Drug Development and Clinical Trials Pat Furlong Parent Project Muscular Dystrophy

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1 Drug Development and Clinical Trials Pat Furlong Parent Project Muscular Dystrophy ParentProjectMD.org

2 -LATE 1990 s Where Are We? - Total NIH funding for MD is $17M -No new drugs in development -Average lifespan for DMD is late teens -No guidelines for care -No pa@ent registries

3 Where Are We Now? -LATE 1990 s TOTAL NIH funding all MDs ($78M) >17 new drugs in DMD trials >Many others in preclinical development Care guidelines for DMD disseminated globally & update underway DMD Lifespan increased by 10+ years Natural History Studies, Registries and other drug development tools - Total NIH funding for MD is $17M -No new drugs in development -Average lifespan for DMD is late teens -No guidelines for care -No pa@ent registries

4 Duchenne Therapeutic Schematic Natural History of DMD (Adapted from Bushby, Connor. Clin Investig (Lond). 2011; McDonald, et al. Muscle Nerve. 2013) 5 Years Prior to Treatment, 1960s Exon-Skipping Gene Therapy Loss of Standing Steroid Dx Replacement Approaches 9 Years 14 Years 20 Years Loss of Ambulation CRISPR/Cas9 Dystrophin Loss of Restoration Self-Feeding /Replacement Stop-Codon Readthrough Stem Cells Traditional Cardiac Drugs Death Anti- Fibrotics Ryanodine Receptors Myostatin Inhibition Inflammation & Fibrosis Spinal Surgery and Ventilation Dx Loss of Standing Regulation Homeostasis Loss of Ambulation Treating Duchenne Loss of Self-Feeding Muscle Growth and Protection Cardiac Blood Flow Follistatin Loss Ambulation Selective Androgen Utrophin via Gene Therapy Receptor Modulators Loss of Self-Feeding nnos Mitochondria Biogenesis Ventilation Stem Cells Contemporary: With Steroids and Improved Cardiac Management Dx Loss of Standing Steroids affect disease progression in DMD over the entire course of the disease, prolonging clinically meaningful functions (time to loss of milestones) Death Enhancers Ventilation Death 8

5 Study Types Multi-Phase Clinical Trials Phase I: First in humans (mechanistic, usually in healthy volunteers, dosing, small n) Phase IIa: Safety and Efficacy Phase IIb: Pivotal Phase III: Classical RCT Phase IV: Post-Marketing Epidemiology and Natural History Studies

6 Duchenne Therapeutic Approaches Exon-Skipping Gene Therapy CRISPR/Cas9 Stop-Codon Readthrough Steroid Replacement Dystrophin Restoration /Replacement Stem Cells Traditional Cardiac Drugs Anti- Fibrotics Inflammation & Fibrosis Regulation Treating Duchenne Cardiac Blood Flow Mitochondria nnos Biogenesis Ryanodine Receptors Homeostasis Muscle Growth and Protection Stem Cells Enhancers Myostatin Inhibition Follistatin via Gene Therapy Selective Androgen Receptor Modulators Utrophin

7 Clinical trials pipeline 2017 DRUG PRECLINICAL PHASE I PHASE I/II PHASE II PHASE III ETEPLIRSEN [SAREPTA] SPIRONOLACTONE & EPLERENONE [OHIO STATE UNIVERSITY] TADALAFIL [ELI LILLY] COMPLETED TRANSLARNA (ATALUREN) [PTC THERAPEUTICS] GIVINOSTAT (ITF2357) [ITALFARMACO] RAXONE (IDEBENONE) [SANTHERA] SRP-4045/SRP-4053 [SAREPTA] COENZYME Q10 & LISINOPRIL [US DEPARTMENT OF DEFENSE] PF [PFIZER] FG-3019 [FIBROGEN] NS-065/NCNP-01 [NS PHARMA] VAMOROLONE (VBP15) [REVERAGEN] CAT-1004 [CATABASIS] EZUTROMID (SMT C1100) [SUMMIT PLC] FOLLISTATIN GENE TRANSFER [NATIONWIDE CHILDREN S] BMS [BRISTOL MYERS SQUIBB] MYOBLAST TRANSPLANTATION [CHU DE QUÉBEC] CAP-1002 [CAPRICOR] GENE TRANSFER OF MICRO-DYSTROPHIN [NATIONWIDE CHILDREN S] Accelerated approval 9/16 completed Condi4onal approval EU *Pipeline graphic represents the clinical trial FAQ sheets included in this booklet and it not intended to be a comprehensive list.

