Disclosures • Grant/Research Support – Pfizer, Baxter, Elan/J&J/Pfizer, Lilly, NIA/NIH Overview of Recent Clinical Trials: • Consultant ways forward – Abbott, AC Immune, Allergan, Allon, AstraZeneca, Dainippon Sumitomo, Elan, Exonhit, Genentech, LSShidMDLon S. Schneider, MD GSK, Lilly, Myriad, Novartis, Pfizer, Roche, University of Southern California Keck School of Medicine Merck/Schering Plough, Servier, SK Life Sciences, Los Angeles, CA Toyama, Transition International Society for CNS Trials Methods Washington, D.C. February 22, 2011 Background Outline • Only cholinesterase inhibitors and memantine approved • Beyond cholinesterase inhibitors and memantine • AD clinical therapeutics seem stalled • Drugs that failed in later clinical development • Current AD trials • Promising drugs appear not to translate efficacy from – Assumptions, design goals, methods, and results animal to man and from phase 2a to 2b/3 – What they trials could teach us (if we wanted to learn) • Recent and current trials have become longer and • Closer examination of 18-month trials depend on the placebo group worsening – The cookie cutter, “consensus” approach to development • Dismal prospects dis-incentivize pharma and biotechs – Strengths and limitations • Ongoing, longer-term trials and development programs • The business case influences advancements of drugs to – Current Phase 2/3 trials phase 2b – Targeted designs by diagnosis and biomarkers – E.g., treating more severe patients is more cost-effective, • Anticipating prevention trials – After $400M and 4-5 years of phase 3 then where will we be? • Drugs discussed: – Or, a positive phase 2a result is a quicker (better?) return on – Cholinesterase inhibitors, memantine, dimebon, tarenfluribil, investment bapineuzimab, semagacestat, scyllo-inositol, ginkgo biloba extract • Future clinical trials and assessments of effectiveness A Couple of Aβ Overviews* What is the ADAS-cog? • A cognitive test used in AD drug studies containing – Immediate recall, 10 word, 3-trial list – Recognition, 12 word, 3-trial list from 12 distractors – Procedural memory (recall of test instructions) – Orientation (date, day, month, year, time, season, place, self) – Confrontational naming (with object prompts increasing in complexity) – Follow commands – Expressive language (rated by examiner from conversation) – Comprehension (rated by examiner from conversation) – Word finding (rated by examiner from conversation) – Copy four figures of increasing complexity – Overlearned task – address letter to self • Scored 0 to 70 errors *The amyloid hypothesis is not quite so dead yet 1 Some Drugs That Failed in Phase 2 or 3 Therapeutics – Recent Developments • Modulation of secretases (SALA) • Modulation of kinases and phosphatases – Tarenflurbil (Myriad), ?E2212 (Eisai) • Cholesterol and lipids • 6 to 12 month long trials • 18 month long trials – γ-secretase inihibitors, GSI • Semagacestat LY450139 (Lilly), E2012 • Low molecular weight glycosaminoglycans – Cholinesterase inhibitors (N ≈ 5) – Xaliproden (2) (Eisai), Begacestat GSI953 (Wyeth), BMS (GAGs) and GAG-mimetics – Selegiline/ Lazabemide (4) – Simvastatin 708163 • Neurotransmitter-based treatments – β- secretase inhibitors,BACE I – Muscarinic agonists (> 4) – Atorvastatin • HPP854 (TransTech), E2609 (Eisai), Lilly, – Cholinesterase inhibitors AZ, CTS-21166 (CoMentis/Astellas), – Anti-glutamate and NMDA inhibitors – Tesofensine (NS2330) – B vitamins (+/- Vitacog) Merck/Schering Plough – Nicotinic modulators • Aggregation inhibitors – α7 nicotinics (AZ/Targacept, Roche, Sanofi) – Ginkgo biloba extract EGb 761 – Tramiprosate (Neurochem) (2) – α4β2 nicotinics (AZ/Targacept 3480) – Tramiprosate (homotaurine) Neurochem/Bellus) – Indirect cholinergic drugs – AZD103/ELN005 (scyllo-inositol) (Elan/Transition) – Conjugated equine estrogens – Tarenflurbil (2) –5-HTantagonist (Lecozotan) • Metal chelator 1A – MEM 1003 – DHA – 5-HT1A agonist (Xaliproden, Sanofi-Aventis) – PB2 (Prana) – blocks formation of Aβ oligomers –5-HT4 agonists (Epix,, GSK) – ABT-089 – Semagacestat (Lilly) (2) • RAGE inhibitor –5-HT6 antagonists (GSK, others) – Phenserine (2) – (Pfizer/TransTech TTP488 PF-04494700, anti-Aβ –H3 antagonist (ex-GSK) • 2 to 4 year trials aggregation, anti-inflammatory, metabolic) – Dimebon (Medivation) – Rosiglitazone (Avandia) (3) – Cholinesterase inhibitors for MCI (4) • Neurotrophic factors and inhibitors • Stem cells – NSAIDs (> 3) – Xaliproden (Sanofi-Aventis) • Gene therapies – NSAIDs – NGF (Ceregene) – NGF (Ceregene) – Corticosteroids • “Prevention” • Active immunotherapy (vaccines) • New drug delivery systems/ methods – MK677 (IGF analogue, Merck) – Elan/Wyeth, Novartis/Cytos, Roche • Neurotransplantation/ neurosurgery –CEE • Passive immunotherapy (antibodies) – Tarenflurbil (2) – Simvastatin – mAbs: Elan/Wyeth, Roche, Pfizer/Rinat, GSK, Lilly – MTC, “methylene blue” (TauRx) – Human extracted biological: ivIg – NSAIDs • Insulin/ metabolic/ anti-Aβ – Dimebon – Gingko biloba extract EGb 761 (2) – Rosiglitazone (Avandia, GSK) AD Drug Targets: Issues to Address • Causes of AD are not known – But! some disease mechanisms are well-described • Are there validated drug targets? • Where along the process should the drug work? – Early or late in the amyloid cascade? – Early or late in the clinical course? • Do targets change over illness course or lifespan? – Antinflammatories? Estrogens? • Is enough ‘pharmacology’ invested in AD drug development? – Drugability? PK/ PD? • An early intervention may not be effective for years • What should be expected outcomes for any given drug? • How do we transcend our previous successes? What Does ‘Successful’ Mean with AD Drugs? Dimebon: “The best data that a phase 2…study has Donepezil’s effect (ca. 1996); the only success we know ever shown,” the largest effect size ever! Doody et al The Lancet 2008 MMSE ≤ 18 MMSE > 18 5.8 points 4.0 points 2.4 points M Lindner et al. In RA McArthur and F Borsini, Animal and Translational Models of Behavioural Disorders, Elsevier, Amsterdam 2008 2 Wait! There’s More! It Only Gets Better!: Dimebon CONNECTION Trial (ADAS-cog) Dimebon Phase 2 Trial – Extended Age 74.3, 66% female, MMSE 17.7, 55% APOE 4, no past AchE use (42%) Age 68, MMSE 18, ADAS-cog = 30 AD Trials Methods Have Not Changed Is Sample Size Related to ADAS-cog Precision? 1989 –2014 (You betcha!) Acquisition: Subjects ms o Diagnosis Age Start 6 - 18 months Severity treatment Cognitive Sympt APOE genotype ADLs Family, SES Global Medication use “Behavior”” •6-month trials: Time •N < 100: had > 37% chance of not showing change •N > 200: > 95% showed significant mean worsening There are at least 110 6- to 12-month trials and 34 18-month trials. Changes in design and methods occur only around the edges. •12-month trials: Perhaps as a result of cholinesterase inhibitors’ success •N’s > 100: > 95% chance for showing decline Regressions weighted, non-significant Placebo ADAS-cog Changes by Size How Sample Sizes Could Have Influenced Phase 2 trials Outcomes (by country) N = 14 to 346 N = 81 N = 29 ADAS-cog drug-placebo difference = -4.10 [95%CI -5.36, -2.84 ], N = 653 Adapted from Schneider LS. Issues in design and conduct of clinical trials Forest plots displaying mean ADAS-cog changes (+/- 95% CI). Area of square s is proportional to sample size of for cognitive-enhancing drugs, In R. McArthur and F. Borsini (eds), Animal trial. Summary estimate is the sample size-weighted overall estimate of mean change. and Translational Models for CNS Drug Discovery, Elsevier, 2008 3 ADAS-cog Changes in 18-month Trials Current (18-month) Trials Methods Main points: About 15 completed Approximately 23 ongoing, most with “anti- amyloid-β” drugs Trials have nearly identical designs Schneider LS, Sano. M Alzheimer’s & Dementia 2009 The Placebo Groups of 18-month Trials RAVLT and ADAS-cog 1-Year Change in ADNI What mild to moderate AD looks like at the patient level (70-75% of MCI are Aβ biomarker positive) The 6-month test-retest reliability is 0.86 (the NTB is reported as 0.92) L. Beckett et al presentation at ADNI Steering Committee, April 14, 2008 http://www.adni-info.org/index.php?option=com_content&task=view&id=86&Itemid=44 Anti-Aβ Approaches Immunotherapy •Aβ Immunotherapy •Aβ Antibodies – Bapineuzumab (JNJ/Pfizer) – Passive – Solaneuzumab (Lilly) –Active – Ponezumab PF4360365 (Pfizer) • γ- secretase inhibitors – Gantenerumab RO 4909832 (Roche) – ABE 4869g (Genentech) • γ- secretase modulators – GSK 933766A • BACE inhibitors – Others: Eisai, JNJ/Pfizer • Immunoglobulins • Fibrilogenesis inhibitors – IVIG Gammagard (Baxter) • Others – IVIG Octagam (Octapharma) • Vaccines – 3 vaccines in phase 2 (Novartis, JNJ/Pfizer, GSK) – 3 vaccines in phase 1 (GSK, United Biochemical, AC Immune) 4 Bapineuzumab 18-month Phase 2 Safety Study by Dose Cohort: Bapineuzumab Development Program Can a small trial inform a phase 3 program? • Phase 2 trial • PIB PET fibrillar amyloid imaging study • Phase 3 – Four separate APOE ε4 and ε3,ε2 carriers trials ongggoing – 800 and 1200 patients each, totaling 4000 Tarenflurbil Clinical Development • Selective A42-lowering agent -secretase modulator – via substrate targeting of APP; improves spatial reference learning and memory performance in mice • Phase 1 – Healthy older volunteers • Safety, tolerability, pharmacokinetics, and effect on A42 • Phase 2 – Multi-dose, open label, prostate cancer – Prostate cancer • No efficacy, well-tolerated up to 4 years at 800 mg bid – Alzheimer’s disease trial • Provided evidence for dose-related effects on ADLs