Download Panel A 0.5 ug V950 / 0 ug IMX

V950
Amyloid-b (Ab)/OMPC
Conjugate Vaccine Program
January, 2007
Laura Rosen, M.D., Ph.D.
Clinical Pharmacology
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Alzheimer’s Disease Epidemiology
Today – 4,000,000
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2040 – 14,000,000
Alzheimer’s disease mostly affects
persons over 65 years of age1
Affects 10% of people > 65 years old1
Affects 50% of people > 85 years old1
If current trends continue, the incidence
of AD could double every 20 years2
Early AD is subtle—the initial signs and
symptoms are easily missed
Less than half of AD patients are
diagnosed
Undiagnosed AD patients face
unnecessary added social, financial, and
medical problems
Early diagnosis and appropriate
intervention may lessen disease burden
1. Alzheimer’s Association. Available at: www.alz.org/hc/overview/stats.htm. Accessed 5/9/2001
2. Internal Report: Janssen Pharmaceutica Products, L.P., June 1999
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Alzheimer’s Disease Clinical
Progression Through Stages
Stage
Mild
• Short term
Symptoms memory
loss
• Language
problems
• Mood
swings
• Personality
changes
• Diminished
judgment
Moderate
• Behavioral,
personality
•
changes
• Unable to learn/recall
new information
• Long-term memory
affected as well
• Wandering, agitation,
aggression,
confusion
• Require assistance
with Activities of
Daily Living (ADL)
Severe
• Gait, incontinence,
motor
disturbances
• Bedridden
• Unable to perform
ADL
• Nursing home
placement needed
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Functional Ability
Cognitive Assessment: Disease Modification
or Symptomatic Improvement?
. .
.
Characterize with Early Frequent
Assessment of Cognitive domains:
•Long Term Memory
•Language
•Attention
•Executive Function
MK
Start Rx
Pbo
Assess
Time
Slowing of
Disease modifying
progression
Symptomatic Symptomatic
benefit
Improvement
Untreated
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Alzheimer Disease Pathophysiology
•3 classic pathological hallmarks:
• amyloid plaques, neurofibrillary tangles, neuronal degeneration
• Brain atrophy on MRI: surrogate marker in clinical trials
years
4
Ab Peptide and the Amyloid Hypothesis
APP
Ab peptide 
toxic oligomers
 plaques
b-secretase
(BACE)
Notch
Furin
g-secretase
AICD
NICD
RNA
Gene promoter
Proteins involved
in cell growth,
differentiation,
synaptic plasticity
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Ab Peptide and the Amyloid Hypothesis
3. BACE Inhibitors
APP
b-secretase
(BACE)
Ab peptide 
toxic oligomers
 plaques
4. AD Vaccine
5. ADDL mAbs
Notch
g-secretase
Furin
1. Gamma Secretase (GS) Inhibitors
2. Gamma Secretase (GS) Modulators
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Merck AD Vaccine Program – Background
• Immunization with Aβ42 leads to:
• Anti-Ab antibodies, reduced Aβ levels in the brain
• Stabilized cognitive function in animals, one human study
(Elan)
• Elan/Wyeth AN-1792 trial halted for
meningoencephalitis
• Invasion of brain by T-cells (vs. just antibodies from Bcells)
• Reduced plaque load noted on post-mortem evaluation
• Memory improvement/stabilization in vaccine responders
• Merck V950 approach
• 8-amino acid peptides to avoid T-cell responses, ?
