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1
V950Amyloid- (A)/OMPC
Conjugate Vaccine Program
January, 2007
Laura Rosen, M.D., Ph.D.Clinical Pharmacology
2
Alzheimer’s Disease Epidemiology • 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 5/9/20012. Internal Report: Janssen Pharmaceutica Products, L.P., June 1999
2040 – 14,000,0002040 – 14,000,000
Today – 4,000,000Today – 4,000,000
3
Alzheimer’s Disease Clinical Progression Through Stages
Mild Moderate
• Short term memory loss
• Language problems
• Mood swings
• Personality changes
• Diminished judgment
• 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)
• Gait, incontinence, motor disturbances
• Bedridden• Unable to perform
ADL• Nursing home
placement needed
Stage
Symptoms
Severe
4
Cognitive Assessment: Disease Modification or Symptomatic Improvement?
Disease modifying
Time
Fu
nct
ion
al
Ab
ilit
y
Slowing ofprogression
Symptomaticbenefit
Untreated
Disease modifying
SymptomaticImprovement
. ..Start Rx
Assess
MK
Pbo
Characterize with Early Frequent Assessment of Cognitive domains:•Long Term Memory•Language•Attention•Executive Function
5
years
Alzheimer Disease Pathophysiology•3 classic pathological hallmarks:
• amyloid plaques, neurofibrillary tangles, neuronal degeneration • Brain atrophy on MRI: surrogate marker in clinical trials
6
Proteins involved in cell growth,differentiation, synaptic plasticity
-secretase(BACE)
-secretase
Apeptide toxic oligomers
plaquesAPP
Gene promoter
RNA
Notch
Furin
AICD NICD
APeptide and the Amyloid Hypothesis
7
-secretase(BACE)
-secretase
Apeptide toxic oligomers
plaquesAPP Notch
Furin
4. AD Vaccine 5. ADDL mAbs
1. Gamma Secretase (GS) Inhibitors2. Gamma Secretase (GS) Modulators
3. BACE Inhibitors
APeptide and the Amyloid Hypothesis
8
Merck AD Vaccine Program – Background • Immunization with Aβ42 leads to:
• Anti-A 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 B-cells)
• 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)
9
V950 Construct – Final L-001509582/OMPC
Ac-EFRHDSGY(Aha)-Lys-Lys(BrAc)-OMPC
Ac-AEDVGSNK(Aha)BrAc = BromoacetylAha = 6-aminohexanoic acidOMPC = N. meningitidis outer
membrane protein complex
Multiple antigenic peptide (MAP) composed of two non-contiguous 8-aa epitopes (3-10 and 21-28) from A
Bromoacetyl peptide conjugated to thiolated OMPC – same chemistry as PedvaxHIB™ and the Bivalent Influenza Peptide Conjugate Vaccine
Peptide loading per OMPC molecule: ca. 2000
10
Non-Human Primate (NHP) – Immunogenicity of V950
(3-10)(21-28)MAP-OMPC immunized monkeys (n=3)
(3-10)(21-28)MAP-OMPC induces antibody responses to the parental A peptide as well as the compositional 8mer peptides
0 4 8 12 1610 2
10 3
10 4
10 5
10 6
IgG
tit
er (
anti
-A
3-10
)
0 4 8 12 1610 2
10 3
10 4
10 5
10 6
IgG
tit
er (
anti
-A
21-2
8)
0 4 8 12 1610 2
10 3
10 4
10 5
10 6
IgG
tit
er (
anti
-A
40)
Weeks post first immunization
11
Human tissue amyloid 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
Some studies suggest better correlation with Elan Phase II efficacy than antibody titers
PB PD3
Human AD brain tissue immunoreactivity
Peptide preabsorption of PD3
+ 0.5ug/ml pepPD3
NHP – V950-induced Antibody Binding to Brain Tissue
12
Immunization with (3-10)(21-28)MAP-OMPC significantly increases plasma Aβ1-40 level – may indicate clearance of Aβ from CNS
0
50
100
150
200
250
300
350 A(3-10)/OMPC
A(21-28)/OMPC
(3-10)(21-28)MAP/OMPC
4PD1
8PD2
12PD3
Weeks post first immunization
Pla
sma
A 1
-40
leve
ls(%
pre
-ble
ed)
NHP – Plasma Aβ Peptide as Potential Biomarker
13
1.E+02
1.E+03
1.E+04
1.E+05
0 4 8 12 16 20 24 28 32 36 40
Weeks post vaccination
An
ti-A
1-
40 G
MT
+/-
s.e.
MAA
MAA+IMX
Vaccine Formulation: MAA/ISCOMATRIX®
Vaccine: 5 mcg A1-18-OMPC in MAA or MAA/ 100 mcg ISCOMATRIX® (MAA/IMX) Rhesus monkeys: 3/group, immunized i.m. @ weeks 0, 8 and 24
A 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
14
Clinical Program – Elan/Wyeth Phase I
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):
Month
Panel: 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 18
15
Clinical Program – Elan/Wyeth Phase II Study Design
372 AD patients; 300 active, 72 placebo 250 ug vaccine, 50 ug QS21 adjuvant Only 2-3 injections before trial halted after
meningoencephalitis Meningoencephalitis (ME)
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
No effect on ADAS-Cog or DAD Less decline on composite Neuropsych Test Battery
(p=0.02)
16
Endpoints for V950
• Primary:• Safety: clinical safety & tolerability• Immunogenicity (anti-A IgG Luminex assay)
• Secondary:• Safety: T-cell activation (-IFN Elipsot assay)• Immunogenicity: persistence
• Exploratory:• Efficacy: CSF Acognitive testing
17
V950 Key Safety IssuesV950 Key Safety Issues Safety
6% meningoencephalitis with full A42 vaccine Preclinical species cannot predict human response FIM must be in AD pts; show lack of A-specific T-cell
activation
Immunogenicity: use of IMX adjuvant Saponin-based adjuvant may have contributed to Elan
trial’s meningoencephalitis by heightening Th1 response to A
18
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
19
• 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
Panel A0.5 ug V950 / 0 ug IMX
Panel Y50 ug V950 / 60 ug IMX
Stage I
Panel B5 ug V950 / 0 ug IMX
Panel C0.5 ug V950 / 20 ug IMX
Stage II
Panel E5 ug V950 / 20 ug IMX
Panel X0.5 ug V950 / 60 ug IMX
Panel D50 ug V950 / 0 ug IMXStage III
Panel F50 ug V950 / 20 ug IMX
Panel G5 ug V950 / 60 ug IMXStage IV
Dose escalate V950 only
Dose escalate IMX only
V950 FIM Dose Escalation
Low dosesMid dosesHigh doses
20
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
21
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
22
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:• IV, IM or oral corticosteroids• Warfarin, heparin or ticlopidine• Regular use of narcotic analgesics or benzodiazepines• Drugs with significant central anticholinergic or antihistaminic
effects
23
Concomitant Medications - Information• Corticosteroids – should NOT be taken within 1
month of vaccination• 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
• permitted if medically necessary• benzotropine, trihexyphenidyl, dicyclomine,
diphenhydramine, cyproheptadine, diphenoxylate, hydroxyzine, meclizine, perchlorperazine, promethazine
24
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)
25
Confidentiality Policy
Information surrounding Merck’s products and clinical studies is confidential 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