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Experimental Therapies for Alzheimer’s Disease

Experimental Therapies for Alzheimer’s Disease. Pierre N. Tariot, MD Director Banner Alzheimer's Institute Phoenix, Arizona Research Professor of Psychiatry University of Arizona College of Medicine. Disclosures.

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Experimental Therapies for Alzheimer’s Disease

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  1. Experimental Therapies for Alzheimer’s Disease Pierre N. Tariot, MD Director Banner Alzheimer's Institute Phoenix, Arizona Research Professor of Psychiatry University of Arizona College of Medicine

  2. Disclosures • Consulting fees: Acadia, AC Immune, Avid, Baxter Healthcare Corp., Bristol Myers Squibb, Eisai, Inc., Epix Pharmaceuticals, Forest Laboratories, Memory Pharmaceuticals, Inc., Myriad Pharmaceuticals, Sanofi-Aventis, Schering-Plough, and Worldwide Clinical Trials; • Consulting fees and research support from Abbott Laboratories, AstraZeneca, AVID, Elan, GlaxoSmithKline, Eli Lilly, Medivation, Merck and Company, Pfizer Inc., Toyama, and Wyeth Laboratories; • Educational fees from Alzheimer’s Foundation of America; • Research support only:NA. • Other research support: NIA, NIMH, Alzheimer’s Association, Arizona Department of Health Services, and the Institute for Mental Health Research. • Investments: none to disclose. • Patents: I am listed as a contributor to a patent, “Biomarkers of Alzheimer’s Disease.” • Speakers’ bureaus: NA.

  3. General Principles for Managing Illness Optimize physical, social, intellectual stimulation Importance of maintenance of medical and dental health Medication oversight Monitor for delirium Healthy diet Discuss possible changes in emotions and behavior that can occur, and how to mitigate them Review driving safety Discuss legal, financial issues Review relevant community resources Discuss coping strategies Discuss availability of clinical trials Establish ongoing monitoring plan

  4. Prevention, Risk Reduction, and/or Optimizing Brain Health? • Social, mental, and physical activity shown to be inversely associated with risk for dementia and AD • Exercise speculated to enhance brain neurotrophic factors and modify apoptosis • Longitudinal cohort studies show risk of AD increased among people who have received shorter periods of education • Intellectually challenging activity has been associated with reduced risk of dementia in longitudinal studies • Reasonable to encourage patients to maintain or increase physical activity, exercise, cognitive and leisure activities, and social interaction, though it is not known whether these interventions reduce dementia risk Bassil N, Grossberg GT. Primary Psychiatry. 2009;16:33-38.

  5. Goals for the Treatment of Alzheimer’s • Improve memory • Improve functional status • Improve behavioral symptoms • Slow progression • Delay or prevent onset

  6. Pharmacologic Treatments for AD ER = extended-release; MOA = mechanism of action; NMDA = N-methyl-D-aspartate. National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH PublicationNo. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

  7. Cholinesterase Inhibitor Therapy in AD Disease Severity Early-Stage Dementia MCI • Benefits cognition? • Benefits cognition Moderate Dementia • Benefits cognition • Preserves global status • Preserves ADLs • Benefits behavior? Severe Dementia • Benefits cognition • Preserves global status • Preserves ADLs • Benefits behavior? Class approved for mild-moderate AD Donepezil also approved for severe AD

  8. Memantine Therapy for AD* Disease Severity Mild-Moderate Dementia MCI • Role unknown • Inconsistent effects Moderate-Severe Dementia • Benefits cognition • Preserves global function • Preserves ADLs • Benefits behavior *Approved for moderate-severe AD in the U.S., alone or in combination with cholinesterase inhibitors

  9. Pharmacologic Treatments for AD: Common Side Effects National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH PublicationNo. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

  10. How Might Promising Advances in AD Treatment Address Unmet Needs? • Disease modification • Increasing neuroprotection against existing Aβ plaques and neurofibrillary tangles • Reverse existing neuronal damage • Improved efficacy • Not just cognition, but also ADLs and behavior • Enduring response • Delay in disability • Fewer side effects • Simple to administer • Reduced number of treatment unresponsive patients Husain MM, et al. Neuropsychiatr Dis Treat. 2008;4(4):765–777.

