Living with ALS (2024)

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Living with ALS Alan I. Leshner, Rebecca A. English, and Joe Alper, Editors Committee on Amyotrophic Lateral Sclerosis: Accelerating Treatments and Improving Quality of Life Board on Health Care Services Board on Health Sciences Policy Health and Medicine Division Consensus Study Report PREPUBLICATION COPY—Uncorrected Proofs 

ii NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by a contract between the National Academy of Sciences and the National Institute of Neurological Disorders and Stroke, National Institutes of Health (contract number HHSN263201800029I, task order 75N98022F00011). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/27739 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2024 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Living with ALS. Washington, DC: The National Academies Press. https://doi.org/10.17226/27739. PREPUBLICATION COPY—Uncorrected Proofs 

iii The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs 

iv Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process, and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs 

v COMMITTEE ON AMYOTROPHIC LATERAL SCLEROSIS: ACCELERATING TREATMENTS AND IMPROVING QUALITY OF LIFE1 ALAN I. LESHNER (Chair), Chief Executive Officer, Emeritus, American Association for the Advancement of Science (retired) SUMA BABU, Assistant Professor of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School; Co-Director, Neurological Clinical Research Institute, Massachusetts General Hospital CHELSEY R. CARTER, Assistant Professor of Public Health, Yale University MACEO CARTER, Person living with ALS GEORGE DEMIRIS, Penn Integrates Knowledge University Professor, University of Pennsylvania JOHN DUNLOP, Chief Scientific Officer, Aliada Therapeutics EVA L. FELDMAN, James W. Albers Distinguished University Professor, University of Michigan; Director, NeuroNetwork for Emerging Therapies and ALS Center of Excellence HOLLY FERNANDEZ LYNCH, Assistant Professor of Medical Ethics and Law, University of Pennsylvania ILEANA HOWARD, Medical Co-Director, ALS Center of Excellence, VA Puget Sound, Veterans Health Administration JEROME E. KURENT, Professor of Neurology and Medicine, Medical University of South Carolina; Ralph H. Johnson Veterans Affairs Medical Center ALS Interdisciplinary Clinic WON YOUNG LEE, Associate Professor of Pulmonary, Critical Care, and Sleep Medicine, University of Texas Southwestern Medical Center HAROLD L. PAZ, Operating Partner, Khosla Ventures TONYA J. ROBERTS, Associate Professor, University of Wisconsin–Madison RITA SATTLER, Professor of Translational Neuroscience, Barrow Neurological Institute JOEL SHAMASKIN, Person living with ALS; Professor Emeritus of Medicine, University of Rochester School of Medicine and Dentistry (retired) JOSHUA SHARFSTEIN, Professor of the Practice, Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health ANANTHA SHEKHAR, Senior Vice Chancellor for the Health Sciences, John and Gertrude Petersen Dean, School of Medicine, University of Pittsburgh MINDY UHRLAUB, Author and familial ALS activist; member, Peer Mentor Team and Familial ALS Team at I AM ALS; founding member, Genetic ALS & FTD: End the Legacy Study Staff REBECCA A. ENGLISH, Study Director ASHLEY BOLOGNA, Senior Program Assistant LYLE CARRERA, Research Associate SHARYL NASS, Senior Director, Board on Health Care Services CLARE STROUD, Senior Director, Board on Health Sciences Policy 1 See Appendix C, Disclosure of Unavoidable Conflicts of Interest. PREPUBLICATION COPY—Uncorrected Proofs 

vi Consultants JOE ALPER, Science writer SARAH LUNSFORD, Public engagement consultant PREPUBLICATION COPY—Uncorrected Proofs 

vii Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: JINSY ANDREWS, Columbia University LORA CLAWSON, Johns Hopkins University School of Medicine MARY CATHERINE COLLET, Independent ALS advocate KULDIP DAVE, ALS Association GREGG GONSALVES, Yale University JOHN HANSEN-FLASCHEN, University of Pennsylvania KATHLEEN U. HOLT, Center for Medicare Advocacy COLLIN HOVINGA, Critical Path Institute STORY LANDIS, National Institute of Neurological Disorders and Stroke (retired) NANCY LEAMOND, AARP JEAN SWIDLER, Genetic ALS & FTD: End the Legacy NETA ZACH, Takeda BERNIE ZIPPRICH, Healthcare innovation expert and person living with ALS Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by JONATHAN M. SAMET, Colorado School of Public Health, and DAN G. BLAZER II, Duke University School of Medicine. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. PREPUBLICATION COPY—Uncorrected Proofs 

