Primary lateral sclerosis natural history study – planning, designing, and early enrollment

Abstract

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK^® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Keywords:

• Primary lateral sclerosis (PLS)
• motor neuron disease (MND)
• natural history study
• PLS Functional Rating Scale (PLSFRS)
• clinical trials

Acknowledgements

The authors are grateful for generous support from funding agencies and Mr. David Marren and family. The authors are also deeply grateful for the participation by our patients with PLS and their families. Cassandra Talerico, PhD, Cleveland Clinic, kindly reviewed the manuscript. We also appreciate PLSNHS Publication Committee for reviewing and approval of the manuscript.

Ethical approval

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Declaration of interest

Author Hiroshi Mitsumoto has received support from NIH, SPF, ALS Association, MDA Wings, Mitsubishi-Tanabe Pharma, private donations, and has served as a paid consultant for Eli-Lilly. Author Ikjae Lee has received research funding from the Myasthenia Gravis Foundation of America, American Academy of Neurology, CReATe consortium and American Brain Foundation and served on Scientific Advisory Committee for Alexion Pharmaceuticals. Author Zachary Simmons has received research support from MT Pharma and has served as a paid consultant for Amylyx, Biogen, Corcept, and Cytokinetics. Author Alexander V. Sherman has received research grants from The ALS Association, ALS Finding a Cure, and the NIH. Author Daragh Heitzman has received clinic support from the ALS Association and MDA. He has received research support from the Neurologix Foundation, Amylyx Pharmaceuticals, Cytokinetics, Mitsubishi Tanabe Pharma and Alexion Pharmaceuticals. He has been a paid speaker and consultant for Amylyx Pharmaceuticals. Author Jinsy Andrews reports has received research funding to the institution from Alexion, AZTherpies, Amylyx, Biogen, Cytokinetics, Orion, Novartis, MGH Foundation, Ra Pharma, Biohaven, Clene, and Prilenia and consulting fees from AL-S. Affinia, Amylyx, Apellis, Biogen, Cytokinetics, Denali, Orphazyme, Neurosense, Novartis, UCB, and Wave Life Sciences. Author Matthew Harms has received support from the ALS Association, Muscular Dystrophy Association, NINDS, Project ALS Foundation, ALS Finding a Cure, Target ALS, Biogen, Amylyx, Mitsubishi Tanabe, and ApicBio. He has served as a paid consultant for the Muscular Dystrophy Association, Biogen, and several medical legal law firms. Author Neil A. Shneider has received research support from Ionis Pharmaceuticals and MeiraGTX, and has served as a paid consultant for Regeneron, and Faze Medicines. Author Sabrina Paganoni has received research grants from Amylyx Therapeutics, Revalesio Corporation, Alector Therapeutics, UCB, Biohaven Pharmaceuticals, Clene Nanomedicine, Prilenia Therapeutics, Seelos Therapeutics, the ALS Association, the American Academy of Neurology, the CDC, ALS Finding a Cure, the Salah Foundation, the Spastic Paraplegia Foundation, the Muscular Dystrophy Association, I AM ALS, Tambourine, Target ALS, Columbia University, Alector Therapeutics, Cytokinetics, Inc., Anelixis Therapeutics, and/or has served as a paid consultant for Cytokinetics, Inc. Author Senda Ajroud-Driss has received research support from Amylyx Pharmaceutical, Biogen, Alnylam, MT-Pharma America, Helixmith, Novartis and served on scientific advisory board for Amylyx pharmaceutical Biogen and Orphazyme. Author J. Americo M. Fernandes has received research funding from MGH Foundation, Ra Pharma, Biohaven, Clene, Prilenia, Seelos Therapeutics, and Columbia University. Author Ali Habib, MD has Research support: Alexion/AstraZeneca; UCB; argenx; Sanofi; VielaBio/Horizon; Immunovant; Genentech/Roche; Regeneron; CabalettaBio. Honoraria/Speaker’s Bureau: Alexion/AstraZeneca; UCB; argenx; Immunovant; Genentech/Roche. Author Nicholas J. Maragakis received research support from NIH/NINDS, Dept. of Defense ALSRP. Clinical Trial Support: Eledon; Apellis Pharma; Biogen Idec; Cytokinetics; Helixmith; Calico; Sanofi; Massachusetts General Hospital; Medicinova. He has been a paid consultant for Amylyx; Cytokinetics; Orion; Orphazyme. Author David Walk has received support from the ALS Association, the Bob Allison Ataxia Research Center and has served as a paid consultant for Mitsubishi Tanabe Pharma America, Biogen, and Amylyx Therapeutics. Author Christina Fournier has received research support from Amylyx, Biogen, Denali, and MT Pharma. Author Terry Heiman-Patterson has received research funding to the institution from Mitsubishi Tanabe Pharma America, Cytokinetics, Amylyx, Dignity Health, Target ALS, and AB Sciences, and the Healy Center and consulting fees from Cytokinetics, Amylyx, Biogen, Mitsubishi Tanabe Pharma America. Author Stephen N Scelsa MD received grant support from Amylyx, A.B. Science and Sanofi, and has served as a paid consultant for Amylyx. Author Lauren Elman has received research support from the NIH and the ALS Association and has served as a paid consultant for Biogen, PTC Therapeutics and Roche. Author Angela Genge, MD has Faculty at McGill University, Executive Director Clinical Research Unit at Montreal Neurological Institute & Hospital; Consultant for QurAlis, Medtronic, ARG, Calico, Annexon, ALS-Pharma, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Eledon, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Biogen, Eli Lilly, Amicus Therapeutics. Author Ghaza Hayat, MD is MTPA Speaker and Alexion, Argenx speaker. Author Wendy Johnston has received grant funding from Brain Canada, University Hospital Foundation Kaye Research fund, research funding to the institution from Alexion, ALS_Pharma, Annexon, Biogen, Cytokinetics, Calico, Orion, Medicinova, Mitsubishi-Tanabe Canada, Sanofi, consulting fees from Amylyx, Biogen, and is on a steering committee for Cytokinetics CourageALS Trial. Author Nanette C. Joyce is the UCD site PI for the phase IV Radicava study sponsored by Mitsubishi Tanabe, otherwise does not have any COI. Author Edward Kasarski has grants: NINDS, ALS Association, Cynthia Shaw Crispen and Heidrich/Team 7 Endowments. Support as member of the ALS Healey Platform Trial group, Amylyx, AB Science, Woolsey. Author Michael Pulley is a medical advisory board member for Alexion. Dr. Pulley has participated in regional advisory board meetings for Argenx, Immunovant, UCB, CSL/Behring, Catalyst and Amylyx. Author Jaimin Shah has received research support from the Muscular Dystrophy Association and clinical trial support from the Healey Center, Corbus Pharmaceuticals, and Argenx. Author Christen Shoesmith, MD has received research funding to their institution from ALS-Pharma, Calico, Cytokinetics, Mitsubishi Tanabe, and Sanofi. Author Lorne Zinman has received research support from The Focused Ultrasound Foundation, NIH, ALS Canada and has served as a paid consultant for Mitsubishi Tanabe Pharma, Amylyx, Biogen, and Cytokinetics. The remaining authors have no conflict of interest.

Additional information

Funding

This work was supported by Spastic Paraplegia Foundation, ALS Association, Mitsubishi-Tanabe Pharma, MDA Wings Over Wall Street, David Marren and the Family; NeuroBank^® performed all data management without cost. Part of the material is contained within a presentation made at Spastic Paraplegia Foundation Annual Meeting, Nashville, July 23, 2022.