  11. Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s Disease and Normal Aging Plaques Normal Alzheimer’s Tangles Courtesy of Harry Vinters, MD.

  12. A Proposed Temporal Progression Of Alzheimer’s Disease Genetic Factors APP mutations Presenilin 1,2 mutations APOE4 alleles APOE2 alleles Family history Environmental factors Head Injury Toxins Age Endogenous Factors Diet Cardiovascular risk factors Diabetes Smoking Education Menopause Physical Activity Intellectual Activity Protective Factors Estrogen Anti-inflammatory Drugs Net effect = stress and vulnerability to stress Molecular Phenotype INITIAL STRESSORS Proximal Apoptosis APP dysregulation Impaired neurotrophic function Oxidative stress Excitotoxicity Neuropathology Normal Normal Clinical Phenotype Normal Normal FAILED STRESS RESPONSE Cell cycle dysregulation Kinase/phosphatase dysfunction Protein misfolding Altered DNA repair Vascular/membrane dysfunction CELL INJURY Inflammation Cytoskeletal dysfunction Synaptic dysfunction Mitochondrial damage Tangles, Plaques Mild Cognitive Impairment CELL DEATH Distal apoptosis Neurotransmitter failure Tangles, Plaques Neurodegeneration Dementia The figure depicts apparently continuous processes, though they are likely to be asynchronous . Yaari and Tariot 2008

  13. Interventions That Might Prevent or Delay AD • Antihypertensive therapy • Hormonal agents (estrogen) • NSAIDs (naproxen and celecoxib) • High-dose vitamin B, folic acid supplementation • Statins • PPAR-gamma agonists • Fish oil, omega 3 fatty acids • Weight control, healthy diet

  14. The Search for New AD Therapies • Drugs/nutraceuticals (based on epidemiologic observations) • Neurotransmitter-based therapies • Glial modulating drugs • Neuroprotective drugs • Amyloid modulating drugs • Tau modulating drugs

  15. Overview of Supplements etc. • Anti-oxidants: no pending treatment trials data; hope for prevention trial at some point, or via dietary study • Anti-inflammatory agents: all AD studies (-); MCI trial (-); ADAPT prevention trial results mixed: no cognitive benefit, possible risk reduction with naproxen only • Hormonal therapies: largest AD treatment studies were (-); discouraging WHIMS results; but none started early enough, possibly wrong form used, so question may still be open. • Homocysteine-lowering: ADCS (B6+B12+folate) trial in AD completed, no benefit seen • Omega-3-fatty acid: anti-amyloid/neuroprotective (ADCS), (-) results in AD; equivocal results in age-associated memory impairment

  16. Neurotransmitter Therapies • Acetylcholine-releasing drugs • Nicotinic agonists (alpha 7, alpha 4-beta 2) • Serotonin: 5-HT4 partial agonists, 5-HT1A agonists/antagonists, 5-HT6 antagonists • Norepinephrine/dopamine: MAO-A and MAO-B inhibitors • GABA: GABA-B antagonists • Glutamate: AMPA potentiators • Glycine: partial agonists MAO=monoamine oxidase; GABA=gamma-aminobutyric acid; AMPA=alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

  17. Glial Modulating Drugs • Affect glial cells directly (nitroflurbiprofen, ONO-2506, tacrolimus) • RAGE receptor antagonists (TTP 488) • TNF alpha antagonists (etanercept)

  18. Neuroprotective/Neurotrophic Strategies • Mitochondrial stabilizers (Dimebon/latrepirdine; also has multineurotransmitter effects) • Phosphodiesterase-4 (PDE4) inhibitors • Neurotrophic drugs

  19. Dimebon/latreperdine clinical outcomes • Dimebon patients improved compared with placebo on 5 efficacy endpoints (n=183, MMSE 10-24; 6 mo followed by 6 mo blinded extension) • Cognition: ADAS-cog, MMSE • Overall global function: CIBIC • Activities of daily living: ADCS-ADL • Behavior: NPI • Results supported by HD study demonstrating effects on MMSE (P=0.03) in Dimebon-treated patients Doody RS, et al. Lancet. 2008;372:207-215.

