Accelerating Gene Therapy for Rare Genetic Diseases

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2 Accelerating Gene Therapy for Rare Genetic Diseases P.J. Brooks, Ph.D. and Stephen C. Groft, Pharm. D. Office of Rare Diseases Research Division of Program Coordination, Planning, and Strategic Initiatives National Institutes of Health Department of Health and Human Services

3 Presenter Disclosure: Stephen C. Groft, Pharm.D P.J. Brooks, Ph.D. Office of Rare Diseases Research No disclosures to report

4 Outline ORDR: Who we are and what do we do Rare disease clinical research network (RDCRN) ORDR efforts related to gene therapy Gene therapy in the RDCRN NIH Common Fund proposal Ideas to facilitate access to gene therapy for rare diseases

5 The NIH Office of Rare Diseases Research established in 1993 ORDR mandate What is ORDR Coordinate and support rare diseases research Provides information on rare diseases Respond to research opportunities for rare diseases Located within Office of the NIH Director Moving into proposed National Center for Accelerating Translational Sciences (NCATS)

6 What is a Rare/Orphan Disease The FDA defines an orphan disease as: A condition affecting <200,000 Americans Significance: Designation under the Orphan Drug Act There are an estimated 7,000 rare diseases Approximately million Americans have a rare disease

7 Office of Rare Diseases Research Some ongoing activities WHO International Classification of Diseases with Rare Diseases Emphasis ( ICD 11 ) with Orphanet Develop Reliable Prevalence Data for Rare Diseases Evaluate Dietary Supplements for Inborn Errors of Metabolism Bench-to-Bedside Awards - Clinical Center Scientific Conferences Program Web-Based Rare Disease Patient Registry and Data Repository Web-Based Searchable Registry of Biospecimen Repositories Research, Condition, Disease Categorization (RCDC) for Rare Diseases Educational Curriculum Module on Rare Diseases for Middle School Students - Office of Science Education

8 The Rare Diseases Clinical Research Network (RDCRN)

9 Challenges for Rare Diseases Research Disease often not well characterized or defined Rarity means: Recruitment for trials is usually quite difficult Study populations become widely dispersed Few expert centers for diagnosis, management, and research Often little high quality evidence available to guide treatment

10 RDCRN Established by the Office of Rare Diseases Research Started in 2003 currently in 2nd 5 year cycle 1st cycle (10 Consortia) supported by ORDR, NCRR, NINDS, NIAMS, NICHD, NHLBI, NIDDK 2nd cycle (19 Consortia) supported by ORDR, NINDS, NIAMS, NICHD, NHLBI, NIDDK, NIAID, NIDCR, NCI 3rd cycle in planning stage Currently involves 208 institutions world wide Collectively studying >200 diseases, >8000 patients

11 Goals of the RDCRN Facilitate clinical research by: Creation of Consortia focused on related diseases Cost sharing research infrastructures Establishing uniform protocols for data collection Making meaningful large scale studies possible Longitudinal cohorts, pilot projects, randomized trials Natural history studies required in RDCRN Directly engage patients and their advocates Train new investigators in rare diseases research

12 DHHS-NIH ORDR, NINDS, NIAMS, NICHD, NHLBI, NIDDK, NIDCR, NIAID, NCI Genetic Disorders of Mucociliary Clearance Consortium Porphyria Rare Disease Clinical Research Consortium Vasculitis Clinical Research Consortium Dystonia Coalition Coalition of Patient Advocacy Groups (CPAG) Chronic Graft Versus Host Disease Consortium North America Mitochondrial Diseases Consortium Primary Immune Deficiency Treatment Consortium The Data Management and Coordinating Center Lysosomal Disease Network Rare Kidney Stone Consortium Inherited Neuropathies Consortium Urea Cycle Disorders Consortium Molecular and Epidemiologic Characterization of Salivary Gland Carcinomas Consortium Collaborative Clinical Research Centralized Data Coordination and Technology Development Public Resources and Education Training Clinical Investigation of Neurological Channelopathies Sterol and Isoprenoid Diseases Consortium Brain Vascular Malformation Consortium Autonomic Rare Diseases Clinical Research Consortium Nephrotic Syndrome Rare Disease Clinical Research Network Angelman, Rett and Prader-Willi Syndromes Consortium Spinocerebellar Ataxia Clinical Research Consortium

13 RDCRN Data Management and Coordinating Center (DMCC) Supports RDCRN by providing technologies, tools, and support of study design and data analysis On line protocol management system Patient enrollment/randomization Data entry and collection with data standards Adverse event reporting Protocol training for research staff Members website: documentation, databases Hosts RDCRN public website (>2 million hits/year) Oversees the RDCRN Patient Contact Registry

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15 Rare genetic diseases: opportunities for accelerating clinical gene therapy Single gene mutations Rationale for gene replacement therapy is clear Often very few patients less vector production needed Limited understanding of pathophysiology No other treatments or therapies available Often fatal without treatment Mitigate safety concerns about possible bad outcomes

16 Gene Therapy in the RDCRN Lysosomal disease network AAV2 for Tay-Sachs (Whitley) Urea cycle disorders consortium Primary immune disorders consortium

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18 The current system Typically 1 disease - 1 clinical trial 1000s of rare genetic diseases <100 patients Many diseases currently too rare to treat despite rational therapeutic strategy available

19 A different approach : grouping for clinical trials Orphan drug act : grouping based on rarity RDCRN: Grouping multiple related rare diseases based on clinical phenotype Basis for grouping in gene therapy Type of disease (e.g. LSDs) Type of vector platform??

20 Benefits of grouping

21 NIH-FDA Regulatory Science Initiative (NCATS) International Rare Disease Community

22 DISEASE Adapted from RARE CS ALD Gene Therapy Clinic FIX FA LCA Tay-Sachs GAN 1 Batten SCID HD DMD

23 NIH Office of Rare Diseases Research Stephen Groft, Pharm.D. Director *P.J. Brooks, Ph.D. Ms. Mary Demory David Eckstein, Ph.D. Marita Eddy (Angel Flight) John Ferguson, M.D. Rashmi Gopal-Srivastava, Ph.D. Christopher Griffin Henrietta Hyatt-Knorr Michele Lloyd-Puryear, M.D., Ph.D. Lata Nerurkar, Ph.D. Susan Orr Lowe Geraldine Pollen Yaffa Rubinstein, Ph.D. * On detail from the Division of Metabolism and Health Effects, NIAAA, NIH

24 Office of Rare Diseases Research National Institutes of Health 6100 Executive Boulevard Room 3A-07, MSC Bethesda, MD Voice: Fax: ORDR@nih.gov