FSMA Funded Research Activities in FY2008

1. FSMA Funded Research Activities in FY2008 Jill Jarecki, Ph.D. Research Director

2. 2008 Research Q&A Session • Jill Jarecki PhD, FSMA-Funded Research Activities - 15 min. • Clinical Trial Panel - 1hr. 15 min. • Kathryn Swoboda MD, University of Utah, Project Cure SMA • John Kissell MD, Ohio State University, Project Cure VALIANT Clinical Trial • Thomas Crawford MD, Johns Hopkins University, Project Cure SMA • Richard Finkel MD, University of Pennsylvania, PNCR • Basic Research & Therapeutics Development Panel - 1hr. 15 min. • Arthur Burghes PhD, Ohio State University, Basic Research Developments • Douglas Kerr MD, PhD, Johns Hopkins University, Stem Cell Therapy • Hans Keirstead PhD, University of California Irvine, Stem Cell Therapy • Chris N Airriess PhD, California Stem Cell Inc, Stem Cell Therapy • David Jacoby  MD PhD, Repligen Corporation, Drug Development • Jill Heemskerk PhD, NINDS-funded SMA Research (basic, clinical, drug discovery)

3. FSMA Funded Research in FY2008 • Invested approximately $4 million in SMA research in Fiscal Year 2008

4. FSMA Funded Research in FY2008 • 25 Basic Research Grants • 3 Therapeutics Development Projects • FSMA / deCODE Project • Quinazolines to increase SMN2 expression • Paratek Pharmaceuticals • Tetracyclines to correct SMN2 splicing • Stem Cell Collaboration with CA Stem Cell Inc. and UC Irvine • Motor neuron replacement therapy • Project Cure SMA Clinical Network ~30 people at 6 sites • Phase II CARNI-VAL trial, completed November 2007 • VALIANT adult ambulatory trial at OSU, started June 2007 • CARNI-VAL TYPE I Trial, started April 2008 • Community funding of International SMA Patient Registry at Indiana University (FSMA, MDA, FightSMA, & SMAF)

5. Basic Research: Biological Basis of SMA • In motor neurons, SMN is found in complexes located in both the cell body and in the cell axons • Why do low levels of SMN cause motor neurons to die? • Which SMN complex is critical? The axonal or the cytoplasmic/nuclear complex? Or both? • When can increasing SMN levels rescue SMA disease progression? • How is SMN expression controlled and regulated? • What is the most effective route for making SMA drugs? • Can we directly replace SMN (gene therapy)? • Can we directly replace lost motor neurons (stem cell therapy)?

6. 9 Newly Funded Basic Research Projects • Charles Y. Cho, Ph.D., Genomics Institute of the Novartis Research Foundation (GNF),Functional Genomic Screens for Novel Regulators of SMN2 Expression and Splicing • Elliot J. Androphy, M.D. University of Massachusetts Medical School,Identification of factors that control SMN protein levels • Megerditch Kiledjian, Ph. D., Rutgers, The State University of New Jersey,Mechanism of Action for a Drug Mediated up Regulation of SMN2 • Joel M. Gottesfeld, Ph.D, The Scripps Research Institute,Novel Histone Deacetylase Inhibitors as Therapeutics for Spinal Muscular Atrophy • Kum- Loong Boon, Ph.D, The Ohio State University,Analysis of motoneuron specific expression of SMN in promoting normal motor axon outgrowth and beta-actin mRNA transport • Christine DiDonato, Ph.D., Northwestern University,New Mouse Models for Pre-clinical Compound Testing • Brunhilde Wirth, Ph.D, Eric Hahnen, Ph.D, MBA, University of Cologne,Analysis of natural and drug-induced epigenetic changes in SMN2 • Christina, B. Brahe, Ph.D ., Istituto di Genetica Medica; Louise R. Simard, Ph.D., University of Manitoba,SMN Biomarker: Towards a validated international Standard Operating Procedure*** • Jean-Yves Masson, Ph.D., Laval University, DNA damage signaling and repair in Spinal Muscular Atrophy and neuronal cells** *Co-funded by Famiglie SMA in Italy and **FSMA Canada

7. Clinical Development Preclinical: Discovery Potency Selectivity Toxicology Pharmacokinetics Physical & Chemical Properties Efficacy Drug Development Process FDA Approval Target ID Assay Dev. Screening Hit to Lead Lead Optimization Pre-Clinical Safety Clinical Trials Phase I, II, III Clinical Candidate IND FIH NDA Paratek Tetracyclines Quinazolines Motor Neuron Replacement IND = Investigation New Drug Application needed for FIH FIH = First in Human NDA = New Drug Application for FDA approval

8. Paratek Drug Discovery Program • Initial seed funding by FSMA has lead to a shared investment by Paratek in third year • 3-fold increase in funding for third year • Tetracycline compounds that correct SMN2 splicing in multiple tissues in SMA mouse models • Lead optimization is ongoing with new analogs synthesized at Paratek • Most interested in compounds that enter the brain • Key collaborators at CSHL in Krainer lab and in Hastings lab at Rosalind and Franklin University

