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

Slide 2 ProgramProduct Preclinical Research Preclinical Devel Clinical Phase 1 Clinical Phase 2 Clinical Phase 3 Parkinson’s Disease CERE-120 (AAV-NTN) Huntingtons Disease Alzheimer’s Disease CERE-110 (AAV-NGF) Retinitis Pigmentosa CERE-140 (AAV-NT4) Macular Degeneration Glaucoma Amyotrophic Lateral Sclerosis (ALS) CERE-135 (AAV-IGF1) Ceregene Pipeline * Phase 2 clinical trial completed Nov 2008 ** New Phase 1/2 clinical trial currently enrolling * **

Parkinson’s Disease: Profound Nigrostriatal Dopamine Neuron Degeneration

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)

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

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

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

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

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

Injecting CERE-120 Into Targeted Site Within Putamen

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.

Page 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)

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

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

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

Page 16 Change From Baseline in UPDRS (Part III) Motor Score “off” (Blinded data; N=30) 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 Improvement

Page 17 Outcome Measures With A Trend for Difference Between Groups (p<0.1) 12 months18 months OUTCOME MEASURE Sham Surgery: Change from Baseline CERE-120: Change from Baseline p Value at 12 Months Sham Surgery: Change from Baseline CERE-120: Change from Baseline p Value at 18 Months UPDRS I UPDRS II "off" UPDRS II “on” Not tested UPDRS III "off" PD Diary "off"-0.23 hrs-1.00 hr hrs-1.48 hr0.09 PD Diary "on without troubling dyskinesia” 0.80 hrs1.00 hr hrs2.25 hr0.05 Timed Walking "off"-3.00 sec-2.65 sec sec-8.11 sec0.02 PDQ Not tested

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

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

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

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

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