Therapeutics for the Muscular Dystrophies

 Mission  Increase the longevity and quality of life of patients with muscular dystrophy  Lead Drug Candidate – LAM-111  Delivered systemically to MDC1A and DMD mouse models  Excellent efficacy with no toxicity  Human LAM-111 in human MDC1A and DMD cells  Human LAM-111 in mouse MDC1A and DMD muscle cells  Stable and scalable human LAM-111 manufacturing process  Under evaluation for treatment of dystroglycanopathy and dysferlinopathy Ashley

SAM Human LAM-111 No LAM-111

Merosin Deficient (MDC1A) mouse treated with laminin-111 (10mg LAM-111/kg/week starting at 10 days of age) Merosin Deficient (MDC1A) mice have a reduced lifespan and normally live between weeks of age, so 1 year is a very significant milestone Picture provided by Prothelia collaborator Dr. Dean Burkin, University of Nevada, Reno Adelina

IndustryScience Drug Development Program Advocacy Government Drug manufacture Animal testing Clinical testing Project coordination Investment Development incentives Funding support Regulatory guidance Rare Disease Program (HTS etc) Preclinical models Natural history Patient identification and accrual Investment Patient referral Trial promotion Investment Maia

Aubrey

Philip

All failed Drugs $400M in opportunity costs Preclinical Development 42% true costs Clinical Development 58% true costs $1B 3 in 5 Phase III Trials Succeed * Data from Pharma drugs developed entirely in-house Adams CP, Brantner VV (2010) “Spending on New Drug Development” Health Econ. 19: 130–141 (2010)Spending on New Drug Development Only 1 in 13 Candidates Succeed Pierce

*LifeSciences World 10/13/2006 Phase I: About $15K/person Phase II: About $19K/person Phase III: About $26K/person What the non-profit and government communities have done (funded): Funding the “Valley of Death” Developing International Patient Registries Developing Clinical Research Networks Developing and Validating Clinical Endpoints Developing Natural History to accurately power studies Standards of Care Areas of improvement: We need biomarkers to decrease testing time We need novel trial designs to reduce costs and time We need centralized IRBs We need electronic medical records We need clinical data standards We need harmonization between the FDA and EMEA Jake

– Brad Hodges, PhDChairman, SMAB; CSO, Prothelia, Inc. – Dean Burkin, PhDLead Investigator; Director, Nevada Transgenic Center for Biomedical Research Excellence, Associate Professor, University of Nevada School of Medicine – Ed Connor, MDDirector, Office of Investigational Therapeutics at Children's National Medical Center and Professor of Pediatrics at George Washington University School of Medicine and Health Sciences – Eric Hoffman, PhDChairman, Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences and Director, Research Center for Genetic Medicine at Children's National Medical Center – George Vella, PhDDirector of Research and Strategic Planning, Charley’s Fund – John M McCall, PhDPresident, PharMac LLC – Markus A Ruegg, PhDProfessor of Neurobiology, Biozentrum University of Basel – Steve D Hauschka, PhDProfessor of Biochemistry, University of Washington – Brad Hodges, PhDChairman, SMAB; CSO, Prothelia, Inc. – Dean Burkin, PhDLead Investigator; Director, Nevada Transgenic Center for Biomedical Research Excellence, Associate Professor, University of Nevada School of Medicine – Ed Connor, MDDirector, Office of Investigational Therapeutics at Children's National Medical Center and Professor of Pediatrics at George Washington University School of Medicine and Health Sciences – Eric Hoffman, PhDChairman, Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences and Director, Research Center for Genetic Medicine at Children's National Medical Center – George Vella, PhDDirector of Research and Strategic Planning, Charley’s Fund – John M McCall, PhDPresident, PharMac LLC – Markus A Ruegg, PhDProfessor of Neurobiology, Biozentrum University of Basel – Steve D Hauschka, PhDProfessor of Biochemistry, University of Washington 10 Kyra

 Scientists/Clinicians – Jim Collins, MD, PhDAssistant Professor of Pediatric Neurology, University of Cincinnati College of Medicine, Pediatric Neurologist, Cincinnati Children’s Hospital Medical Center – Jim Dowling, MD, PhDAssistant Professor, Division of Pediatric Neurology, Pediatric Neurologist, University of Michigan – Kathy Mathews, MDDirector, Division of Pediatric Neurology, Development and Behavior Professor, Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, University of Iowa Children’s Hospital – Xiao Xiao, PhDFred Eshelman Distinguished Professor of Gene Therapy, University of North Carolina, UNC Eshelman School of Pharmacy – Brenda Wong, MDAssociate Professor of Clinical Pediatrics and Neurology, Director, Pediatric Neuromuscular Program and MDA Clinic, Cincinnati Children’s Hospital Medical Center – Robert Griggs, MD, FAANProfessor of Neurology, Medicine, Pediatrics Pathology and Laboratory Medicine, University of Rochester School of Medicine, Chair, Muscle Study Group Executive Committee  Scientists/Clinicians – Jim Collins, MD, PhDAssistant Professor of Pediatric Neurology, University of Cincinnati College of Medicine, Pediatric Neurologist, Cincinnati Children’s Hospital Medical Center – Jim Dowling, MD, PhDAssistant Professor, Division of Pediatric Neurology, Pediatric Neurologist, University of Michigan – Kathy Mathews, MDDirector, Division of Pediatric Neurology, Development and Behavior Professor, Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, University of Iowa Children’s Hospital – Xiao Xiao, PhDFred Eshelman Distinguished Professor of Gene Therapy, University of North Carolina, UNC Eshelman School of Pharmacy – Brenda Wong, MDAssociate Professor of Clinical Pediatrics and Neurology, Director, Pediatric Neuromuscular Program and MDA Clinic, Cincinnati Children’s Hospital Medical Center – Robert Griggs, MD, FAANProfessor of Neurology, Medicine, Pediatrics Pathology and Laboratory Medicine, University of Rochester School of Medicine, Chair, Muscle Study Group Executive Committee 11

 Patient Advocacy Groups – Cure CMD (Congenital Muscular Dystrophy) – Struggle Against Muscular Dystrophy (SAM), Ireland – Muscular Dystrophy Association (MDA) – Parent Project Muscular Dystrophy (PPMDP) – Charley’s Fund, Inc.  Government Organizations – National Institute of Health (NIH) – financial support (3 grants) – Treat-NMD (Neuromuscular Disease), European Union  Patient Advocacy Groups – Cure CMD (Congenital Muscular Dystrophy) – Struggle Against Muscular Dystrophy (SAM), Ireland – Muscular Dystrophy Association (MDA) – Parent Project Muscular Dystrophy (PPMDP) – Charley’s Fund, Inc.  Government Organizations – National Institute of Health (NIH) – financial support (3 grants) – Treat-NMD (Neuromuscular Disease), European Union 12