Progress in Alzheimer s disease diagnostics validation and use of cognitive endpoints and surrogate markers

Transcription

1 Progress in Alzheimer s disease diagnostics validation and use of cognitive endpoints and surrogate markers Randall Bateman, Tammie Benzinger, Nigel Cairns, John Morris, Nick Fox, Bill Klunk, Anne Fagan, Chris Rowe, Cliff Jack, Henrik Zetterberg and the DIAN We gratefully acknowledge the DIAN and DIAN TU participants and family members, DIAN Team, Alzheimer s Association, Pharma Partners (Eli Lilly, Hoffman LaRoche, Avid Radiopharmaceuticals, CogState), NIA, DIAN TU Pharma Consortium, GHR, Anonymous Foundation, and Regulatory Representatives for support.

2 Alzheimer s disease the challenge The most common form of dementia Pathology of loss of synapses and neurons, and amyloid and tau deposits Clinically begins with gradual cognitive loss Progressive memory loss, decreased judgment, communication challenges, personality changes & confusion Worsens over time until death Has common pathophysiology but may have a variety of pathogenic causes No cure (or disease modifying treatment) currently for Alzheimer's (universally fatal). >30 million patients suffering from Alzheimer s world wide 5 million in the US. 6 th leading cause of death and only increasing major cause of death. >$200 Billion annual cost. ~90% of research grants rejected and not funded.

3 Brain atrophy from Alzheimer s disease AD brain normal brain Courtesy of ADRC Neuropathology Core

4 Pathologic Lesions of AD: Neuritic Plaque (left) and Neurofibrillary Tangle (right) Modified Bielschowsky silver impregnation Courtesy of WU ADRC Neuropathology Core

5 Dominantly Inherited Alzheimer s Disease in the first Alzheimer s patient <1% of AD cases result from autosomal dominant mutations in 3 genes directly involved in amyloid beta (A ) production Amyloid precursor protein (APP) Presenilin 1 (PSEN1) Presenilin 2 (PSEN2) Auguste D., the first AD patient described by Dr. Alois Alzheimer, was found to carry an ADAD mutation in Presenilin 1 (F176L)

6 DIAN Observational and Trial sites DIAN Observational ONLY DIAN TU ONLY DIAN Observational & DIAN TU Potential Future Sites

7 DIAN amyloid deposition by estimated age of onset Courtesy of Tammie Benzinger; Bateman et. al NEJM 2012

8 Courtesy of Tammie Benzinger - DIAN

9 DIAN Clinical and Cognitive Data Significant differences in CDR SB and MMSE scores are significant 5 years before expected symptom onset A significant difference in the delayed recall portion of the Logical Memory test is detected 10 years before expected symptom onset Bateman et. al., al NEJM

10 Stages of dominantly inherited AD 1 prevent 2 prevent Cog decline prodromal Mild Moderate dementia The DIAN; Bateman et. al NEJM 2012

11 Biomarkers and Cognition in Sporadic Alzheimer s disease

12 Imaging for Neurodegenerative Disease Tailored Imaging MRI FDG PET Beta-amyloid imaging (PET) Tau Imaging

13 Atrophy accelerates pre-diagnosis Chan et al Lancet 2003;362:

14 Video by Scott Ziolko & Julie Price Going Beyond: Amyloid Imaging Allows a 3- Quantitative Rendering Across the Entire Br University of Pittsburgh Amyloid Imaging Group

15 Progression to from normal to very mild dementia by CSF biomarkers * Corrected for age, sex, education, APOE genotype (Vos et al., 2013, Lancet Neurol)

16 Comparison of Autosomal Dominant and Sporadic AD Measure Autosomal Dominant AD Sporadic AD Clinical presentation Amnestic Amnestic Cognitive deterioration Memory, frontal/executive, generalized cognitive decline Memory, frontal/executive, generalized cognitive decline MRI Hippocampal atrophy and whole brain atrophy Hippocampal atrophy and whole brain atrophy PiB PET Cortex plus basal ganglia Cortex FDG PET Parieto occipital hypometabolism Parieto occipital hypometabolism CSF Aβ 42 Decreased by 50% Decreased by 50% CSF tau Increased by 2 fold Increased by 2 fold

17 Disease Modification treat processes thought to underlie the disease or reduce the rate of damage Outcome: Clinical, Cognitive, Biological, Functional (ADLs), Disability, Death Rate: slow disease progression (slope change), sustained benefit after withdrawal Biomarkers of disease pathology or pathophysiology Prevention, Delay, or Cure? Pharmacology, Lifestyle (diet, activity, exercise), genetic (Icelandic mutation)

18 Disease Modifying Therapeutic Attempts Class (date of available results) Target/MOA (+ = human CNS target engagement) Outcome AN1792 (2002) Amyloid active vaccination (+) Negative (AEs) NSAIDs (2004) Inflammation Neutral Tarenflubil (2005) Gamma secretase Neutral Atorvastatin; simvastatin (2010) Cholesterol (HMG CoA reductase Neutral inhibitor) Rosiglitazone (2010) Insulin (PPAR gamma agonist) Neutral Latrepirdine (2010) Mitochondrial function Neutral Tramiprosate (2011) Amyloid anti-aggregation Neutral Bapineuzumab (2012) Aggregate Aβ passive vaccination (+/- decrease progression) Solanezumab (2012) Soluble Aβ passive vaccination (++ binds significant soluble Aβ ) Semagacestat; avagacestat (2013) Gamma secretase (+ decreases production by 15-25% per day) Neutral IVIG (2013) Nonselective immunorx Neutral Adapted from The DANA Foundation. 1_V2final_lg.jpg Website accessed November 1, Neutral (positive mild AD) Negative (AEs) Beta Secretase Inhibitors Beta secretase (+++) pending

19 Challenges for disease modification Too late? Focus on earlier stages of the disease including secondary prevention. Too little? Biomarker engagement in the human CNS of the mechanism of action has been inconsistently shown in many trials. No drug has normalized AD biomarkers Wrong target? Which Aβ species, tau species, other? Not all targets may be safe to maximally effect (e.g. general gamma secretase inhibitors)

20 Through public/private support and partnership, the DIAN TU has launched trials to provide advancement of treatments, scientific understanding and improvements in the approach to Alzheimer s disease drug developments. DIAN Pharma Consortium U01 AG042791, R01 AG *Financial support has also been provided by anonymous sources.

