Mitochondrial Disease Externally-led Patient-Focused Drug Development Meeting March 29, 2019 | HYATTSVILLE, MD VOICE OF THE PATIENT REPORT Mitochondrial Disease: Adults with Myopathy Children with Neurologic Symptoms HOSTED BY UNITED MITOCHONDRIAL DISEASE FOUNDATION IN COLLABORATION WITH MITOACTION AND MUSCULAR DYSTROPHY ASSOCIATION REPORT DATE: DECEMBER 3, 2019 Voice of the Patient Report “Mitochondrial Disease: Adults with Myopathy, Children with Neurologic Symptoms” This report represents the summary report composed by the United Mitochondrial Disease Foundation (UMDF) as a result of an Externally-led Patient-Focused Drug Development meeting held on March 29, 2019 in Hyattsville, MD. This report reflects the host organization’s account of the perspectives of patients and caregivers who participated in the public meeting. Submission: This report is submitted as patient experience data for consideration pursuant to section 569C of the Federal Food, Drug and Cosmetic Act to: Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) U.S. Food and Drug Administration (FDA) Authors and collaborators: Elizabeth White, White Biotech Solutions, Philip E. Yeske, Ph.D., Katarina Gray, transcript reviewer, Kara Strittmatter, Brittany Hernandez, MDA, Kira Mann, MitoAction and James Valentine, JD, MHS. Yeske, Gray and Strittmatter are all affiliated with UMDF and have no additional disclosures. White, Hernandez and Mann have no disclosures. Valentine is employed by Hyman, Phelps & McNamara, P.C., a law firm that represents sponsors who are developing drugs for rare diseases as well as rare disease patient advocacy organizations, including UMDF. Funding received: Sponsorship of the meeting was provided by UMDF, Stealth BioTherapeutics, BioElectron (since acquired by PTC Therapeutics), Edith L. Trees Charitable Trust, Muscular Dystrophy Association, MitoAction, Summit Health Pharmacy, Modis Therapeutics (now a subsidiary of Zogenix), Reneo Pharmaceuticals, The Pharmaceutical Research and Manufacturers of America, NeuroVive Pharmaceutical AB, B-Mogen Biotechnologies and Everylife Foundation. These funds were used to secure meeting space and to support other logistical and consulting services for the initiative. UMDF explicitly states that the sponsors had no control over the meeting content or related activities. Statement of use: UMDF has all necessary permissions to submit this report and linking from the FDA website will not violate the proprietary rights of others. Permission to link from the FDA website is granted by UMDF (www.umdf.org). Version Date: December 3, 2019 Revision statement: This document has not been revised and/or modified after the version date listed above. Point of Contact: Philip E. Yeske, UMDF Science & Alliance Officer, [email protected] Mitochondrial Disease Voice of the Patient Report i | Page A MESSAGE OF THANKS On March 29, 2019, hundreds of mitochondrial disease patients, caregivers, advocates, healthcare providers, industry representatives, and government officials came together for an Externally-led Patient-Focused Drug Development (El-PFDD) meeting to have our voices heard. On behalf of our patient community, their families and caregivers, thank you for your commitment and support! The “Energy in Action” El-PFDD meeting for mitochondrial disease aimed to set the groundwork for creating effective therapies for mitochondrial disease. This was truly a milestone for our community. It also served as a testament to the power of individual patient advocacy groups to come together to benefit our disease community. The meeting was the culmination of more than a year of planning and collaboration by the patient advocacy groups facilitating this meeting. We are thankful for the leadership of our friends at MitoAction and the Muscular Dystrophy Association, who helped us pull this tremendous meeting together. We were grateful for the opportunity to amplify our collective voice for our distinguished guests from the U.S. Food and Drug Administration. Thank you for your time and support in bringing this meeting to fruition. Special thanks to Dr. Lucas Kempf, Acting Associate Director to the Rare Disease program in the Office of New Drugs, and Dr. Larissa Lapteva, Associate Director in the Division of Clinical Evaluation, Pharmacology, and Toxicology, Office of Tissues and Advanced Therapy, Center for Biologics Evaluation and Research, who provided great support and insightful commentary. Many thanks also to James Valentine, for his dedication to rare disease communities and his outstanding facilitation of our meeting. We are also grateful to Dr. Michio Hirano and Dr. Amy Goldstein for their excellent clinical presentations on mitochondrial disease and their enduring commitment to our