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V950Amyloid- (A)/OMPC

Conjugate Vaccine Program

January, 2007

Laura Rosen, M.D., Ph.D.Clinical Pharmacology

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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

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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

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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

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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

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-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

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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)

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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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• 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

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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:• 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• 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

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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 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