21 Adaptive Design for drug(s) to continue to a Cognitive Endpoint Trial Outcomes: If drug(s) demonstrate positive biomarker profiles, enrollment continues for a cognitive endpoint registration trial. If drug(s) don t have positive biomarker or safety profiles, then new drugs will be added to the platform. A B C DIAN study (run-in) 3:1 active to placebo (pooled placebo) Drug A, B, or C monthly for 24 mo Years Years A (80) A (80) D (80) B (80) B (240) B (80) E (80) Biomarker, clinical, and cognitive measures and samples C (80) C (80) F (80) D (80) E (80)

22 DIAN TU trial design: Biomarker Phase for parallel adaptive drug design. Enrollment of both mutation carriers and noncarriers. Option of non disclosure of genetic status to participate in the DIAN TU trial

23 The DIAN TU Adaptive Prevention Trial (APT) YEARS 24

24 Historical Precedent: Treatment of inherited high cholesterol with statin drug Pre treatment Post treatment

25 Amyloid deposition in the 30 s and 40 s in people with ADAD Mutations A B C 15 years prior to estimated symptoms 10 Years prior to estimated symptoms ~5 years after Alzheimer s disease symptoms Courtesy of Mark Mintun and Randy Bateman

26 A brief (biased) history of Alzheimer s disease modifying prevention 2014 Prevention trials targeting at risk individuals 2012 first prevention trial against amyloid beta is launched 2012 Aβ lowering mutation discovered which dramatically protects against Alzheimer s 1906 Dr. Alois Alzheimer describes first Alzheimer s disease patient disease of brain plaques and tangles Senility known throughout history 2000 s first drugs targeting Aβ A cause of Alzheimer s are developed 1991 Mutations discovered that cause early onset Alzheimer s in families later discovered in Alzheimer s first patient

27 DIAN TU Administrative and Clinical Operations Team Randall Bateman PI, Stephanie Belyew, Virginia Buckles, Matt Carril, David Clifford, Tamara Donahue, Angela Fuqua, Ron Hawley, Amanda Houchin, Jacki Mallmann, Susan Mills, John Morris, Angela Oliver, Davis Ryman, Anna Santacruz, Wendy Sigurdson, Jessi DIAN TU Cores Administrative: Randall Bateman and team Biomarkers: Anne Fagan and team Biostatistics: Chengjie Xiong and team Clinical: Dave Clifford and team Cognition: Peter Snyder and team, Jason Hassenstab Genetics: Alison Goate and team Imaging: Tammie Benzinger and team Informatics: Dan Marcus and team We gratefully acknowledge the DIAN participants and family members, DIAN Team, DIAN Steering Committee, Alzheimer s Association, ADAD Forum, NIH U01AG042791, DIAN TU Pharma Consortium, Pharma Partners Eli Lilly, Hoffman LaRoche, Avid, CogState, Anonymous Foundations and Regulatory Representatives. Smith, Joy Snider, Ellen Ziegemeier DIAN TU Collaborators Project Arm Leaders : Steve Salloway, Martin Farlow, Martin Rossor ADCS: Ron Thomas and Paul Aisen University of Michigan: Robert Koeppe Mayo Clinic: Clifford Jack Consultants : Univ of Rochester Cornelia Kamp, Berry Consultants, Univ of Pittsburgh Scott Mason DIAN TU Therapy Evaluation Committee: Paul Aisen, Randall Bateman, Maria Carillo, Dave Clifford, David Cribbs, Bart De Strooper, David Holtzman, Jeffrey Kelly, William Klunk, Cynthia Lemere, Eric McDade, Susan Mills, John Morris, Laurie Ryan, Raymond Tait, William Thies DSMB Members: Karl Kieburtz, Steve Greenberg, David Knopman, Allan Levey, Scott Kim, Gary Cutter

28 The Dominantly Inherited Alzheimer s Network Observation and Trials The DIAN participants and family members The Alzheimer s Association, ADAD Forum, DIAN Pharma Consortium DIAN Principal Investigator DIAN TU Principal Investigator JC Morris RJ Bateman Coordinating Center Cores Admin JC Morris Clinical RJ Bateman Biomarkers AM Fagan Biostatistics C Xiong Performance Sites Genetics AM Goate Imaging T Benzinger Informatics D Marcus Neuropathology NJ Cairns United States: Washington Univ (Bateman), MGH/BWH (Sperling), Butler Hosp/Brown Univ (Salloway), Columbia Univ (Mayeux), Indiana Univ (Ghetti), UCLA (Ringman), U of Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff Radford) Europe: Institute of Neurology, Univ College London (Rossor), Ludwig Maximilians Universität München (Danek), University of Tübingen (Jucker) Australia: Prince of Wales Medical Research Institutes, Sydney (Schofield), Mental Health Health Research Institute, Melbourne (Masters), Edith Cowan Univ, Perth (Martins) f Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff Radford)