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AAV2-NRTN (CERE-120) In Parkinson’s Disease: Phase 2 Trial Results and Path Forward

AAV2-NRTN (CERE-120) In Parkinson’s Disease: Phase 2 Trial Results and Path Forward. ASENT 12 th Annual Meeting March, 2010. Joao Siffert, MD Chief Medical Officer Ceregene, Inc. San Diego, CA. Ceregene Pipeline. *. **. * Phase 2 clinical trial completed Nov 2008

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AAV2-NRTN (CERE-120) In Parkinson’s Disease: Phase 2 Trial Results and Path Forward

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  1. AAV2-NRTN (CERE-120) In Parkinson’s Disease: Phase 2 Trial Results and Path Forward ASENT 12th Annual Meeting March, 2010 Joao Siffert, MD Chief Medical Officer Ceregene, Inc. San Diego, CA

  2. Ceregene Pipeline * ** • * Phase 2 clinical trial completed Nov 2008 • ** New Phase 1/2 clinical trial currently enrolling

  3. Parkinson’s Disease: Profound Nigrostriatal Dopamine Neuron Degeneration

  4. Neurotrophic Factors Naturally occurring proteins essential for neuron growth, function and survival Involve many varieties Different neurons use different neurotrophic factors Nigrostriatal dopamine neurons use GDNF and NRTN (neurturin)

  5. Neurotrophic Factor Protein In PD Neurology, 2003 Ann Neurol, 2006 GDNF protein delivery into either the cerebral ventricles or directly into the putamen failed to show clinical benefits

  6. L-ITR R-ITR CAG promoter NEURTURIN cDNA hGH polyA CERE-120 (AAV2-neurturin) AAV Capsid

  7. CERE-120 Nonclinical Results 18 separate pharmacology, efficacy and safety/tox studies conducted over 2 year period, establishing: Excellent control of protein expression via orderly dose-response Extensive coverage of striatum and substantia nigra, yet confined to intended target area No further spread after 1 month Steady, continuous NRTN expression confirmed beyond 2 years Extensive evidence of efficacy in range of rodent and monkey models relevant to PD Strong safety/toxicity profile, over range of excessive doses, up to 1 year in monkeys and rats No toxicity seen in any animals

  8. Delivery Paradigm: Distribute growth factor throughout major areas of Putamen…

  9. … While at same time, avoiding protein spread outside targeted Putamen…

  10. Injecting CERE-120 Into Targeted Site Within Putamen

  11. Interpretation: The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available.

  12. CERE-120 Phase 2 in PD Randomized, double blind, sham surgery controlled study (efficacy and safety) Nine leading movement disorder sites in USA N=58, randomized 2:1 ratio (CERE-120 : sham surgery) Bilateral intraputaminal injections One dose level (higher of two Phase 1 doses) Page 12

  13. Phase 2 Efficacy at 12 months • Primary endpoint (UPDRS-motor off) failed to distinguish CERE-120 from control group • Both groups showed significant improvement over baseline • Several secondary endpoints did suggest modest clinical improvement from CERE-120 at 12 months and also at 18 months

  14. Primary Efficacy Endpoint: Improvement in UPDRS Motor “Off” (Part III) at 12 Months p=0.91 Improvement

  15. Efficacy Data Beyond 12 mos • Of 58 patients enrolled in the Phase 2 study • 30 patients completed a blinded assessment at 15 months • Of those 30 patients, 14 also completed a blinded assessment at 18 months • Opportunity to evaluate the longer-term effects of CERE-120 under controlled, blinded conditions

  16. Improvement p=0.025* target clinical response * ANCOVA model with a main effect for treatment group and baseline UPDRS Part III motor score in the practically defined off condition as covariate.Note: at 18 mos, 14 subjects have scores; therefore 16 subjects: LOCF Change From Baseline in UPDRS (Part III) Motor Score “off” (Blinded data; N=30)

  17. Outcome Measures With A Trend for Difference Between Groups (p<0.1)

  18. Additional Information Was Be Gained From Autopsy Results in Two Study Subjects

  19. Clear NRTN Expression in Putamen But Not in Substantia Nigra 1904L Clear NRTN Signal in Study Subject’s Putamen However, despite adequate putaminal expression of NRTN, very little to no NRTN signal was seen in substantia nigra of the same individuals

  20. NRTN and Tyrosine Hydroxylase (TH) in the Human Putamen Only sparse evidence of TH induction, a key biochemical marker of dopamine neuron integrity and function

  21. TH CERE-120 Bioactivity: Simulation in Normal versus PD Brain following Striatal Administration Normal axonal transport Impaired axonal transport CERE-120 Injection CERE-120 Injection Striatum Striatum Neurturin Neurturin TH TH NRTN / CERE-120 NRTN/ CERE-120 ? ? Substantia Nigra SubstantiaNigra

  22. Putamen Substantia Nigra Key Modifications for CERE-120 Dosing in Current Phase 1/2 Study • Add CERE-120 administration to the substantia nigra • Increase CERE-120 dose to putamen

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