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 A42-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 A42 • 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 and global function in patients with mild AD • Phase 3 – US/Canada trial (n = 1684) – International trial (n = 900) 28

Tarenflurbil 12-month Phase 2 Results Can a small trial inform a phase 3 program?

• Greater dropouts in the 400 mg bid treatment than 800 mg group • No significant effects overall • Significant effects on ADLs and CDR-sb in mild sub-group for 800 mg bid (and in moderate sub-group on CDR-sb for placebo!) • In order to get this “significant” effect we had to ignore the 400 mg treatment group and that placebo was better for moderate patients, or we discounted 116 of 210 patients

Wilcock et al. Lancet Neurol 2008;7(6):483 RC Green et al JAMA 2009

5 APOE ε4 Carriers in Trials γ-secretase inhibitors (recently) in development (“Everyone knows” they have a worse course)

• Semagacestat (LY 450139) • BMS 299897 • BMS 708163 • MK0752 • BttBegacestat (GSI 953) • ELND006

Semagacestat Lilly halts development of semagacestat • -secretase inhibitor • Indianapolis, Aug 17, 2010 PRNewswire – … preliminary results from two ongoing long-term Phase III studies showed it did not slow disease progression and was • MAD and SAD studies associated with worsening of clinical measures of cognition and the ability to perform – 40% decreases in Aβ activities of daily living. … from a pre-planned interim analyses… showed that, as • SILK (stable isotope-labeled kinetics) study expected, cognition and the ability to complete activities of daily living of placebo- treated patients worsened. …patients treated with semagacestat worsened to a – 28 male volunteers, 21-50 y.o. statistically significantly greater degree than those treated with placebo. – 47 to 84% decrease in new Aβ, no change in clearance …semagacestat is associated with an increased risk of skin cancer…. » (Bateman et al Ann Neurol 2009) • "This is disappointing news for the millions of Alzheimer's patients …," said Jan M. • 1st phase 2a trial Lundberg, Ph.D., President, Lilly Research Laboratories. "This is a setback, but Lilly 's commitment to beating Alzheimer's will not waver.“ ….Lilly's clinical team will continue – 70 patients, 30, 40 mg/d, or placebo to gather and evaluate data from these studies, and will publish the results for the – 40% decrease in Aβ in blood, no change in CSF benefit of future Alzheimer's research. … Lilly plans to continue collecting safety data, •2nd phase 2a trial, N = 51 including cognitive scores, for at least six months …. • The decision …is expected to result in a third-quarter charge to earnings of – 51 patients, 100, 140 mg/d, or placebo for 6 weeks approximately $.03 to $.04 per share [based on] 2010 earnings per share guidance • Two phase 3 trials range of $4.44 to $4.59 on a reported basis – 1100 patients for 15 months • “…Lilly's innovation strategy,…, does not rest on the success or failure of any single compound," said John C. Lechleiter Ph.D. “Despite this and other recent setbacks, Eli – 1500 patients for 15 months Lilly and Company remains financially strong and is even more determined to prevail – Biomarker subgroups in our quest to provide new treatments for Alzheimer's and other serious diseases." • FDG-PET, AV45-PET, vMRI, CSF Aβ and tau

BACE inhibitors Scyllo-inositol phase 2 trial • DUBLIN, Dec 15, 2009 – Elan and Transition Therapeutics cut the 2 highest doses …from a phase II study [due to] concern about 9 deaths... The emergence of a [potential] safety problem …will inevitably raise concerns about whether [lower doses] can still be effective. [The companies] will • HPP854 (TransTech) use results … to determine whether or not to push the drug forward into pivotal phase III …Patients being treated with 1000 mg and 2000 mg doses…are being withdrawn… patients treated with a • E2609 (Eisai) 250 mg dose or placebo will continue... • Business Wire, Aug 9, 2010 – …results of a Phase 2 placebo-controlled study in 351 patients with • Lilly? mild to moderate AD who received study drug for up to 18 months … subjects with MMSE scores between 16 and 26 received …250 mg, 1000 mg or 2000 mg twice daily or… placebo. The study’s cognitive (NTB) and functional (ADCS-ADL) co-primary endpoints did not achieve statistical • AstraZeneca? significance. • The 250mg twice daily dose demonstrated a biological effect on amyloid-beta protein in the CSF in • CTS-21166 (CMCoMen tis/AtllAstellas) a subgroup …. This dose achieved targeted drug levels in the CSF, and showed some effects on clinical endpoints in an exploratory analysis. After reviewing the final safety data with the … safety • Merck/Schering Plough monitoring committee we concluded that the 250mg twice daily dose has acceptable safety and tolerability. • …final analysis was based on subjects who received either 250mg twice daily or placebo for up to 18 months. • Based on the preponderance of evidence from both biomarker and clinical data, and after extensive discussions with experts in the field, Elan and Transition Therapeutics intend to advance ELND005 into Phase 3 development. Specifics of the Phase 3 study design will be finalized after receiving input and concurrence from regulatory authorities. • Dec 27, 2010 – Transition sells ownership for $9M, $20M if Elan starts a trial, up to $113 M if commercialized plus royalties

6 Prevention Trials Past ‘Prevention’ Trials

• Why do prevention trials

Zahs and Ashe 2010 • Past trials • Proposals

Golde, Schneider, Koo, 2011

Prevention trials: issues and proposals The Imminent Future

• Amyloid cascade and Aβ continue as drug targets • Drug? • Trials will likely include earlier diagnosed AD • Sample selection, sample size – ‘prodromal’ AD or ‘MCI due to AD’ or ‘preclinical’ AD • Recruitment methods • Will likely include biomarkers •Outcomes – For both diagnosis and as supporting outcomes • Safety – CSF Aβ and tau, PET Aβ, MRI volumes •Biomarkers • Trials get “targeted” designs • External validity • They become longer still • Cost, profits, health economics, and regulatory • Outcomes get tweaked • The ‘initiatives’ – ‘NTB.’ executive function, and episodic memory tests – API • “Prevention” trials evolve with enhanced samples –DIAN – PS 1 (“presymptomatic AD”), ApoE ε4, biomarker-positive – ADCS (“preclinical AD”)

Concluding Comments Next steps? • Clinical development programs and trials can be better • Inherent heterogeneity (i.e., inconsistency) in patients, ratings, sites, clinical course, and outcomes • Test drugs in designs that are relevant to their targets • Little clinical change in AD and MCI over 2 years • Re-think and minimize causes of variability, when • Undersized, imprecise, underpowered “cookie-cutter” trials mean: possible – effective drugs may not be recognized – Examples: training, centralized ratings, re-scaling, repeated – ineffective drugs may be misidentified measures, ‘leaner and meaner’ outcomes, recruitment •Anyyp perceived evidence of effect obtained in phase 2a likel y illusor y; • Use multivariate outcomes consistent with expected phase 2 trials do not predict success; ‘POC’ trials usually are not actions of drug • Large phase 3 trials have proven definitive • Are we progressing or just rearranging deck chairs? • Put the pharmacology, the drug, back into AD drug development –Or – • Do the same thing we’ve been doing for 20 years but expect a different result • Wait for a drug with a strong effect

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