  20. –3.0 Clinical Improvement –2.0 –1.0 0.0 1.0 2.0 3.0 4.0 Dimebon (n = 89) Clinical Deterioration 5.0 Placebo (n = 94) 6.0 Dimebon Effects: ADAS-cog P=0.0077 P<0.0001 P<0.0001 P<0.0001 2.0 4.0 5.9 6.9 Dimebon-Placebo Difference Mean Change From Baseline Score Baseline 12 26* 39 52 Week * Patients were moved to blinded extension. Doody RS, et al. Lancet. 2008;372:207-215.

  21. Latrepirdine Study Results: Adverse EventsAEs >3% in placebo group and at least twice the rate of latrepirdine Adapted with permission from Doody RS, et al. Lancet. 2008;372:207-215.

  22. Confirmatory Phase 3 dimebon Trial: Negative • Enrollment in confirmatory trial of dimebon in mild-to-moderate AD began Spring 2008 • Pla, 5 TID, 20 TID • OLEX offered • Enrollment completed in June with 598 patients (initial goal was 525) • @ 70 sites in the US, Europe, and South America • Primary endpoints were ADAS-cog and CIBIC-plus

  23. Other Phase 3 Dimebon studies: • 12-month trial of Dimebon added to ongoing treatment with donepezil HCl tablets in mild-moderate AD • Pla, 5 TID, 20 TID • Enrollment began April2009, with target enrollment of 1050 patients • 6-month trial of dimebon added to ongoing treatment with donepezil in mod severe AD w behavioral symptoms • Plavs 20 TID • 6-month trial of dimebon added to ongoing treatment with memantine in mod severe AD • Plavs 20 TID

  24. Case Example: Why Amyloid Matters • Plaques are a hallmark of the illness • The major (rare) causes of familial Alzheimer’s all involve abnormal processing of the amyloid protein • Leads to highly toxic intermediates • Can we block this cascade?

  25. b-Amyloid–related disease-modifying strategies APPgene Production APP Cu++Chelator A Monomer ? Immunotherapy Antisense AOligomer Secretase modulators AFibril Aggregation Deposition Diffuse Plaque Fibrillogenesis modulators Senile Plaque Relkin, 2006.

  26. Anti-amyloid Immunotherapy:Amyloid “Vaccine” Reduces Plaque Burden and Memory Loss in Transgenic Mouse Model of AD Amyloid Stain (Mouse Brain) Vaccinated Unvaccinated Morgan et al. Nature. 2000;408:982-985.

  27. Active Immunization • Elan Phase II clinical trial of active immunization with an aggregated Aβ in adjuvant (AN1792) (Gilman et al. Neurology. 2005) • n=372 • terminated prematurely • 18/300 receiving AN1792 developed a sterile meningoencephalitis related to cerebral T lymphocyte infiltration (0/72 on placebo) • 59 (19.7%) developed adequate Aβ response • This is seen with other active vaccines • No clinical benefit seen in Aβ responders or non-responders on most clinical measures —continued

  28. Vaccination with AN-1792: First demonstration of reversal of AD neuropathology ? Parietal neocortex, non-immunized patient at comparable stage of AD Parietal neocortex, immunized AD patient in Elan AN-1792 Trial Nicoll et al. Nat Med. 2003;9:448-452.

