ASENT 12 th Annual Meeting
March, 2010
AAV2-NRTN (CERE120) In Parkinson’s Disease:
Phase 2 Trial Results and Path Forward
Joao Siffert, MD
Chief Medical Officer
Ceregene, Inc.
San Diego, CA

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

Parkinson’s Disease: Profound Nigrostriatal
Dopamine Neuron Degeneration


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)

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
CAG promoter NEURTURIN cDNA
R-ITR hGH polyA
AAV Capsid


18 separate pharmacology, efficacy and safety/tox studies conducted over 2 year period, establishing:
•
Excellent control of protein expression via orderly doseresponse
–
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.


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


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

Primary Efficacy Endpoint: Improvement in
UPDRS Motor “Off” (Part III) at 12 Months
-8
-9
-10
-5
-6
-7
0
-1
-2
-3
-4
Baseline
CERE-120
Sham Surgery
Mon th 3
Mon th 6
Mon th 9 p=0.91
Mon th 1
2


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

Change From Baseline in UPDRS (Part III)
Motor Score “off” (Blinded data; N=30)
0
-2
-4
-6
-8
-10
-12
Sham Surgery
CERE-120 p=0.025*
-14 target clinical response
-16
Baseline Month 3 Month 6 Month 9 Month 12 Month 15 Month 18
* ANCOVA model with a main effect for treatment group and baseline UPDRS Part III motor score in the practically

Outcome Measures With A Trend for Difference Between Groups (p<0.1)
12 months
OUTCOME
MEASURE
Sham
Surgery:
Change from
Baseline
CERE-120:
Change from
Baseline p Value at
12 Months
18 months
Sham
Surgery:
Change from
Baseline
CERE-120:
Change from
Baseline p Value at
18 Months
0.02
0.07
UPDRS I
UPDRS II "off"
UPDRS II “on”
UPDRS III "off"
PD Diary "off"
PD Diary "on without troubling dyskinesia”
0.95
-2.25
1.6
-6.95
-0.23 hrs
0.80 hrs
-0.32
-3.35
-0.89
-7.19
-1.00 hr
1.00 hr
0.002
0.4
0.03
0.9
0.07
0.3
1.27
0.82
-5.64
-0.52 hrs
0.55 hrs
-0.26
-3.32
Not tested
-11.21
-1.48 hr
2.25 hr
0.025
0.09
0.05
0.02
Timed Walking "off" -3.00 sec
PDQ-39 1.20
-2.65 sec
-2.83
0.6
Page 17
0.03
-0.55 sec -8.11 sec
Not tested

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

Clear NRTN Expression in Putamen But Not in Substantia Nigra
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

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
TH
Normal axonal transport
CERE-120
Injection
Striatum
Neurturin
TH
NRTN / CERE-120
Impaired axonal transport
CERE-120
Injection
Striatum
Neurturin
TH
NRTN / CERE-120
?
?
Substantia Nigra
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
Page 22
Putamen
Substantia Nigra