9.7.16 yarp keynote presentation final · *, leslie williams 1, marcel maier 2, robert dunstan 1,...
TRANSCRIPT
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Translating Biological Gerontology to Alzheimer’s Therapy
Thank you to the Yulgilbar Foundation!
AGING
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What Dr. Alzheimer Observed:Clues to Therapy?
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No Progress on Alzheimer’s Disease Until ~1970
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AGINGIS THE LEADING RISK FACTOR FOR ALZHEIMER’S DISEASE
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BIOLOGICAL GERONTOLOGY:ACCUMULATION OF DAMAGE & DISEASE
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The “Accumulation of Damage” View of Brain Aging and Alzheimers:Novel Therapeutic Targets
Systemic Inflammation
Neuroinflammation
Epigenetic changes
Mitochondrial dysfunction
Oxidation Failed energetics
Microvascular dysfunction
Hypoxia BBB dysfunctionDysregulation of stress response
Neuroendocrine aging
Accumulation of misfolded proteinssuch as tau and beta-amyloid
Failure of chaperones, autophagy, and proteosomal quality control
Oxidation and Other Post-translational changes
Synaptic Dysfunction and Degeneration
Neuronal dysfunction and death (tangles)
Retrograde and anterograde spreading
Amyloid?Tau?
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DEVELOPING NOVEL DRUGS
FOR ALZHEIMERS
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>$212 +YEARS
BILLION
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Drug Discovery: A Vital Stage in Drug DevelopmentWhen Innovation is Created
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Challenges: How a Chemist Thinks About Targets for Drug DiscoverySuccess Rates of Target Types
GPCREnzyme
Ion channelNuclear receptor
ProteaseProtein kinaseProtein-protein
“RELATIVELY”HIGH SUCCESS RATE
From: T. Bartfai and GV Lees,, 2006
“RELATIVELY”LOW SUCCESS RATE
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The Universe of SMALL MOLECULES:
~50M compounds in Chem Abstracts
1040-10100 possible small molecules
BIOLOGICALS:
20,000 human genes
100,000 proteins
ASPIRIN
The Origins of FDA-Approved Drugs: Chemical Space is Relatively “Unlimited”
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SMALL MOLECULES BIOLOGICALS
~10,000 Approved Drugs
T. Bartfai and GV Lees, 2006;Le Couteur, et al 2011
Fewer than 500 distinct chemical entities
Less than 300 drug-able genes
Fewer than 50 unique chemical scaffolds
Many are variants on formulation and delivery
But “Drug-able” Chemical Space is Very Limited
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• Animal models have contributed to our understanding of the mechanisms of disease, but are generally poorly predictive of clinical trial outcomes
• Lack of standards in design, conduct and analysis of animal trials persist
• Apply the scientific and procedural rigor of clinical trials to animal trials
Challenges: Improving the Predictive Value of Animal Trials
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Challenges: Drug Discovery and Development Requires Multidisciplinary Teams of Scientists
Clinical DevelopmentClinical Trialists
IND enabling studies: ADMET, formulation and scale-up chemistry
Pharmaceutical and Regulatory Scientists
In vivo Testing and Preclinical Proof of MechanismBiomarker Development
Animal Trialists
Lead Identification and optimizationMedicinal Chemistry, Pharmacology
High Throughput Screening
Structure Based Chemistry
Assay DevelopmentChemical Libraries
Computational Chemistry
Target identification Basic Neurobiology
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93Therapies in
Active Clinical Trials
24 in Phase 3
45 in Phase 2
24 in Phase 1Cummings et al, Alz & Dem 2016
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ENABLING TECHNOLOGY:
ALZHEIMERSBIOMARKERS
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• Earlier and more accurate diagnosis
• More scientifically rigorous and efficient clinical trials
• Enabled prevention:
– Disease starts ~20 years before symptoms begin
– Anti-amyloid prevention clinical trials are underway
PLACEBO TREATMENT
VACCINE TREATMENT
AMYLOID PET SCANNINGAnd CSF Testing
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Aducanumab: N-terminal Anti-beta amyloid antibody
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The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease Jeff sevigny1*, ping chiao1*, Thierry bussière1*, paul H. Weinreb1*, Leslie Williams1, marcel maier2, Robert Dunstan1, stephen salloway3, Tianle chen1, Yan Ling1, John O’Gorman1, Fang Qian1, mahin Arastu1, mingwei Li1, sowmya chollate1, melanie s. brennan1, Omar Quintero-monzon1, Robert H. scannevin1, H. moore Arnold1, Thomas Engber1, Kenneth Rhodes1, James Ferrero1, Yaming Hang1, Alvydas mikulskis1, Jan Grimm2, christoph Hock2,4, Roger m. Nitsch2,4§ & Alfred sandrock1§
Nature, September 2016
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Aducanumab: N-terminal Anti-beta amyloid antibody
From Biogen Phase 1b Clinical Trial
• Reduces Amyloid Plaques
• Effects on cognition and function?