9. FSMA Quninazoline Project: Novel SMN Enhancing Drug • Over 1000 2,4-diaminoquinazolines made and tested at deCODE for ability to increase SMN2 gene activity • One Clinical Candidate Selected in 2007 • Potent • Oral bioavailability and stable • Very efficiently enters brain • Excellent carcinogenicity profile • Increases SMN protein levels • Increases survival time in SMA animal models • Protein target now identified as the mRNA decapping enzyme DcpS

10. Current Quinazoline Project Status • Quinazoline clinical candidate is undergoing the core battery of IND-enabling safety studies • IND allows for first in human testing to begin • Studies required by FDA for IND include: • Efficacy data proving drug works • Increases SMN levels in cells and in animal tissues • Increases survival and motor function in SMA animal models • Safety Studies • General toxicology (dosing in animals for equal duration as human trials) • Safety Pharmacology (heart function, brain function, breathing) • Genotoxicity (carcinogenic or not) • Chemistry Manufacturing and Control (clinical grade manufacturing process)

11. Current Quinazoline Project Status • Safety studies began in Fall of 2007 -- 12 months to complete • General Toxicology Studies -- dosing phase complete • 28 day safety studies in rat and dog to support Phase I studies • Detailed autopsy, clinical chemistry, hematology, drug level analysis in August • Safety Pharmacology (CNS, pulmonary, cardiovascular) • dosing phase complete -- awaiting final results • Genotoxicity -- complete • Chemistry Manufacturing and Control data (cGMP production/ clinical grade) -- leaving for commercial partner • Actively looking for industry partner to develop through human testing All studies are completed GLP (good laboratory practice). This means experiments in compliance with FDA quality assurance protocols.

12. Motor Neuron Replacement Project • Replacement of lost motor neurons • Collaboration with FSMA, CA Stem Cell (CSC), & UC Irvine to advance to human clinical trials • Project currently focused on FDA required animal safety studies • tumorigenicity, toxicity, biodistribution, and pain • CSC provides manufacturing protocols for clinical-grade motor neurons • Keirstead and Kerr labs demonstrate proof-of-concept efficacy data in animal models of motor neuron disease • First clinical trials planned in infants with Type I SMA • Stepping stone to adults with SMA, ALS, and Spinal Cord Injury

13. First CARNI-VAL Phase II Trial Results - Cohort 1 • Results Cohort 1 -- children with Type II SMA, ages 2 to 8 years • Randomly given VPA/Carnitine OR placebo for 6 months; all kids received drug next 6 months • No increase in primary outcome measure (MHFMS) at 6 months • Secondary analysis: significant improvement in MHFMS seen in younger (< 3 yrs) and lighter children at 12 months • Requires a formal placebo-controlled study designed to prove this hypothesis • Weight gain was primary drug-related side effect • Increased fat mass during drug treatment correlates with decreased motor function • Data not yet available for motor neuron function (cMAP) and SMN levels for cohort 1 • Cohort II data analysis is ongoing MHFMS is a scored series of 20 tests that provides a standardized measurement of functional motor ability in children with type II SMA.

14. 1. CARNI-VAL Type I 2. Stop SMA 3. Nptune 01 4. Nptune 02 5. Trophos 19622 6. VALIANT 7. Stanford HU Type I 8. HU Taiwan Ongoing SMA Drug Trials (as listed on www.clinicaltrials.gov) Project Cure SMA: Open-label safety study of VPA/Carnitine in SMA Type I infants U of Utah: Open-label study of Sodium Phenyl butyrate in pre-symptomatic SMA Type I/II NINDS: Open-label Sodium Phenyl butyrate in SMA Type II/III (to assess optimal dose) NINDS: Open-label Sodium Phenyl butyrate in SMA Type I ((to assess optimal dose) French Company Trophos: Open-label safety study in SMA Type I/II/III Project Cure SMA: Placebo-controlled study of VPA in ambulatory adults with SMA (OSU) Stanford University: Placebo-controlled Study of Hydroxyurea in SMA Type I Taiwan: Placebo-controlled Study of Hydroxyurea in SMA Type II/III Two Trials Recently Completed: Stanford HU in Type II/III AND Project Cure SMA CARNI-VAL Phase II

15. Acknowledgements Paratek Paul Higgins Joel Berniac Paul Abato Michael Draper Adrian Krainer Michelle Hasings Ying Hsiu Louise Simard Dennis Molnar SAB Chris Spancake Adrian Krainer Douglas Kerr Arthur Burghes Mark Gurney Stephen Strittmatter Thomas Crawford Kathryn Swoboda Louise Simard Project Cure SMA Sandy Reyna Kathryn Swoboda Thomas Crawford Gyula Acsadi Guy Danjou Mary Schroth John Kissel Kristin Krosschell Louise Simard Bernie LaSalle Susan Sorensen Chuck Scott deCODE Jasbir Singh Emmanuel Onua Grace Furman Mark Gurney David Zembower Arthur Burghes Matt Butchbach Chris Spancake Brian Pollok Shin-Wu Liu Mike Kiledjian Stem Cell Project CA Stem Cell Charles River Laboratory Hans Keirstead Chris Airriess Douglas Kerr