the national center for advancing translational sciences · • comprehensive pre- ind tox and adme...
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The National Center for Advancing Translational Sciences Catalyzing Translational Innovation
CHRISTOPHER P. AUSTIN, M.D. DIRECTOR, NCATS
NIH DEMYSTIFYING MEDICINE
APRIL 14, 2015
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Disorders with Known Molecular Basis
Source: Online Mendelian Inheritance in Man, Morbid Anatomy of the Human Genome
~500 with therapy
SO….
What is Translation?
Translation is the process of turning observations in
the laboratory, clinic, and community into
interventions that improve the health of individuals
and the public - from diagnostics and therapeutics to
medical procedures and behavioral changes.
What is Translational Science?
Translational Science is the field of investigation
focused on understanding the scientific and
operational principles underlying each step of the
translational process.
NCATS studies translation as a
scientific and organizational problem.
Translational Science Spectrum
NCATS Mission
To catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.
Some of the scientific translational problems on NCATS’ to-do list
• Predictive toxicology • Predictive efficacy • Derisking undruggable targets/untreatable diseases • Data interoperability • Biomarker qualification process • Clinical trial networks • Patient recruitment • Electronic Health Records for research • Harmonized IRBs • Clinical diagnostic criteria • Clinical outcome criteria (e.g., PROs) • Adaptive clinical trial designs • Shortening time of intervention adoption • Methods to better measure impact on health (or lack of)
NCATS “3D’s”
evelop emonstrate isseminate
NCATS Scientific Initiatives • Clinical Translational Science
Clinical and Translational Science Awards Rare Disease Clinical Research Network New Therapeutic Uses program
• Preclinical Translational Science NIH Chemical Genomics Center Therapeutics for Rare and Neglected Diseases program Bridging Interventional Development Gaps program
• Re-engineering Translational Sciences Toxicology in the 21st Century Microphysiological Systems (Tissue Chip) program Office of Rare Diseases Research
Innovation in Preclinical Development: Therapeutics for Rare and Neglected Diseases
(TRND) Program
• Model: Collaboration between NCATS labs with preclinical drug development expertise and extramural labs with disease-area/target expertise
• Projects:
Entry from Probe to IND-enabling Taken to stage needed to attract external organization to adopt for
completion of clinical development Serve to develop new generally applicable platform technologies and
paradigms • Eligible Applicants:
Academic, Non-Profit, Government Lab, Biotech, Pharma Ex-U.S. applicants accepted
• Intellectual Property:
Partnerships are creative TRND may generate intellectual property
TRND Scope
Medicinal chemistry optimization
Evaluation of functional activity, potency, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy
Biomarker development
Definition or optimization of dose and schedule for in vivo activity
Development of pharmacology assays
Conduct of pharmacology studies with a pre-determined assay
Acquisition of bulk substance (GMP and non-GMP)
Development of suitable formulations
Development of analytical methods for bulk substances
Production of dosage forms
Stability assurance of dosage forms
Range-finding initial toxicity
Investigational New Drug (IND)-directed toxicology, with correlative pharmacology and histopathology
Planning of clinical trials
Regulatory and IND filing support
First-in-Human clinical trials, as needed to support external adoption
TRND Scope
Medicinal chemistry optimization
Evaluation of functional activity, potency, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy
Biomarker development
Definition or optimization of dose and schedule for in vivo activity
Development of pharmacology assays
Conduct of pharmacology studies with a pre-determined assay
Acquisition of bulk substance (GMP and non-GMP)
Development of suitable formulations
Development of analytical methods for bulk substances
Production of dosage forms
Stability assurance of dosage forms
Range-finding initial toxicity
Investigational New Drug (IND)-directed toxicology, with correlative pharmacology and histopathology
Planning of clinical trials
Regulatory and IND filing support
First-in-Human clinical trials, as needed to support external adoption
Therapeutics for Rare and Neglected Diseases Program
Therapeutic Area/Disease Organization Name(s) Partner Type(s)
Autoimmune pulmonary alveolar proteinosis
Cincinnati Children’s Hospital Academic
Creatine Transporter Defect Lumos Pharma, Inc. Biotech Chronic lymphocytic leukemia Leukemia & Lymphoma Society, University of Kansas Cancer
Center Disease foundation, academic
Core binding factor leukemia NHGRI NIH intramural labs
Fibrodysplasia ossificans progressiva Massachusetts General Hospital Academic
GNE Myopathy (Hereditary Inclusion Body Myopathy NIBM)
New Zealand Pharmaceuticals, NHGRI Biotech and NIH intramural clinical labs
