Director’s Report NCA TS Advisory Council and CAN Review Board CHRISTOPHER P . AUSTIN, M.D. DIRECTOR, NCATS JUNE 13, 2016
Selected Translational Innovation Highlights • Early-st age t ranslat ion: chemical probe/ lead development for target validation and therapeutic hypothesis testing • Mid-st age t ranslat ion: preclinical development to first-in-human studies • Lat e-st age t ranslat ion: large-scale studies in humans 2
Rapid Antidepressant Effect of Ketamine in Unmedicated Treatment Resistant Depression Hamilton Depression Rating Scale (HAM-D) Drop in Depression Rating following 30 a Single Ketamine Infusion (N=18) 25 ● Rapid Effect in Major Depressive Disorder 20 ● Rapid Decreases in * 15 Suicidal Ideation ● Rapid Effect in 10 Treatment Resistant ** *** *** ** *** Bipolar (BP) Depression 5 Placebo Ketamine 0 Day Day Day Day -60 40 80 110 230 1 2 3 7 Zarate et al. Arch Gen Psychiatry 2006 3
DPI Ketamine Metabolites for Depression • Collaborators University of Maryland S chool of Medicine National Institute of Mental Health and National Institute on Aging • Background S evere depression affects ~16% of the world population Current therapies require prolonged administration for clinical improvement and some patients are non-responsive • Proj ect Non-competitive, glutamatergic NMDAR antagonist (R,S )-ketamine exerts quick and prolonged antidepressant effects after a single dose, but also has side effects. S howed that ketamine metabolite ((2R,6R)-HNK) reversed depression-like behaviors in mice without triggering anesthetic, dissociative, or addictive side effects Data illustrate novel mechanism and have potential for the development of next-generation antidepressants 4
Extensive metabolism of ketamine -norketamine -DHNK -ketamine ( R,S ) ( R,S ) ( R,S ) -DHNK -norketamine -DHNK -norketamine ( S ) -ketamine ( S ) ( R ) -ketamine ( R ) ( S ) ( R ) O O O O O O MeHN MeHN H 2 N H 2 N H 2 N H 2 N Cl Cl Cl Cl Cl Cl -ketamine derived HNKs and HKs R ) ( O O O O O O O O H 2 N H 2 N MeHN MeHN H 2 N H 2 N H 2 N H 2 N OH OH OH OH OH OH ClOH ClOH Cl Cl Cl Cl Cl Cl -HNK -HK -HK -HNK -HNK -HNK -HNK -HNK ( 2R,6S ) ( 2R,6S ) ( 2R,6R ) ( 2R,6R ) ( 2R,5R ) ( 2R,5S ) ( 2R,4S ) ( 2R,4R ) -ketamine derived HNKs and HKs S ) ( O O O O O O O O H 2 N H 2 N MeHN MeHN H 2 N H 2 N H 2 N H 2 N OH OH OH OH OH OH ClOH ClOH Cl Cl Cl Cl Cl Cl -HNK -HK -HK -HNK -HNK -HNK -HNK -HNK ( 2S,6R ) ( 2S,6R ) ( 2S,6S ) ( 2S,6S ) ( 2S,5S ) ( 2S,5R ) ( 2S,4R ) ( 2S,4S ) 5
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Selected Translational Innovation Highlights • Early-st age t ranslat ion: chemical probe/ lead development for target validation and therapeutic hypothesis testing • Mid-st age t ranslat ion: preclinical development to first-in-human studies • Lat e-st age t ranslat ion: large-scale studies in humans 10
Coalition of Patient NIH Porphyria Rare Disease Clinical ORDR/NCATS, NCI, NHLBI, Advocacy Groups Research Consortium NIAID, NIAMS, NICHD, NIDCR, Dystonia (CPAG for RDCRN) PAG NIDDK, NIMH, NINDS, ODS Coalition North America Mitochondrial Diseases Consortium PAG Developmental Synaptopathies PAG Primary Immune Deficiency Associated with TSC, PTEN Treatment Consortium And SHANK3 Mutations PAG PAG The Frontotemporal Lobar Brittle Bone Disorders Consortium Degeneration Clinical PAG Research Consortium PAG Chronic Graft Versus Inherited Neuropathies Host Disease Consortium PAG PAG The Data Management and Nephrotic Syndrome Coordinating Center Study Network PAG • Collaborative Clinical Research Rare Lung Diseases Urea Cycle Disorders • Centralized Data Consortium Consortium PAG Coordination and PAG Technology Development Lysosomal Brain Vascular • Public Resources and Disease Network Malformation Consortium PAG Education PAG Rare Kidney • Training Genetic Disorders of Stone Consortium PAG PAG Mucociliary Clearance Vasculitis Clinical Consortium of Eosinophilic Research Consortium PAG PAG Gastrointestinal Disease Researchers PAG Clinical Research in ALS & Related PAG Disorders for Therapeutic Development PAG PAG Rett, MECP2 Duplications Autonomic Disorders Sterol and Isoprenoid and Rett-Related Consortium Diseases Consortium Disorders Consortium 11
Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that primarily affects women of childbearing age that is often fatal 12
RDCRN-Rare Lung Diseases Consortium (RLDC) Development of sirolimus for LAM • S irolimus (aka rapamycin, Rapamune) is an mTOR inhibitor originally approved for prevention of transplant rej ection • LAM is associated with inappropriate activation of mTOR signaling, which regulates cellular growth and lymphangiogenesis • RLDC conducted Multicenter International LAM Efficacy and S afety of S irolimus (MILES ) trial PI: Frank McCormack, University of Cincinnati Collaborative effort among RDCRN-RLDC, Pfizer, LAM Foundation • FDA approved sirolimus for LAM in March 2015 First drug approved by FDA for the treatment of this rare disease 13
New Therapeutic Uses Program • First round of proj ects Disease Academic Partner Pharma Partner Alzheimer’s Disease Yale AstraZeneca Alcoholism U Rhode Island/NIAAA Pfizer Calcific Aortic Stenosis Mayo Clinic Sanofi Duchenne Muscular Dystrophy Kennedy Krieger/UWash Sanofi Lymphangioleiomyomatosis Baylor AstraZeneca Peripheral Artery Disease U Virginia AstraZeneca Smoking Cessation VCU/Pittsburgh Janssen Schizophrenia (2) Indiana U Lilly Yale Pfizer • Translational Innovation S uccess Measures Does use of template agreements speed negotiation time? Does crowdsourcing of indications generate new ideas? Do studies result in new indications/ approvals? 14
NTU project: AZD0530 (saracatinib) for LAM • S rc family kinase inhibitor originally developed for cancer Also being t est ed in NTU for Alzheimer’s Disease • S rc is activated in LAM cells Cont ribut es t o oncogenic propert ies of LAM cells • NTU LAM Phase 2a trial ongoing PI: Tony Eissa (Baylor) Frank McCormack (Universit y of Cincinnat i) S t ephen Rouss (S t anford Universit y) Daniel Dilling (Loyola Universit y, Chicago) Elizabet h Henske & S ouheil El-Chemaly (Brigham and Women’s Hospit al) 15
Selected Translational Innovation Highlights • Early-st age t ranslat ion: chemical probe/ lead development for target validation and therapeutic hypothesis testing • Mid-st age t ranslat ion: preclinical development to first-in-human studies • Lat e-st age t ranslat ion: large-scale studies in humans 16
The NCATS Clinical and Translational Science Awards Program CTSA Hubs 17
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Clinical Trials Opportunity for Operational Innovation Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014 19
Clinical Trials Opportunity for Operational Innovation Current Work Models Small, frequently single-center studies Inconsistent power, rigor Poor enrollment Suboptimal scientific impact Operational Challenges Research:Clinical parallel universes Fragmented, duplicative infrastructure Lack of collaborative efforts Misaligned incentives Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014 20
Clinical Trials Opportunity for Operational Innovation Current Work Models Opportunity for Small, frequently single-center studies Operational Innovation Inconsistent power, rigor Poor enrollment Suboptimal scientific impact Invent and deploy new Operational Challenges approaches Research:Clinical parallel universes to clinical studies Fragmented, duplicative infrastructure Lack of collaborative efforts Misaligned incentives Califf RM et al. JAMA 2012; Hirsch BR et al. JAMA Intern Med 2013; Goswami ND et al. PLOS One 2013; Alexander KP et al. JAHA 2013;Todd JL et al. Annals ATS 2013; Inrig JK et al. Am J Kidney Dis 2014 21
NIH Clinical Trials Opportunity for Operational Excellence NIH Budget – FY 2015 Clinical Trials $3.2 B ~10% $27.1 B NIH Budget Office; Mullard A. Nature Reviews Drug Disc 2016; GAO Report, 2016; Innovation for Healthier Americans, 2015 22
NIH Clinical Trials Opportunity for Operational Excellence NIH Budget – FY 2015 Results of Current Work Models Clinical Trials not finishing on time or within budget Trials Frequently large unobligated balances $3.2 B Suboptimal return on research investments ~10% Decreased public trust Operational Challenge Enhance stewardship and accountability of NIH clinical trials $27.1 B NIH Budget Office; Mullard A. Nature Reviews Drug Disc 2016; GAO Report, 2016; Innovation for Healthier Americans, 2015 23
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