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V950 Amyloid-b (Ab)/OMPC Conjugate Vaccine Program January, 2007 Laura Rosen, M.D., Ph.D. Clinical Pharmacology 0 Alzheimer’s Disease Epidemiology Today – 4,000,000 • • • • • • • • 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 1 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 2 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 3 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 5 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 6 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) 7 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 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 8 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 9 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 10 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 11 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 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 12 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): 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 18 13 Clinical Program – Elan/Wyeth Phase II Study Design Meningoencephalitis (ME) 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 No effect on ADAS-Cog or DAD Less decline on composite Neuropsych Test Battery (p=0.02) 14 Endpoints for V950 • • • • • • • • 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 15 V950 Key Safety Issues Safety 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 Saponin-based adjuvant may have contributed to Elan trial’s meningoencephalitis by heightening Th1 response to Ab 16 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 17 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 18 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 19 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 20 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 21 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 22 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) 23 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 24