viii Acknowledgments The committee and project staff extend their gratitude to the many people and organizations who were critical in supporting and informing the committee’s work. This study was sponsored by the National Institutes of Health (NIH) and, in particular, was supported by the National Institute of Neurological Diseases and Stroke (NINDS). The committee thanks NIH and NINDS for their support, and the committee thanks Congress for initiating this important study. People with amyotrophic lateral sclerosis (ALS), their caregivers and family members, representatives of ALS nonprofit organizations, researchers, and clinicians graciously offered their expertise and perspectives throughout the study process. This information was not only useful but also courageous, heartfelt, and inspiring. The committee heard from many people in different ways throughout the study and would like to extend its appreciation to each. Over the course of its meetings, the committee heard from many people who shared their stories about ALS. This allowed the committee to center their work in the real-world lived experiences of those living with and affected by this disease, as well as to gain valuable insight as to the challenges and opportunities faced by those who fight against ALS in their daily lives, at labs or clinics, and alongside countless community organizations. The committee thanks the many participants in its public sessions: Lori Banker-Horner, James Berry, Sunny Brous, Katrina Byrd, Nora Capocci, Blair Casey, Jim Clingman, Sylvia Clingman, Cathy Collet, Norah Crossnohere, Penny Dacks, Dan Doctoroff, Sonya Elling, Ron Faretra, Albert Faro, Sarah Fontaine, Renee Golden, John Hansen-Flaschen, Bob Hebron, Terry Heiman-Patterson, Colleen Hoarty, Collin Hovinga, Justin Ichida, Vanessa Jackson, Asia Jami, Desiree Galvez Kessler, Lisa Latts, Ashley Lee, Melanie Lendnal, Joanne Lynn, Paul Mehta, Paul Melmeyer, Indu Navar, Siobhan Pandya, Juliet Pierce, Terri Postma, Kristin Rankin, Julian Rodriguez, Bruce Rosenblum, Paul Seifert, Jean Swidler, Neil Thakur, Fernando Vieira, and William Woods. The committee also benefited from the perspectives of six individuals appointed as lived experience consultants (volunteers). The lived experience consultants provided reflections on some excerpts of draft report text between January and March 2024. The committee expresses its gratitude to Michael Cosgray, Desiree Galvez Kessler, Bernadine A. Okeke, Ann Oliff, Kristin Rankin, and Julian (Jules) Rodriguez for their participation in the study process as lived experience consultants. The committee also thanks Sarah Lunsford, who served as a consultant to organize many of these public engagement opportunities. The staff of the National Academies of Sciences, Engineering, and Medicine contributed in many ways throughout the study process. The committee extends its sincerest gratitude to the study team for their hard work and dedication throughout this project: Rebecca A. English, Lyle Carrera, and Ashley Bologna. The committee is grateful for the many staff within the Health and Medicine Division who provided support for the project. Special thanks are extended to Christie Bell, senior financial business partner; Lori Brenig, editorial projects coordinator; and Mark Goodin for his editorial assistance in preparing the report. PREPUBLICATION COPY—Uncorrected Proofs 