meningoenceph
• OMPC-conjugated, Iscomatrix (IMX) adjuvant
(proprietary w/ CSL)
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V950 Construct – Final
L-001509582/OMPC
Ac-EFRHDSGY(Aha)-Lys-Lys(BrAc)-OMPC
Ac-AEDVGSNK(Aha)
BrAc = Bromoacetyl
Aha
= 6-aminohexanoic acid
OMPC = N. meningitidis outer
membrane protein complex
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Multiple antigenic peptide (MAP) composed of two non-contiguous 8aa epitopes (3-10 and 21-28) from Ab
Bromoacetyl peptide conjugated to thiolated OMPC – same chemistry
as PedvaxHIB™ and the Bivalent Influenza Peptide Conjugate Vaccine
Peptide loading per OMPC molecule: ca. 2000
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Non-Human Primate (NHP) –
Immunogenicity of V950
(3-10)(21-28)MAP-OMPC immunized monkeys (n=3)
10 4
10 3
0
4
8
12 16
IgG titer (anti-Ab21-28)
10 5
10 2
10 6
10 6
IgG titer (anti-Ab3-10)
IgG titer (anti-Ab40)
10 6
10 5
10 4
10 3
10 2
10 5
10 4
10 3
10 2
0
4
8
12 16
0
4
8
12 16
Weeks post first immunization

(3-10)(21-28)MAP-OMPC induces antibody responses to the parental Ab
peptide as well as the compositional 8mer peptides
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NHP – V950-induced Antibody Binding
to Brain Tissue
 Human tissue amyloid
Human AD brain tissue immunoreactivity
plaque immunoreactivity
(hTAPIR)
 (3-10)(21-28)MAP-OMPC
anti-sera bind senile
plaques in AD brain
 Completely blocked by
pre-absorption with
(3-10)(21-28)MAP
PB
PD3
Peptide preabsorption of PD3
 Some studies suggest
better correlation with
Elan Phase II efficacy
than antibody titers
PD3
+ 0.5ug/ml pep
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NHP – Plasma Aβ Peptide as Potential
Biomarker
(3-10)(21-28)MAP/OMPC
Plasma Ab1-40 levels
(% pre-bleed)
350
Ab(3-10)/OMPC
Ab(21-28)/OMPC
300
250
200
150
100
50
0
4
PD1
8
PD2
12
PD3
Weeks post first immunization
 Immunization with (3-10)(21-28)MAP-OMPC significantly increases
plasma Aβ1-40 level – may indicate clearance of Aβ from CNS
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Vaccine Formulation: MAA/ISCOMATRIX®
Vaccine: 5 mcg Ab1-18-OMPC in MAA or MAA/ 100 mcg ISCOMATRIX® (MAA/IMX)
Rhesus monkeys: 3/group, immunized i.m. @ weeks 0, 8 and 24
Anti-Ab 1-40 GMT +/- s.e.
1.E+05
1.E+04
MAA
MAA+IMX
1.E+03
1.E+02
0
4
8
12
16
20
24
28
32
36
40
Weeks post vaccination
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Ab conjugate in MAA/ISCOMATRIX® elicited significantly
higher antibody titers than that in MAA
Merck has an exclusive license for ISCOMATRIX® use in
Alzheimer’s and related diseases
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Clinical Program – Elan/Wyeth Phase I
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80 AD patients; 64 active, 16 placebo
4 panels at 50 or 250 ug vaccine + 50 or 100 ug QS21 adjuvant
Immunizations at 0, 1, 3, 6 mo; extensions at 9, 12, 15, 18 mo
Generally S&T, no dose-related AEs; one case meningoencephalitis
diagnosed post-mortem (patient died 1 yr after last dose of PE; 1.6%
Immunogenicity: antibody titers after 4 injections (6 months):
Panel:
Month
A
B
C
D
Vaccine:
50 ug
50 ug
250 ug
250 ug
QS21:
50 ug
100 ug
50 ug
100 ug
0
Imm 1
0
0
0
0
1
Imm 2
0
0
7
0
3
Imm 3
20
13
27
0
6
Imm 4
20
13
33
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Clinical Program – Elan/Wyeth Phase II
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Study Design
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Meningoencephalitis (ME)
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372 AD patients; 300 active, 72 placebo
250 ug vaccine, 50 ug QS21 adjuvant
Only 2-3 injections before trial halted after
meningoencephalitis
18 / 300 active (0/72 pbo) developed ME (= 6%)
12 fully recovered; 6 with neuro sequelae
One case after 1 injection vaccine; 16 cases after two; 1
after 3
Median time to sx = 75 days / 40 days after first / last
immunization
Efficacy in antibody responders without ME
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No effect on ADAS-Cog or DAD
Less decline on composite Neuropsych Test Battery
(p=0.02)
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Endpoints for V950
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Primary:
Safety: clinical safety & tolerability
Immunogenicity (anti-Ab IgG Luminex assay)
Secondary:
Safety: T-cell activation (g-IFN Elipsot assay)
Immunogenicity: persistence
Exploratory:
Efficacy: CSF Ab, cognitive testing
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V950 Key Safety Issues
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Safety
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6% meningoencephalitis with full Ab42 vaccine
Preclinical species cannot predict human response
FIM must be in AD pts; show lack of Ab-specific T-cell
activation
Immunogenicity: use of IMX adjuvant
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Saponin-based adjuvant may have contributed to
Elan trial’s meningoencephalitis by heightening Th1
response to Ab
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V950 PN001: Study Design
