1. Pathway to Clinical Trials Jennifer Farmer, MS, CGC Coordinator, Collaborative Clinical Research Network in FA Executive Director, FARA (484) 875 3015 Jen.farmer@curefa.org

2. Finding treatments and curing a rare disease Understanding the mechanisms Drug discovery Identify compounds, drugs, technologies that can be used to slow, stop and reverse the dx Drug development Optimizing compound Pharmacokinetics Toxicology Manufacturing Clinical research and trials Understand the disease in patients and how to measure change Testing safety and efficacy of the drug in patients

3. A Decade of Progress 1996 - 1999 FA gene identified Diagnostic Test for FA 1 st major Break-through in understanding the cause of the disease 2000-2003 Elucidation of disease process Reduced amounts of frataxin Altered iron metabolism Impaired energy production 2004-2007 Drug discovery and development Collaborative Clinical research network Clinical Trials 3

4. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity Increase Frataxin Expression (Compounds) Idebenone Iron Chelator Santhera Edison 1 Clinical Trial 3 Potential Treatments/Approaches A0001 FA Treatment Pipeline - 2004

5. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery HDAC - New Idebenone HDAC - Leading Iron Chelator – DeferiproneFe-S clusters HSV-1 FRDA TAT Frataxin EPO & EPO mimetics Santhera Penwest ApoPharma Mitochondrial Function Frataxin FRDA Gene Transcription NIH/Harvard Repligen Scripps Institute, La Jolla, CA University of Madrid and University of Oxford Wells Center for Pediatric Research, Indianapolis, IN University of Pennsylvania &University of California, Davis Mayo Clinic, Rochester, MN MD Anderson, Houston, TX & Murdoch Children’s Research Institute, Australia Pioglitazone INSERM - Hôpital Robert Debré FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches A0001 FA Treatment Pipeline - 2009 Mt Gene Therapy University of Minnesota and Mayo Clinic Varenicline / Chantix University of South Florida And Children’s Hospital of Phila Neuro- Transmission Modifying Therapy University of Pennsylvania RNAi Neuro- protection EGb761 IPSEN MUV, Austria & Other groups Lu AA24493 (cEPO) Epigenetic Multiple Groups Lundbeck

6. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery Fe-S clusters HSV-1 FRDA Mitochondrial Function Frataxin FRDA Gene Transcription NIH/Harvard University of Madrid and University of Oxford University of Pennsylvania &University of California, Davis Mayo Clinic, Rochester, MN MD Anderson, Houston, TX & Murdoch Children’s Research Institute, Australia FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches FA Treatment Pipeline - 2009 Mt Gene Therapy University of Minnesota and Mayo Clinic Neuro- Transmission Modifying Therapy University of Pennsylvania RNAi Neuro- protection Epigenetic Multiple Groups

7. Research / Drug Discovery Program Targeted research based on mechanism of the disease –Fe-S Clusters –Gene therapy Develop assays for screening drug targets at each of those steps 7

8. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery HDAC - New HDAC - LeadingTAT Frataxin Repligen Scripps Institute, La Jolla, CA Wells Center for Pediatric Research, Indianapolis, IN FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches FA Treatment Pipeline - 2009 Neuro- Transmission Modifying Therapy Neuro- protection

9. Pre – Clinical Drug Development 9

10. 10

11. New assets for drug discovery and development Neuronal and cardiac cellular models –Stem cell technology Characterize and optimize mouse models New assays that target frataxin in high throughput drug screening Skipping steps or moving too quickly can lead to failure –Abandon a good drug candidate –Take a poor drug candidate to humans Improving research tools to identify drugs with highest likelihood of success as quick as possible 11

12. Induced Pluripotent Stem Cells 12

13. Induced Pluripotent Stem Cells 13

14. Phase I Dose Finding/ Drug Metabolism/ Safety Phase II Further Evaluate Safety & Efficacy Phase III Prove Efficacy in Larger Group/ Compare to Standard Phase IV Evaluates Long- term Risks/ Benefits *(usually post FDA approval) Ia- 20-80 Healthy Volunteers get 1 dose & safety monitor Ia- 20-80 Healthy Volunteers get 1 dose & safety monitor Ib- Healthy Volunteers get longer drug exposure- MTD Ib- Healthy Volunteers get longer drug exposure- MTD Clinical Trials

15. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery Penwest FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches A0001 FA Treatment Pipeline - 2009 Neuro- Transmission Modifying Therapy Neuro- protection

16. Phase I Dose Finding/ Drug Metabolism/ Safety Phase II Further Evaluate Safety & Efficacy Phase III Prove Efficacy in Larger Group/ Compare to Standard Phase IV Evaluates Long- term Risks/ Benefits *(usually post FDA approval) Ia- 20-80 Healthy Volunteers get 1 dose & safety monitor Ia- 20-80 Healthy Volunteers get 1 dose & safety monitor Ib- Healthy Volunteers get longer drug exposure- MTD Ib- Healthy Volunteers get longer drug exposure- MTD Clinical Trials