ix Contents Acronyms and Abbreviations xiii Preface xv Summary S-1 1 Introduction and Study Context 1-1 Epidemiology ......................................................................................................................... 1-2 Study Task .............................................................................................................................. 1-3 The Nature of ALS and Its Symptoms ................................................................................... 1-3 Study Approach and Scope .................................................................................................. 1-12 References ............................................................................................................................ 1-18 2 Living with ALS Today 2-1 Making ALS Livable in 10 Years .......................................................................................... 2-1 Racial Inequities in ALS Diagnosis, Care, and Outcomes ................................................... 2-13 Concluding Comments ......................................................................................................... 2-15 References ............................................................................................................................ 2-16 3 Making ALS Livable in the Near Term 3-1 Insurance Challenges.............................................................................................................. 3-1 Inadequate Home Services ..................................................................................................... 3-4 High Out-of-Pocket Costs ...................................................................................................... 3-7 Supporting Caregivers .......................................................................................................... 3-11 Respiratory Management of ALS ........................................................................................ 3-17 References ............................................................................................................................ 3-20 4 Creating a Sustainable and Accessible ALS Clinical Care and Research System 4-1 ALS Multidisciplinary Care ................................................................................................... 4-3 Integrating Clinical Research into the ALS Care Delivery Network ..................................... 4-9 Building the Ideal ALS Care Delivery System .................................................................... 4-11 ALS Care System Challenges .............................................................................................. 4-20 References ............................................................................................................................ 4-29 5 Advancing ALS Research and Accelerating Therapeutic Development 5-1 ALS Drug Development Through the Years .......................................................................... 5-2 ALS Clinical Trials and Natural History Studies ................................................................... 5-3 PREPUBLICATION COPY—Uncorrected Proofs 

x Developing ALS Biomarkers and Other Clinical Endpoints to Serve as Indicators of Drug Efficacy .................................................................................................................... 5-10 Trade-offs in ALS Drug Development and Approval .......................................................... 5-12 Establishing a Comprehensive ALS Registry ...................................................................... 5-14 New and Emerging Non-Pharmacological Technologies .................................................... 5-22 References ............................................................................................................................ 5-24 6 Preventing ALS 6-1 Identifying At-Risk Genetic Carriers ..................................................................................... 6-1 Non-Genetic Factors and Prevention ..................................................................................... 6-7 References .............................................................................................................................. 6-8 Appendixes A Public Session Agendas A-1 B Biographical Sketches of Committee Members and Staff B-1 C Disclosure of Unavoidable Conflicts and Interest C-1 PREPUBLICATION COPY—Uncorrected Proofs 

xi Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 1-3 1-2 Lived Experience Consultants, 1-16 2-1 Perspectives on Living with ALS, 2-4 2-2 Caregiver Views on Quality of Life, 2-5 2-3 Action List for the ALS Community, 2-6 2-4 Diagnostic Delay in ALS, 2-9 3-1 Perspectives from Caregivers of People Living with ALS, 3-12 4-1 ALSA Certification Process for Treatment Centers of Excellence, 4-4 4-2 Specialty Care Medical Home: A Model for Coordinating Community-Based Multidisciplinary Care for ALS, 4-18 5-1 Types of Biomarkers, 5-11 5-2 Registries and Natural History Studies, 5-15 5-3 National ALS Registry Data Needs, 5-19 FIGURES 1-1 Most common ALS subtypes, natural history, and multidisciplinary treatment, 1-5 2-1 One individual’s lived experience with diagnostic delay, 2-8 2-2 thinkALS diagnostic guide for clinicians, 2-11 3-1 How individuals living with ALS pay for their mobility equipment, 3-8 4-1 ALS clinic map, 4-5 4-2 A reimagined ALS hub-and-spoke care system to increase access to multidisciplinary care, 4-15 5-1 ALS pathophysiology, genetic causes, and risk factors, 5-3 PREPUBLICATION COPY—Uncorrected Proofs 

xii TABLES 1-1 ALS Subtypes, Mean Onset Age, Median Survival, and Other Characteristics, 1-8 2-1 Diagnostic Delay After Symptom Onset, 2-8 2-2 Adjusted Hazard Ratios for ALS Mortality by Race and Ethnicity, 2-14 4-1 ALS Clinic Team Requirements and Expectations Across VA, ALSA, and MDA Clinics, 4-6 4-2 Differences in VA Versus Non-VA ALS Care, 4-8 4-3 Comparing the Current ALS Clinical Care and Research System to the Committee’s Proposal for an Integrated ALS Care and Research System, 4-19 5-1 Attributes of Three ALS Research Networks and Resources, 5-6 PREPUBLICATION COPY—Uncorrected Proofs 