• A randomized, double-blind (with in-house blinding),
placebo-controlled study to assess the safety,
tolerability, and immunogenicity of V950 in patients
with mild-to-moderate AD
• ~13 sites worldwide (8 US, 5 ex-US)
• ~7 panels of N=10 per panel (8 active, 2 placebo)
• Immunizations at 0-, 2-, and 6-months; 3-year
safety follow-up
• Staged dose escalation:
• Start low dose vaccine (V950) with Merck Aluminum
Adjuvant (MAA) but no IMX
• In animals, minimal immunoogenicity of V950 without
IMX
• If similar in humans, dose escalate the vaccine and
IMX components in parallel
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Stage I
V950 FIM
Dose Escalation
Panel B
5 ug V950 / 0 ug IMX
Stage II
Stage III
Panel A
0.5 ug V950 / 0 ug IMX
Panel D
50 ug V950 / 0 ug IMX
Stage IV
Panel C
0.5 ug V950 / 20 ug IMX
Panel E
5 ug V950 / 20 ug IMX
Panel F
50 ug V950 / 20 ug IMX
Low doses
Mid doses
High doses
Panel X
0.5 ug V950 / 60 ug IMX
Panel G
5 ug V950 / 60 ug IMX
Dose escalate V950 only
Dose escalate IMX only
Panel Y
50 ug V950 / 60 ug IMX
• Key Assumption: V950 will not be immunogenic without IMX (animal data)
• IF Panel A is completely negative, cautiously dose escalate EITHER V950 dose OR IMX
dose in parallel panels to be conducted concurrently
• Panels X and Y may be added in future depending on S&T, immunogenicity of Panels A-G
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Main Inclusion Criteria
• Patients have a diagnosis of probable AD
(NINCDS-ADRDA)
• Patients’ MMSE is between 18 and 26, inclusive
• Patients have an MHIS of ≤4
• Patients’ MRI scan at screening is consistent with
AD
• Patient has a reliable informant/caregiver
• Medications for conditions other than AD have
been stable for at least 4 weeks prior to
screening
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Main Exclusion Criteria
• Patient has a neurodegenerative disorder other
than AD
• Patient has a history of:
• stroke or multiple lacunar infarcts
• History (within 2 years prior to screening) or current
evidence of a psychotic disorder, a major untreated
depressive disorder, or substance abuse
• Note: Patients on stable doses of antidepressants for
≥3 months and in remission are eligible to participate
• History or significant cardiac disease, dysrhythmia
• History of malignancy within the last 5 years
• Abnormal B12, TSH, folate
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Main Exclusion Criteria, cont’d
• Patient has initiated any AD treatment less than 3
months prior to screening (including memantine,
cholinesterase inhibitors OR has discontinued any of
these treatments <2 months prior to screening
• Patient is taking any of the following medications:
• within 3 months prior to screening:
• Tacrine
• Anti-Parkinsonian medications
• Regular use of conventional neuroleptics
• within 1 month prior to screening:
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IV, IM or oral corticosteroids
Warfarin, heparin or ticlopidine
Regular use of narcotic analgesics or benzodiazepines
Drugs with significant central anticholinergic or
antihistaminic effects
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Concomitant Medications - Information
• Corticosteroids – should NOT be taken within 1
month of vaccination
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i.e., Study Month -1 through Month 3; Month 5 through
Month 7
From screening through Month 12, corticosteroids should be
restricted to <14 days for a single course and <28 days per
year
methotrexate
• Narcotic analgesics, benzodiazapines, and other
drugs with anticholinergic or antihistaminic effects
– should NOT be taken within 12 hours preceding
cognitive testing
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•
permitted if medically necessary
benzotropine, trihexyphenidyl, dicyclomine,
diphenhydramine, cyproheptadine, diphenoxylate,
hydroxyzine, meclizine, perchlorperazine, promethazine
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Concomitant Medications – Information
(cont’d)
• No investigational vaccines may be administered
during the study
• Licensed vaccines – may be administered:
• Live virus – administered ≥21 days prior to each
vaccination or following postvaccination blood sample
(Postdose 3)
• Inactivated – administered ≥14 days prior to each
vaccination or following postvaccination blood sample
(Postdose 4)
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Confidentiality Policy

Information surrounding Merck’s products and
clinical studies is confidential
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Protocols
Confidential Investigator Brochure (CIB)
Other study related materials
Disclosures to any third parties other than those
involved in approval, supervision, or conduct of
the study is prohibited
It is your obligation to take precautions to protect
such information from loss, inadvertent
disclosure, or access by third parties
Merck sincerely appreciates your attention to this
important matter
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