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Aducanumab: N-terminal Anti-beta amyloid antibody
From Biogen Phase 1b Clinical Trial
• Reduces Amyloid Plaques
• Some effects on cognition
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Aducanumab: N-terminal Anti-beta amyloid antibody
From Biogen Phase 1b Clinical Trial
• Reduces Amyloid Plaques
• Some effects on cognition
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MRI BrainDetect white matter disease, microvascular disease
ADVANCES IN MRI NEUROIMAGING
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STRUCTURAL NEUROIMAGING to DETECT NEURODEGENERATION
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Volumetric analysis (NeuroQuant®) Clinically measures hippocampal and ventricular volume
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Recent Advances in Neuroimaging Alzheimers: Seeing the Plaques and Tangles
MRI Tangles Amyloid Glucose
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NOVELTHERAPEUTIC
TARGETS
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“Tau” Targets for Alzheimer’s Disease
Lo et al, Sci Transl Med 2014
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Lifelong risk factors cause cellular stress, resulting in the chemical modification of genes and their expression
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With Aging, Epigenetic Changes May Cause Neurodegeneration
NATURE | VOL 483 | 8 MARCH 2012
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Drugs Are In Development To Treat Alzheimers Based on Epigenetics
HDACsHATs
Ac Ac
Ac Ac
Open reading of DNA for memory and learning genes
HDAC inhibitors
Me
Lysine Specific DemethylaseInhibitors
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Epigenetic Drugs in Development
Tamara Maes, PhDBarcelona, SpainDRUG: ORY-2001; Lysine Specific Demethylase 1/ MAO-B InhibitorSTAGE: Phase 1 Clinical Trial
Berkley Lynch, PhDBoston, USADRUG: HDAC2 InhibitorSTAGE: Preclinical
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“Applying Insights of Epigenetics to Neurological Disorders”
ADDF is Helping Rodin to Develop Specific HDAC Inhibitors for Alzheimers Through Venture Philanthropy
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Neuroinflammation
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Chronic systemic and central neuroinflammationcan accelerate Alzheimer’s and may be a trigger of the disease.
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Repurposing to Reduce Systemic Neuroinflammation
Clive Holmes, PhD
University of Southampton, UKDrug: Etanercept
Phase 2 Clinical Trial
Krishna: is target correct?
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Drug: GC021109Phase 1 Clinical TrialTarget: P2Y6
Neuroinflammation: Microglial Purinergic Receptors
Drug: AXX00179871PreclinicalTarget: P2X7
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Philip Haydon, PhDGliaCure, Boston
Paolo Pevarello, PhDAxxam SpA, Milan
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MitochondrialDysfunctionWith Aging
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Brain is 3% of body weight, uses 25% of available energy
The most metabolically active organ, dependent on glucose and oxygen
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Drug: LiraglutidePhase 2 Clinical Trial
Repurposing to Improve Neuronal Energy Failure
Paul Edison, MD, PhDImperial College London
Drug: RasagilinePhase 2 Clinical Trial
Jeffrey L. Cummings, MDThe Cleveland Clinic
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White Matter Lesions
• Over 65% elderly have hypertension
• Hypertension is associated with white matter lesions
• Treatment of hypertension may reduce white matter lesions, slow cognitive decline and progression to dementia
Clinical trials of neuroprotective anti-hypertensives for Alzheimer’s disease
• Clinical trials of angiotensin receptor blockers in patients with MCI
• NILVAD: clinical trial supported by the European Commission of a calcium channel blocker
Hypertension, the White Matter and Alzheimer’s Disease
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Neuroprotection
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Neuroprotective treatment strategies seek to shield nerve cells from degeneration and death
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Drug: RiluzolePhase 2 Clinical Trial
Ana Pereira, MD The Rockefeller University
Neuroprotection
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Neuroprotection
Frank Longo, MD, PhDStanford University
School of Medicine & Pharmatrophix
DrugLM11A-31
StagePhase 2 Clinical Trial
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P75 Receptor
LM11A-31
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Neuroprotection
Frank Longo, MD, PhDPharmatrophix
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Basic Research
Target/Lead Discovery & Validation
Pre-Clinical Development
Clinical Development
Approval & Marketing
Traditional Philanthropy
Biomedical Venture Philanthropy
Venture Capital
Private Equity/Public Markets
FINANCING GAP
HIGH RISK LOW RISK
Basic Research
Target/Lead Discovery & Validation
Pre-Clinical Development
Clinical Development
Approval & Marketing
HIGH RISK LOW RISK
VENTURE PHILANTHROPY IN DRUG DISCOVERY
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92$
MILLIONINVESTED
PROGRAMS IN18 COUNTRIES
Funded 500+ 85BIOTECHS
+
+
OVER 100 ACTIVE PROGRAMS, INCLUDING 17 CLINICAL TRIALS
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ADDF PARTNERSHIPS
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• Early diagnosis of Alzheimer’s disease is possible
• Disease modifying drugs to prevent and treat Alzheimer’s disease are in human clinical trials
• Prevention of Alzheimer’s disease by mid-life strategies is possible
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Today, Conquering Alzheimer’s is an Achievable Goal