The Potential for New Treatments for Alzheimer’s Disease: ‘ Where Are We Headed ?’ Dr. Howard Feldman Professor of Neurology Executive Associate Dean, Research Faculty of Medicine University of British Columbia 1 1
Disclosure From 2009-2011, Dr. Feldman was on leave from UBC and employed full-time at Bristol-Myers Squibb Company in Connecticut where he directed Global Clinical Research in Neuroscience 2 2
Objectives To understand the underlying basis of Alzheimer’s disease and how the disease evolves To briefly review the current treatments of the disease To anticipate new treatment approaches that are being tested in research today 3 3
August D : The first clinical and pathological description of Alzheimer’s Disease (1906) Memory: Rapidly worsening forgetfulness Couldn’t negotiate around her house Language: Decreased comprehension Errors in language Orientation Perplexed in the hospital Entirely disoriented Behavior ■ Yelling loudly fearful Other features Normal gait and extremities Alzheimer A Allgemeine Zeitschrift fur Psychiatrie 1907;64 4 4
Neuropathology of August D (1906) Dr. Alzheimer reported her case to a psychiatric conference in Tübingen 3 Key Neuropathological Findings: Damage to neurons and numbers Brain atrophy Progressive accumulation of abnormal material in the brain and blood vessels – amyloid plaques (amyloid core) – neurofibrillary tangles (p-tau ) Title “On the peculiar disease process of the cerebral cortex” Über eine eigenartige Erkrankung der Hirnrinde ; Alzheimer 1906) Allgemeine Zeitschrift fur Psychiatrie 1907;64 5 5
Brain Amyloid: Processing to Neuritic Plaques and Blood Vessel Walls NH 2 Protofibrils Oligomers Blood vessel amyloid β -secretase γ - secretase Brain amyloid Membrane Amyloid Amyloid β (A β ) Species 1-40,1-42 Precursor Protein (APP) 6 6
PET Scanning to Image Brain Amyloid SUVR Mean cortical SUVR = 0.87, PET score = 0 β -Amyloid burden = 0.15% β -Amyloid AV 45 antibody 4G8 Scans Immuno histochemistry Mean cortical SUVR = 1.17, PET score = 2 β -Amyloid burden = 1.63% β -Amyloid burden = 7.92% Mean cortical SUVR = 1.68, PET score = 4 Clark et al. JAMA . 2011;305:275-283. 7 7 7
Tau Processing to Tangles Tau protein Tangles Tau Paired Helical Filaments Tau abnormalities can be measured in spinal fluid Querfurth HW, LaFerla,FM N Engl J Med 2010:362:329-44 8 8
Serial MRI Scans Over 36 Months: Early AD Medial Temporal Lobe Coronal MRI Courtesy of Dr. Nick Fox London UK 9 9
Alzheimer’s Disease Pathogenesis: An Empiric Model Abnormal A β accumulation (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI) tau-mediated neuronal injury (CSF) Brain structure (volumetric MRI) Biomarker magnitude Cognition Clinical function A β FDG-PET Tau vMRI Clinical Cognition CSF PET fMRI CSF function Normal Asymptomatic Mild Dementia Cognitive Clinical disease stage Impairment Sperling R, et al . Alz and Dementia. 2011;7:280-292. 10 10
The Pathogenic Cascade of AD Synapse dysfunction Evolution over Decades Oxidative stress A β Tangle Antecedent events Inflammation production, formation Genes/environment Calcium Aggregation, dysregulation clearance Impaired plasticity and Brain co-morbidities: infarcts, other neurogenesis protein aggregates, aging Neuro- transmitter imbalances Modified from Mattson MP, et al. Nature 2004 Snowdon D et al JAMA 1996 11 11
Therapy for AD: The first hundred years and looking forward………. Memantine NMDA Uncompetitive Receptor Antagonist 1906 1910 1974 1982 1997 2004 2010 2015 The Acetylcholinesterase cholinergic inhibitors (AchEI), hypothesis ? First Disease Modifying Treatments Passive immunotherapy ■ IVIG ■ Bapineuzumab ■ Solaneuzumab 12 12
Donepezil and Cognition Mild to Moderate AD (MMSE 12-24) -3 � -2 � -1 � p < 0.0001 � Total 0 � ADAS- Cog 1 � (Mean±SE) 2 � Placebo 5 mg/day 3 � 10 mg/day � 4 � Decline � 6 12 18 24 30 � Memory Attention Language Praxis Rogers SL et al, Neurology 1998 Orientation Reasoning 13 13
Donepezil: Clinical Global Impression of Change Mild to Moderate AD 50 +11 % 45 -16.8% Percentage of patients 40 35 +17% 30 25 -8.2% 20 15 10 -1.9% 0% 5 0 Moderately Minimally No Change Minimally Moderately Markedly Improved Improved Worse Worse Worse placebo (endpoint) donepezil (endpoint) Rogers SL et al, Neurology 1998 14 14