xiii Acronyms and Abbreviations ACT for ALS Accelerating Access to Critical Therapies for ALS Act AHRQ Agency for Healthcare Research and Quality ALS amyotrophic lateral sclerosis ALSA ALS Association ALSFRA-R Revised Amyotrophic Lateral Sclerosis Functional Rating Scale AMP ALS Accelerating Medicines Partnership for ALS ARC ALS Research Collaborative BCI brain–computer interface CACRCE Comprehensive ALS Care and Research Center of Excellence CDC Centers for Disease Control and Prevention CFF Cystic Fibrosis Foundation CFFPR Cystic Fibrosis Foundation Patient Registry CMS Centers for Medicare & Medicaid Services CSP Caregiver Support Program DVT deep venous thrombosis FDA U.S. Food and Drug Administration FQHC Federally Qualified Health Center FTD frontotemporal dementia GINA Genetic Information Nondiscrimination Act HMV home mechanical ventilation MDA Muscular Dystrophy Association MDC multidisciplinary clinic or multidisciplinary care MGH Massachusetts General Hospital MND motor neuron disease NCI National Cancer Institute NEALS Northwest ALS Consortium NeuroNEXT Network for Excellence in Neuroscience Clinical Trials PREPUBLICATION COPY—Uncorrected Proofs 

xiv NfL neurofilament light chain NIH National Institutes of Health NINDS National Institute of Neurological Disorders and Stroke NIV noninvasive ventilation NPO nonprofit organization PFT pulmonary function test Pre-fALS Pre-symptomatic Familial ALS Study PRO-ACT Pooled Resource Open-Access ALS Clinical Trials Database SSDI Social Security Disability Insurance TDI Therapy Development Institute USPSTF U.S. Preventive Services Task Force VA U.S. Department of Veterans Affairs PREPUBLICATION COPY—Uncorrected Proofs 

xv Preface Amyotrophic lateral sclerosis (ALS) is a terrible, inevitably fatal disease. Receiving a diagnosis of ALS is devastating for people living with ALS, their families, and their caregivers. Dealing with this illness requires a complex array of medical and support service interventions, and the intensity of care required increases exponentially over time. This report lays out an agenda that, if implemented, would provide greater and more equitable access to state-of-the-art multidisciplinary care, accelerate the development of more effective treatments, improve the quality of life and health of those individuals suffering from the illness both now and in the future, and provide better support for their families and caregivers. Implementing this agenda would go far toward the goal set in the committee’s charge of making ALS a livable disease within a decade. This consensus report is the product of a committee of scientific and clinical experts from a variety of fields, as well as individuals living with the disease and people at clear risk for developing it. In addition, the committee met with a variety of other people living with the illness and asked them to reflect on the relevance of the committee’s thinking and its potential recommendations. Including these individuals in our work helped greatly to ground the committee’s work in real-life experiences and, I believe, significantly improved both the quality of this report and the appropriateness of its recommendations. As discussed in the report, the committee was aware that at the same time it was working on this project, many other, often parallel projects with similar goals were ongoing. We tried to remain cognizant of those efforts in framing our report and recommendations so as to avoid inadvertent conflicts or excessive duplication in strategies for accomplishing our shared goals. Achieving the vision underlying this report will require commitment and leadership from many different stakeholders. Some of the report’s recommendations require substantial resources, but their impacts will be great for the more than 30,000 individuals living with ALS and the thousands more who are at clear risk of developing the disease. The steps recommended here include developing a comprehensive multidisciplinary care and research network that would do much to ensure substantially more equitable access to state-of-the-art care for all individuals with ALS, reduce unacceptably long delays in receiving an accurate diagnosis, significantly expand the research infrastructure needed to develop new and improved treatments and support services, and explore new ways to help finance appropriate care and supports. As with all endeavors with grand goals, achieving the agenda laid out here out will not only require substantial resources and leadership from a variety of stakeholders, but these diverse groups will have to come together with a common focus and consistent messages about what is needed to make real progress against this dreaded disease. I am extremely grateful to my colleagues on the National Academies of Sciences, Engineering, and Medicine committee that authored this report. It was both an honor and a pleasure to work with them all. I also want to express, on behalf of the whole committee, our PREPUBLICATION COPY—Uncorrected Proofs 

xvi gratitude to the exceptionally competent and dedicated staff of the National Academies, led by the study director, Rebecca English, and the many others cited in the acknowledgments. Alan I. Leshner, Chair Committee on Amyotrophic Lateral Sclerosis: Accelerating Treatments and Improving Quality of Life PREPUBLICATION COPY—Uncorrected Proofs