17. Research (Finding Potential Therapies/Drugs) Pre-Clinical (Testing in Laboratory) Phase I (Human Safety Trial) Phase II (Human Safety and Efficacy Trial) Phase III (Definitive Trial) Available to Patients Decrease Oxidative Stress and/or Increase Mitochondrial Function Decrease Iron Toxicity & Increase Fe-S clusters Increase Frataxin or FA gene Expression Gene Therapy Frataxin Protein- Replacement High-Throughput Screening for New Drug Discovery Iron Chelator – Deferiprone ApoPharma Pioglitazone INSERM - Hôpital Robert Debré FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts. 7 Clinical Trials 8 Approaches FA Treatment Pipeline - 2009 Varenicline / Chantix University of South Florida And Children’s Hospital of Phila Neuro- Transmission Modifying Therapy Neuro- protection EGb761 IPSEN Lu AA24493 (cEPO) Lundbeck

18. Clinical Trials A clinical trial is a biomedical or health-related RESEARCH studies in HUMAN beings that follow a pre- defined PROTOCOL. –Strict instructions for conducting the studies –Double-blind placebo controlled trial –Who can participate – inclusion and exclusion criteria, number of subjects – When study visits need to occur, safety and efficacy measures –Plan for data safety and monitoring, analysis of study results 18

19. Clinical Trials – Be Informed How do you know if a trial is happening? –ClinicalTrials.gov –FARA patient registry – www.curefa.org/registrywww.curefa.org/registry Are you a candidate for the clinical trial? –Inclusion and exclusion criteria age, gender, the type and stage of a disease, previous treatment history, and other medical conditions identify appropriate participants and keep them safe and help ensure that researchers will be able to answer the questions they plan to study –Before joining a clinical trial, a participant must qualify for the study. 19

20. Clinical Trials – Be Informed How do you decide about participation in a trial? –Informed consent is the process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. Benefits and risks Procedures or tests required How will the trial affect your daily life and how long will it last…. Travel??? Who is in charge of my care? Payment, reimbursement Results 20

21. Clinical Trials – Be Informed Can a participant leave a clinical trial after it has begun? Yes. A participant can leave a clinical trial, at any time. What if you don’t qualify for the trial, can you still get the drug? –Expanded access - FDA regulations enable manufacturers of investigational new drugs to provide for "expanded access" use of the drugFDA clinical investigators are actively studying the experimental treatment in well-controlled studies, or all studies have been completed there must be evidence that the drug may be an effective treatment in patients the drug cannot expose patients to unreasonable risks given the severity of the disease to be treated. 21

22. Clinical Research in FA Current Clinical Research Studies in FA –Collaborative Clinical Research Network in FA – Natural history –Cardiac MRI Study, Ohio State University –Hearing study, Wilmington, DE Current Clinical Trials in FA –Phase III – Idebenone – US extension study (Philadelphia, PA and Los Angeles) and European study –Phase II – Chantix (Philadelphia, PA and Tampa, FL) –Phase II – cEPO (Europe) –Phase II – Pioglitizone (France) –Phase II – Deferiprone extension study (Europe, Canada) Upcoming –Phase II – A0001 (Philadelphia, PA) FARA Patient Registry Be informed and carefully consider participation.

23. Collaborative Clinical Research Network in Friedreich’s Ataxia (CCRN in FA) PI: Dr. David R. Lynch Sites: Children’s Hospital of Philadelphia, PA – Dr. David Lynch University of California Los Angeles, CA – Dr. Susan Perlman University of Chicago, IL – Dr. Chris Gomez University of Minnesota, MN – Dr. Khalaf Bushara University of Iowa, IA – Dr. Kathy Matthews University of Rochester, NY – Dr. Bernard Ravina University of Florida – Dr. Tee Ashizawa and Dr. Sub Subramony Murdoch Childrens Research Institute, Australia – Dr. Martin Delatycki 23

24. Hope, Confidence and Urgency Brain not affected We understand the cause of the disease Gene is intact – just need to make more frataxin We are approaching treatment from multiple directions Treatment trials are now! Treatment will come through an iterative process –Slow, stop, and reverse –Newborn screening Insights into FA are having impact on advancing treatments for other conditions We have a dedicated fast-moving and highly collaborative research community 24

25. Hope, Confidence and Urgency 25 Evan Luebbe and Tiki Barber Keith Andrus Samantha and Alexandria Bode with Mary Stuart Masterson Acting alone, there is very little we can accomplish. Acting together, there is very little we will NOT accomplish!