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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
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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
***
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Parkinson’s Disease: Profound Nigrostriatal
Dopamine Neuron Degeneration
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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)
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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
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L-ITR R-ITRCAG promoter NEURTURIN cDNA
hGH polyA
CERE-120 (AAV2-neurturin)
AAV Capsid
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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
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Delivery Paradigm: Distribute growthfactor throughout major areas of Putamen…
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… While at same time, avoiding protein
spread outside targeted Putamen…
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Injecting CERE-120 Into Targeted Site Within Putamen
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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.
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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)
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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
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Imp
rove
men
t
p=0.91
Primary Efficacy Endpoint: Improvement in UPDRS Motor “Off” (Part III) at 12 Months
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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
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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
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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
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Additional Information Was Be Gained From Autopsy Results in Two Study Subjects
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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
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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
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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
?
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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