  29. Active Immunization: Followup • Ongoing follow-up offered after active treatment stopped • 288 had paired volumetric MRIs (Fox et al. 2005) • Those with higher anti-AN1792 Aβs had greater: • decreases in WBV • ventricular enlargement • Not correlated with impaired cognition • 1-year follow-up of those who at least 1 dose of AN1792 showed that patients with an anti-Aβ antibody response exhibited slower rates of cognitive and functional decline and reduced cerebral spinal fluid (CSF) concentrations of tau protein compared with nonresponders

  30. Holmes et al followup (2008)

  31. Holmes et al, cont’d

  32. Active Vaccination, cont’d • 2nd-generation vaccines use small pieces of Aß to avoid activating T-cells responsible for meningoencephalitis • Since T cell epitopes exist mainly in the C-terminal portion of Aβ, vaccines using shorter N-terminal peptides are in development. • Since T helper 1 (Th1) immune responses activate encephalitogenic T cells and induce continuous inflammation in the CNS, vaccines inducing Th2 immune responses may hold promise. • N-terminal short Aβ peptides with Th2 adjuvant or Th2-stimulating molecules, • DNA vaccines, • recombinant viral vector vaccines, • recombinant vegetables • others.

  33. Active Vaccination, cont’d • ACC-001 is in phase II testing in patients with mild-moderate AD. • CAD106 consists of the first 6 N-terminal amino acids of Aβ attached to a virus-like particle, which is believed to stimulate B cells while preventing excessive T-cell activation thereby avoiding T-cell mediated adverse effects

  34. Passive Immunization • Monoclonal antibodies in development are designed to target 1 of 3 domains of the Aβ protein: the n-terminus, the middle portion, or the c-terminus. • It is possible that efficacy, safety, or both may be substantially different depending on the binding domain. • Elan/Wyeth, bapineuzumab (AAB-001) is a humanized monoclonal antibody to N-terminus of Aβ in phase III development • Lilly, LY206430 (a humanized version of m266) targets A β and is in phase II (Bales et al. Neurobiol Aging. 2004) • Others are in development as well

  35. Preclinical Data With AAB-001 (bapineuzumab) Contralateral Ipsilateral A Anti-Aβ injection Contralateral Ipsilateral E F 1mm B C 1mm Tau staining 500 µm G H D E 1mm 250 µm F G 200 µm 250 µm Intra-hippocampal anti-Aβ clears extracellular and intracellular Aβ aggregates Early anti-Aβ administration clears also non-phosphorylated tau Reprinted with permission from Oddo S, et al. Neuron. 2004;43:321-322.

  36. Phase 2 Trial of BapineuzumabRandomized, multicenter, placebo-controlled, parallel-group, ascending-dose study • 234 patients enrolled • Randomization: Bapineuzumab or placebo (8:7) • Treatment: 6 infusions 13 weeks apart • 4 dose cohorts: 0.15, 0.5, 1.0, and 2.0 mg/kg • Final Assessment: Week 78 Salloway S, et al. Neurology. 2009. In press.

  37. Bapineuzumab Phase II Results • No drug-placebo differences on ADAS-cog, DAD, NTB, CDR-SB • Based on a post hoc analysis of E4 non-carriers, ADAS-cog, NTB, and CDR-SB significantly favored the drug Salloway S, et al. Neurology. 2009.

  38. Bapi phase II (Salloway et al 2009)

  39. Bapineuzumab Phase 2 Results: Safety • AEs generally mild-to-moderate, transient, not dose-related • % of patients with SAEs similar between bapineuzumab and placebo except for vasogenic edema • In 0.5, 1.0, and 2.0 mg/kg cohorts • 3 deaths in bapineuzumab-treated patients, unrelated to treatment • Selected AEs in <5% of bapineuzumab-treated patients: syncope, DVT, PE, and cataract Salloway S, et al. Neurology. 2009.

  40. Bapineuzumab and Vasogenic Edema in phase II • 12/124 (9.7%) patients on bapi (0 on placebo) developed vasogenic edema (VE) • Most frequently detected by MRI, with few or no clinical symptoms, and resolved in weeks to months • 10 ApoE4 carriers, 2 non-carriers • 2 mg/kg (6 carriers, 2 non-carriers) • 1 mg/kg (3 carriers) • 0.5 mg/kg (0 carriers) • 0.15 mg/kg (1 carrier) • 6 of 12 patients resumed treatment with no VE recurrence Salloway S, et al. Neurology. 2009.

