Transcript (CERE-120) In Parkinson`s Disease

ASENT 12th Annual Meeting
March, 2010
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
Ceregene Pipeline
Program
Parkinson’s
Disease
Huntingtons
Disease
Alzheimer’s
Disease
Product
Preclinical
Research
Preclinical
Devel
CERE-120
(AAV-NTN)
CERE-110
(AAV-NGF)
Retinitis
Pigmentosa
Macular
Degeneration
CERE-140
(AAV-NT4)
Glaucoma
Amyotrophic
Lateral Sclerosis
(ALS)
*
CERE-135
(AAV-IGF1)
Phase 2 clinical trial completed Nov 2008
** New Phase 1/2 clinical trial currently enrolling
Slide 2
Clinical
Phase 1
Clinical
Phase 2
Clinical
Phase 3
*
**
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
CERE-120 (AAV2-neurturin)
L-ITR
R-ITR
CAG promoter
NEURTURIN cDNA
hGH polyA
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 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.
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
UPDRS III Motor "OFF": Mean Change From Baseline (+/- SEM)
Improvement
Primary Efficacy Endpoint: Improvement in
UPDRS Motor “Off” (Part III) at 12 Months
0
-1
-2
-3
-4
p=0.91
-5
-6
-7
-8
-9
CERE-120
Sham Surgery
-10
eline
Bas
th 3
Mon
th 6
Mon
th 9
Mon
th 12
Mon
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
UPDRS Motor "off" (Change from Baseline +/- SEM)
Improvement
Change From Baseline in UPDRS (Part III)
Motor Score “off” (Blinded data; N=30)
0
-2
-4
-6
-8
-10
Sham Surgery
p=0.025*
CERE-120
-12
-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
defined off condition as covariate. Note: at 18 mos,
1416
subjects have scores; therefore 16 subjects: LOCF
Page
Outcome Measures With A Trend
for Difference Between Groups (p<0.1)
12 months
18 months
p Value
at
12 Months
Sham
Surgery:
Change
from
Baseline
CERE-120:
Change from
Baseline
at
18 Months
-0.32
0.002
1.27
-0.26
0.02
-2.25
-3.35
0.4
0.82
-3.32
0.07
UPDRS II “on”
1.6
-0.89
0.03
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
OUTCOME
MEASURE
Sham
Surgery:
Change from
Baseline
CERE-120:
Change
from
Baseline
UPDRS I
0.95
UPDRS II "off"
Not tested
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PDQ-39
1.20
-2.83
0.03
p Value
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
1904L
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
Normal axonal
transport
Impaired axonal
transport
CERE-120
Injection
Striatum
Striatum
CERE-120
Injection
Neurturin
Neurturin
TH
TH
NRTN / CERE-120
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
Putamen
Substantia Nigra
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