community. Our patient families brought their voices to help us better understand their experiences, their struggles, and their hope. Courageous panelists put their energy in action and made a choice to share their perspective of certainty, amidst a path of often uncertainty. Our broader community came forward with a loud voice, through active participation in our meeting and our surveys. To our hundreds of participants, we are most grateful for your candor and your courage. Because of all of you, we have a renewed sense of optimism that may lead us towards new and innovative therapies and treatments, and a world without mitochondrial disease. Thank you for your tremendous support and commitment, Brian Harman President & CEO The United Mitochondrial Disease Foundation Mitochondrial Disease Voice of the Patient Report ii | Page TABLE OF CONTENTS EXECUTIVE SUMMARY .......................................................................................................................................... 1 MITOCHONDRIAL DISEASE EXTERNALLY-LED PFDD MEETING DESIGN ..................................................................... 7 BACKGROUND ON MITOCHONDRIAL DISEASE ....................................................................................................... 8 What is Mitochondrial Disease? ...................................................................................................................................... 8 How is Mitochondrial Disease Diagnosed? ..................................................................................................................... 8 What are the Symptoms of Mitochondrial Disease? ....................................................................................................... 9 How is Mitochondrial Disease Currently Treated and Managed? ................................................................................... 9 What Research is Currently Being Conducted to Develop New Therapies for Mitochondrial Disease?......................... 9 SESSION 1: THE VOICE OF THE MITOCHONDRIAL DISEASE PATIENT – PERSPECTIVES FROM ADULTS WITH MITOCHONDRIAL MYOPATHY ............................................................................................................................. 11 Panel #1 - Symptoms and Daily Impacts ........................................................................................................................ 11 Panel #2 - Current and Future Approaches to Treatments ........................................................................................... 16 SESSION 2: THE VOICE OF THE MITOCHONDRIAL DISEASE PATIENT – PERSPECTIVES FROM PEDIATRIC PATIENTS AND CAREGIVERS ON NEUROLOGIC MANIFESTATIONS IN CHILDREN .................................................................... 22 Panel #3 - Symptoms and Daily Impacts ........................................................................................................................ 22 Panel #4 - Current and Future Approaches to Treatments ........................................................................................... 28 PRELIMINARY BENEFIT-RISK FRAMEWORK PROPOSAL FOR MITOCHONDRIAL DISEASE ......................................... 34 Sample Benefit-Risk Framework for Adults with Mitochondrial Myopathy ................................................................. 35 Sample Benefit-Risk Framework for Pediatric Patients with Neurologic Manifestations ............................................. 36 CONCLUSIONS .................................................................................................................................................... 37 APPENDIX 1 – REFERENCES AND RESOURCE MATERIALS ...................................................................................... 38 APPENDIX 2 – FULL PATIENT AND CAREGIVER TESTIMONIES ................................................................................ 39 Panel #1 - Symptoms and Daily Impacts (Adults with Mitochondrial Myopathy) ......................................................... 39 Panel #2 - Current and Future Approaches to Treatments (Adults with Mitochondrial Myopathy) ............................ 45 Panel #3 - Symptoms and Daily Impacts (Neurologic Manifestations in Children) ....................................................... 52 Panel #4 - Current and Future Approaches to Treatments (Neurologic Manifestations in Children)........................... 59 APPENDIX 3 – DETAILS OF POLLING QUESTIONNAIRES ......................................................................................... 66 Mitochondrial Disease Voice of the Patient Report iii | Page EXECUTIVE SUMMARY Mitochondrial disease is a family of serious, debilitating disorders that result from