1. Pharmacogenomics: Implications for CNS Drug Development in the 21st Century Challenges for Development & Approval – Patient & Funding Agency Perspective Valerie A. Cwik, M.D. Senior VP – Research & Medical Director MDA

2. Rare diseases

3. Advances in Duchenne muscular dystrophy Described in 1868 Gene identified in 1986 Dystrophin identified 1987 Nearly all mutations now identified through genetic testing 2009: gene therapy, stop codon readthrough and exon skipping in human clinical trials ~15,000 individuals living with Duchenne/Becker MD in the US Fewer than 250 currently participating in human clinical trials for genetic based therapies

4. “Current therapy is not sufficient for recovery”

5. ALS Paralysis and death within 2-5 years There is no cure and no effective treatments SLOW the disease Stop, reverse, prevent/cure

6. Patient/family perspective Too little focus on rare diseases Too little funding Research moves too slowly Breakthroughs come too late for many

7. Not enough focus or funding Rare diseases Limited research funding (governmental and non- governmental)

8. Challenges to therapy development Rare diseases Limited research funding (governmental and non- governmental) Bottlenecks in moving from the lab into humans Limited interest from pharmaceutical companies Designer drugs Finding potential study subjects Exclusion of potential study subjects “disenfranchised” groups

9. Basic Research Drug Screening Target Identification “Proof-of-Principle” Testing in Animals Translational Research “Preclinical Drug Development” Clinical Research Including Trials MDA Funding in Millions $54.4 $16.9 $7.6 $19.4 $5.0 MDA’s Research Portfolio - Bottlenecks

10. Challenges to therapy development Rare diseases Limited research funding (governmental and non- governmental) Bottlenecks in moving from the lab into humans Limited interest from pharmaceutical companies Designer drugs Finding potential study subjects Exclusion of potential study subjects “disenfranchised” groups

11. Challenges to Therapy Development: Required Resources Burden of disease studies Patient registries Natural history studies Genotyping Biomarkers Clinically meaningful outcome measures

12. Challenges to developing outcome measures: - define “clinically meaningful” - age of individuals - stage of disease - physical abilities - cognitive abilities

13. Challenges to therapy development: “legal” issues Funding agency perspective Scientific due diligence Financial due diligence Tech transfer/IP issues Delays in initiation of clinical trials due to the time it takes for IRB approvals

14. Challenges to therapy development: “technology” issues Electronic communication is impacting the conduct of clinical trials (i.e., traditional research moves too slowly) Social networking and on-line forums such as “Patients Like Me” --- sharing of information Off-label use of approved drugs

15. What’s needed More focus on and funding for rare diseases Conduct needed studies – burden of disease, natural history studies, registry development, biomarker development, etc Speed up the process Reduce bottlenecks Expand studies to include as many patients as possible