  41. PIB-PET data from phase II (Rinne et al 2010)

  42. Bapineuzumab: Phase III Summary • Mild-moderate (MMSE: 16-26) • Infusion frequency: Q13 weeks; Infusion duration: 60 minutes • Four trials (Primary endpoints: ADAS-cog, DAD; Secondary endpoints: NTB, CDR-SB; Other: MRI, LP) • 301 • E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09) • 302 • E4+ carriers: 0.5 mg/kg • 3000 • E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09) • 3001 • E4+ carriers: 0.5 mg/kg

  43. Passive Immunization, cont’d: IVIg • Beneficial results of monthly infusions of IVIg have reported in OL study by Dodel et al of 5 patients with mild-moderate AD (J Neurol Neurosurg Psych. 2005) • Reported effects included increased plasma Aβ levels and decreased CSF Aβ consistent with expectations for increased clearance of Aβ from the brain. • Relkin et al report similar early experience with small OL study presented in abstract form (AAN. 2005) • Relkin et al have conducted a phase II trial showing encouraging effects • ADCS/Baxter have launched a phase III trial

  44. 3rd generation vaccines • 2nd generation vaccines and antibodies both target linear amino acid sequences found in APP and in amyloid deposits. • Antibodies against normal human proteins can cause autoimmune side effects. • It is difficult to make antibodies against self-proteins because of immune suppression of auto antibodies. • 3rd generation vaccines use antibodies that target structures specific to amyloid aggregates and that do not react with normal human proteins.

  45. Secretase Pathway • Beta secretase (“BACE”) inhibitor • Most attractive theoretically? • Prior agents have failed • Several agents in/approaching • Gamma secretase inhibitor • Various agents have shown the desired biological effect • 2 in phase II-III trials now (Lilly, BMS) • Others pending • Tarenflurbil (“Flurizan”), a putative gamma secretase modulator, failed to show benefit in phase III trial; concerns re lack of demonstration of target engagement

  46. Anti-aggregant Therapies • Tramiprosate (“Alzhemed”) failed in phase III trials • Elan has compound in phase II now

  47. Anti Amyloid Therapy: Conclusions • Many medications and immunotherapies exist that can alter the processing of amyloid in the lab and in animal models • They have shown at least some ability to alter blood, spinal fluid, PiB, and pathological measures of different types of amyloid in normals and/or people with AD • Effects on MRI, FDG PET, other biomarkers in humans unclear/unknown • Dose ranges not established in all cases • Clinical significance of encouraging proof of concept biomarkers remain unknown

  48. Tangles Axon Microtubules Neuron Tau Proteins Paired Helical Filament Dendrites Tau proteins, which normally stabilize microtubules in brain cells... thus creating tangles that disrupt cell functions and lead to cell death. undergo abnormal chemical changes and assemble into spirals called paired helical filaments... Theories of How DamageOccurs in AD From Inside the Cell: Tangle Formation Sources: Dr John Trojanowski and Dr Virginia M. Y. Lee. University of Pennsylvania Medical Center.

  49. Antitangle Therapies for Alzheimer’s Disease • Minocyline • Microtubule stabilizers • kinase inhibitors: • GSK 3: AstraZeneca compound in early development, large ADCS valproate trial was (-), ADCS lithium trial abandoned after (-) European Li trial completed • vaccination approaches in early development • CDK5 • AZD-1080 • AL-108 (NAP) • PDE4 inhibitors

  50. Methylthioninium Chloride (rember™) • Thought to inhibit tau aggregation by • Blocking the formation of Tau oligomers and their conversion to Paired helical filaments • Solvating / dissolving Tau oligomers and paired helical filaments into the short truncated monomers that comprise the proteolytically stable core of the Paired helical filaments • Once reduced to its constituent monomers, the truncated Tau monomers become susceptible to proteases and are of a size that can be cleared efficiently through the proteasomal clearance pathway • Phase 3 trial underway TauRx Therapeutics Ltd. Pipeline—Alzheimer’s disease. 2008. Available at: www.taurx.com/pipeline_first.aspx. Accessed June 8, 2009.

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