Hemoglobinopathies Phoenicia Biosciences, Inc. Biotech
Hypoparathyroidism Eli Lilly & Co. Pharmaceutical
LEOPARD syndrome Beth Israel Deaconess Medical Center Academic
Malaria Loyola University Chicago Academic
Niemann-Pick disease type C Ara Parseghian Medical Research Foundation, Niemann-Pick Type C Support of Accelerated Research (NPC-SOAR), Einstein College of Medicine, University of Pennsylvania, Washington University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Human Genome Research Institute (NHGRI)
Disease foundation, academic, NIH intramural labs
Retinitis pigmentosa University of California, Irvine Academic
Schistosomiasis CoNCERT Pharmaceuticals Biotech
Sickle cell disease Aes-Rx, National Heart, Lung and Blood Institute Biotech, NIH intramural labs
Therapeutics for Rare and Neglected Diseases Program
Therapeutic Area/Disease Organization Name(s) Partner Type(s)
Autoimmune pulmonary alveolar proteinosis
Cincinnati Children’s Hospital Academic
Creatine Transporter Defect Lumos Pharma, Inc. Biotech Chronic lymphocytic leukemia Leukemia & Lymphoma Society, University of Kansas Cancer
Center Disease foundation, academic
Core binding factor leukemia NHGRI NIH intramural labs
Fibrodysplasia ossificans progressiva Massachusetts General Hospital Academic
GNE Myopathy (Hereditary Inclusion Body Myopathy NIBM)
New Zealand Pharmaceuticals, NHGRI Biotech and NIH intramural clinical labs
Hemoglobinopathies Phoenicia Biosciences, Inc. Biotech
Hypoparathyroidism Eli Lilly & Co. Pharmaceutical
LEOPARD syndrome Beth Israel Deaconess Medical Center Academic
Malaria Loyola University Chicago Academic
Niemann-Pick disease type C Ara Parseghian Medical Research Foundation, Niemann-Pick Type C Support of Accelerated Research (NPC-SOAR), Einstein College of Medicine, University of Pennsylvania, Washington University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Human Genome Research Institute (NHGRI)
Disease foundation, academic, NIH intramural labs
Retinitis pigmentosa University of California, Irvine Academic
Schistosomiasis CoNCERT Pharmaceuticals Biotech
Sickle cell disease Aes-Rx, National Heart, Lung and Blood Institute Biotech, NIH intramural labs
TRND Collaboration Sickle Cell Disease
Collaborator: AesRx, LLC Compound: Aes-103 (5-hydroxymethyl-2-furfural)
– Binds to sickle hemoglobin, increases O2 affinity
Roadblocks in drug development – Animal toxicology studies – CMC (Chemistry, Manufacturing, and Quality Control) – Regulatory: interactions with FDA, IND filing
TRND collaborated with AesRx on IND-enabling pre-clinical animal toxicology, CMC
– Project initiation to patients in <12 mos
Phase Ia-1b-IIa clinical trials at NIH Clinical Center and Quintiles – (Greg Kato, NHLBI) and CRU
Scope of TRND Sickle Cell Project
Medicinal chemistry optimization
Evaluation of functional activity, potency, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy
Biomarker development
Definition or optimization of dose and schedule for in vivo activity
Development of pharmacology assays
Conduct of pharmacology studies with a pre-determined assay
Acquisition of bulk substance (GMP and non-GMP)
Development of suitable formulations
Development of analytical methods for bulk substances
Production of dosage forms
Stability assurance of dosage forms
Range-finding initial toxicity
Investigational New Drug (IND)-directed toxicology, with correlative pharmacology and histopathology
Planning of clinical trials
Regulatory and IND filing support
First-in-Human clinical trials, as needed to support external adoption
TRND Sickle Cell Project Accomplishments
18
• Comprehensive pre-IND tox and ADME program. Determined high-level RBC drug uptake, wide safety window
• Regulatory endpoints clarified with FDA
• Completed Phase 1 safety trials in healthy African-American volunteers and sickle cell patients
• Phase 2a trial in sickle cell patients commenced. Clean safety profile and clinical Proof-of-Concept established
• Lead molecule to Phase 2 Proof-of-Concept in less than 3 years. Now most advanced anti-sickling agent in development.
The Tale of Translating Aes103
Manufacturing and Control
Target/specificity
PKDM PD/Toxicology
Formulation
5%
June 2010, CDA
Human testing
The number of new drugs approved by the FDA per billion US dollars (inflation-adjusted) spent on research and development (R&D) has
halved roughly every 9 years since 1950.
Scannell et al., Nature Reviews Drug Discovery 11:191, 2012
Eroom’s Law
Science Translational Medicine 7: 276ps3, 26 Jan 2015
Eroom’s Law: Bendable!
Costs lower
Success rates higher
Program Leads at NCATS • Preclinical Innovation: Anton Simeonov
• Clinical Innovation: Petra Kaufmann » [email protected]
• Office of Rare Diseases: Pamela McInnes » [email protected]
• Tissue Chip: Dan Tagle » [email protected]
• New Therapeutic Uses: Christine Colvis » [email protected]
• Strategic Alliances: Lili Portilla » [email protected]
Learn More About NCATS
Website: www.ncats.nih.gov Facebook: facebook.com/ncats.nih.gov Twitter: twitter.com/ncats_nih_gov YouTube: youtube.com/user/ncatsmedia E-Newsletter: ncats.nih.gov/news-and- events/e-news/e-news.html
Email us! [email protected]