8 Clinical trials pipeline DRUG PRECLINICAL PHASE I PHASE I/II PHASE II PHASE III ETEPLIRSEN [SAREPTA] SPIRONOLACTONE & EPLERENONE [OHIO STATE UNIVERSITY] TADALAFIL [ELI LILLY] COMPLETED Target/MOA Study Design Some inclusion/exclusion criteria Endpoints Sites TRANSLARNA (ATALUREN) [PTC THERAPEUTICS] GIVINOSTAT (ITF2357) [ITALFARMACO] RAXONE (IDEBENONE) [SANTHERA] SRP-4045/SRP-4053 [SAREPTA] COENZYME Q10 & LISINOPRIL [US DEPARTMENT OF DEFENSE] PF [PFIZER] FG-3019 [FIBROGEN] NS-065/NCNP-01 [NS PHARMA] VAMOROLONE (VBP15) [REVERAGEN] CAT-1004 [CATABASIS] EZUTROMID (SMT C1100) [SUMMIT PLC] FOLLISTATIN GENE TRANSFER [NATIONWIDE CHILDREN S] BMS [BRISTOL MYERS SQUIBB] MYOBLAST TRANSPLANTATION [CHU DE QUÉBEC] CAP-1002 [CAPRICOR] GENE TRANSFER OF MICRO-DYSTROPHIN [NATIONWIDE CHILDREN S] *Pipeline graphic represents the clinical trial FAQ sheets included in this booklet and it not intended to be a comprehensive list.

9 Study Design Phase? randomized Different doses? Placebo Controlled 2:1 LENGTH OF STUDY? STUDY SITE? Frequency of visits Extension Study/EAP Informed Consent/Assent OUTCOME MEASURES Primary, Secondary, Exploratory

10 Duchenne Therapeutic Approaches Exon-Skipping Gene Therapy CRISPR/Cas9 Stop-Codon Readthrough Steroid Replacement Dystrophin Restoration /Replacement Stem Cells Traditional Cardiac Drugs Anti- Fibrotics Inflammation & Fibrosis Regulation Treating Duchenne Cardiac Blood Flow Mitochondria nnos Biogenesis Ryanodine Receptors Homeostasis Muscle Growth and Protection Stem Cells Enhancers Myostatin Inhibition Follistatin via Gene Therapy Selective Androgen Receptor Modulators Utrophin

11 Duchenne Therapeutic Approaches Exon-Skipping Gene Therapy CRISPR/Cas9 Stop-Codon Readthrough Steroid Replacement Dystrophin Restoration /Replacement Stem Cells Traditional Cardiac Drugs Anti- Fibrotics Inflammation & Fibrosis Regulation Treating Duchenne Cardiac Blood Flow Mitochondria nnos Biogenesis Ryanodine Receptors Homeostasis Muscle Growth and Protection Stem Cells Enhancers Myostatin Inhibition Follistatin via Gene Therapy Selective Androgen Receptor Modulators Utrophin

12 Duchenne Therapeutic Approaches Exon-Skipping Gene Therapy CRISPR/Cas9 Stop-Codon Readthrough Steroid Replacement Dystrophin Restoration /Replacement Stem Cells Traditional Cardiac Drugs Anti- Fibrotics Inflammation & Fibrosis Regulation Treating Duchenne Cardiac Blood Flow Mitochondria nnos Biogenesis Ryanodine Receptors Homeostasis Muscle Growth and Protection Stem Cells Enhancers Myostatin Inhibition Follistatin via Gene Therapy Selective Androgen Receptor Modulators Utrophin

13 Duchenne Connect

14 THANK YOU TO ALL THE BOYS AND FAMILIES PARTICIPATING IN TRIALS ParentProjectMD.org