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

Joao Siffert, MDChief Medical Officer

Ceregene, Inc.San Diego, CA

ASENT 12th Annual Meeting

March, 2010

Slide 2

Program ProductPreclinical 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-ITR R-ITRCAG 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 growthfactor 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

Imp

rove

men

t

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

Imp

rove

men

t

Page 17

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

12 months 18 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 0.95 -0.32 0.002 1.27 -0.26 0.02

UPDRS II "off" -2.25 -3.35 0.4  0.82 -3.32 0.07

UPDRS II “on” 1.6 -0.89 0.03 Not tested

UPDRS III "off" -6.95 -7.19 0.9  -5.64 -11.21 0.025

             

PD Diary "off" -0.23 hrs -1.00 hr  0.07 -0.52 hrs -1.48 hr 0.09

PD Diary "on

without troubling

dyskinesia”

0.80 hrs 1.00 hr  0.3 0.55 hrs 2.25 hr 0.05

           

Timed Walking "off" -3.00 sec -2.65 sec 0.6  -0.55 sec -8.11 sec 0.02

             

PDQ-39 1.20 -2.83 0.03 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

CERE-120 Injection

Normal axonal transport

NeurturinNeurturin

NRTN / CERE-120

?

TH

TH

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