Long-Term Tofersen in <i>SOD1</i> Amyotrophic Lateral Sclerosis
Timothy M. Miller, Merit Cudkowicz, Pamela Shaw, Angela Genge, Gen Sobue, Robert C. Bucelli, Adriano Chiò, Philip Van Damme, Albert C. Ludolph, Jonathan D. Glass, Jinsy Andrews, Suma Babu, Michael Benatar, C. McDermott, François Salachas, Gaëlle Bruneteau, Ammar Al-Chalabi, Matthew Amorin, Ivan Nestorov, Danielle Graham, Luan Lin, Peng Sun, Manjit McNeill, Sohail Malek, Jennifer Inra, Steve Garafalo, Stephanie Fradette, VALOR and OLE Working Group, Lien Beullens, Kristl Claeys, Thomas Claeys, Goedele Couwelier, Ann D'Hondt, Elisa Debien, Sebastiaan De Keersmaecker, Laetitia della Faille, Koen Delmotte, Sofie DR Depoortere, Laura de Velder, Laurens Dobbels, Jeroen Gijs, Simon Horckmans, Nikita Lamaire, Hannelore Liessens, Pegah Masrori, Céline Nysten, Caroline Schotte, Anouk Serrien, Bart Swinnen, Petra Tilkin, Sien Hilde Van Daele, Van Damme Pa, Jan Vynckier, Anke Wouters, Agessandro Abrahão, Mark Angle, Mohamed Badawy, Maxime Berube, Vanessa Bertone, Sarah Marie Cooper, Peter Dobrowolski, Helen Fong, Angela Genge, Matthew Hannouche, Denise Hartley, Michael Hogan, Wendy Johnston, Yousra Khalfallah, Lawrence Korngut, Gina Kroetsch, Justin Létourneau, Claire Magnussen, José Corberá Martínez, Rami Massie, Theodore Mobach, Jahan Mookshah, Timur Özelsel, Andrea Parks, Janet Petrillo, Gerald Pfeffer, Shirley Pham, Liane Phung, Rodney Shiungsun, Li Pi-Shan, Denizart Santos, Kristiana Salmon, Natalie Saunders, Dylan Sembinelli, Kelsey Tymkow, Berchman Wong, Lorne Zinman, Merete Karlsborg, Therese Pedersen Lomholt, Sigrid Nilsson, Lisette Salvesen, P. Stahl Skov, Kristen Svenstrup, Gaëlle Bruneteau, Frederic Clarencon, Raquel Guimarães Costa
Abstract
Importance: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene. Objective: To evaluate the long-term effects of tofersen in adults with SOD1-ALS. Design, Setting, and Participants: The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024). Intervention and Exposure: Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen. Main Outcomes and Measures: Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival. Results: VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation. Conclusions and Relevance: Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population. Trial Registration: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.