to generate the application
                                                                              this stage.
                                                                              designed to treat Spinal Muscular Atrophy has reached
                                                                            • This is the first time a drug candidate specifically
                                                                            FSMA FUNDED PROGRAM SELECTS CLINICAL CANDIDATE

Highland Park, IL 60035
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