Memantine and Neuropsychiatric Symptoms Moderate to Severe AD -2 LS mean change from baseline p<0.001 Improvement Memantine p<0.001 -1.5 p<0.05 p<0.05 Placebo -1 in NPI total score p<0.01 -0.5 0 Pooled data, mod to severe AD 0.5 (MMSE <20) 1 Worsening NPI total score 1.5 2 6 RCTS 2.5 3 Endpoint /28 0 4 8 12 16 20 24 28 Treatment week LOCF Gauthier S et al ICAD Poster Presentation 2006 15 15
Amyloid-Related Approach to Potential New Treatment APP Production gene Fe, Cu 2+ Chelator Immunotherapy APP PBT2 Bapineuzumab Solaneuzumab A β Antisense IVIG Monomer Si RNA A β Secretase Oligomer inhibitors & modulators A β Aggregation Beta and Fibril Deposition Gamma Fibrillogenesis Secretase modulators Diffuse inhibitors & Plaque Scylloinositol modulators Tramiprosate Senile Plaque Courtesy of Dr. Norman Relkin, Weill Cornell Medical School, New York, NY. 16 16
Amyloid and Tau Directed AD Clinical Trials Phase III Results: Negative Xaliproden Tramiprosate Tarenflurbil Semagacestat Rage Inhibitor Phase III Trials: in process Dimebon Bapineuzumab Solanezumab Intravenous Gamma Globulin (IVIG) TauRx 17 17
Bapineuzumab: Phase 2 Clinical Outcomes N= 234 5 arm trial Salloway S et al Neurology 2009 18 18
Summary There are no ‘new’ treatments today for AD Current standards include AchEIs and Memantine Major unmet need for symptomatic and disease modifying treatments Better understanding of the disease pathway and in- vivo biomarkers Potential for earlier intervention; stage is set Awaiting amyloid-lowering immunotherapy trials Tau/microtubule targeted treatments starting in Clinic “Amyloid may be necessary but not sufficient to cause or treat the disease “ 19 19
Acknowledgments To our patients and families who UBC CARD Research trust and share in what we are trying to advance and participate Ian Mackenzie Sherri Hayden Claudia Jacova in our studies………….. Emily Dwosh GY Robin Hsiung Rachel Butler Blair Leavitt Judy Illes Collaborations Pheth Sengdy Michele Assaly Brad Hallam Benita Mudge Brain Research Center Dean Foti The ACCORD Study Lynn Beattie Many others……. A Jon Stoessl Support from the Ralph Fisher Tom Ruth & Alzheimer Society of BC Dessa Sadovni ck Professorship in Alzheimer’s Research 20 20
The End………………… 21 21
Treatments Directed at Microtubules and Tau Pathology Tideglusib GSK 3 Inhibitor Lithium, Valproate Davunetide NAP Epothilone D Methylene Blue Paclitaxol Davunetide HDAC Inhibitors Immunotherapy directed at tau oligomers Adapted from Brunden et al Nature Rev Drug Discovery 2009; Boutajangout et al J Neurosci 2010 22 22
Tau Function & Potential Disease-Modifying Targets Tangles Tau protein Misfolded Hyperphosphorylated Refold/ Tau Oligomers P Microtubule Degrade Neurodegeneration Kinase Inhibitors Microtubule Cognitive deficits Gsk3b Stabilizers (Epothilone) Tau protein binds & stabilizes microtubules Phospho-Tau aggregates linked to neurodegeneration by familial mutations & preclinical studies Complements A β approaches 2 23 23 3
Tau and MT Function: Tangle Formation Brunden et al Nature Rev Drug Discovery 2009 24 24
MT Stabilization for Tauopathies Control Neuron Neuron expressing mutant Tau Abnormal Tau disrupts microtubules in neurons from mice, Drosophila, and Aplysia Microtubule abnormalities are prevented by low concentrations of microtubule stabilizers, such as BMS-241027 Studies at BMS and UPenn show that BMS-241027 prevents behavioral deficits and neurodegeneration in Tau transgenic mice Shemesh and Spira (2010) Acta Neuropathol 120: 209 2 25 25 5
26 26
Paclitaxol and Mt human tau mRNA Shemesh, O et al Neurobiol Dis (2011); Bruden KR et al J Neurosci 2010 27 27
Exploratory Discovery for Anti-Tau Therapies Wild-type Neurons 20 pA 0.5 seconds Tau-P301L Neurons mEPSC Peak Amplitude and Frequency are Reduced in TauP 301L Neurons These deficits can be rescued by compounds or shRNAs providing an assay to evaluate new targets 2 28 28 8
Normal and Hyperphosphorylation of Tau 29 29
Schematic Model of Fibrillar Tau and Neuropil Threads Brunden et al Nature Rev Drug Discovery 2009 30 30
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