| Title: |
Long-term tofersen in SOD1 amyotrophic lateral sclerosis |
| Authors: |
Miller, T.M.; Cudkowicz, M.E.; Shaw, P.J.; Genge, A.; Sobue, G.; Bucelli, R.C.; Chiò, A.; Van Damme, P.; Ludolph, A.C.; Glass, J.D.; Andrews, J.A.; Babu, S.; Benatar, M.; McDermott, C.J.; Salachas, F.; Bruneteau, G.; Al-Chalabi, A.; Amorin, M.; Nestorov, I.; Graham, D.; Lin, L.; Sun, P.; McNeill, M.; Malek, S.; Inra, J.; Garafalo, S.; Fradette, S.; Beullens, L.; Claeys, K.; Claeys, T.; Couwelier, G.; D'Hondt, A.; Debien, E.; de Keersmaecker, S.; della Faille, L.; Delmotte, K.; Depoortere, S.; de Velder, L.; Dobbels, L.; Gijs, J.; Horckmans, S.; Lamaire, N.; Liessens, H.; Masrori, P.; Nysten, C.; Schotte, C.; Serrien, A.; Swinnen, B.; Tilkin, P.; van Daele, S.; Vynckier, J.; Wouters, A.; Abrahao, A.; Angle, M.; Badawy, M.; Berube, M.; Bertone, V.; Cooper, S.M.; Dobrowolski, P.; Fong, H.; Hannouche, M.; Hartley, D.; Hogan, M.; Johnston, W.; Khalfallah, Y.; Korngut, L.; Kroetsch, G.; Letourneau, J.; Magnussen, C.; Martinez, J.; Massie, R.; Mobach, T.; Mookshah, J.; Ozelsel, T.; Parks, A.; Petrillo, J.; Pfeffer, G.; Pham, S.; Phung, L.; Shiungsun, R.; Pi-Shan, L.; Santos, D.; Salmon, K.; Saunders, N.; Sembinelli, D.; Tymkow, K.; Wong, B.; Zinman, L.; Karlsborg, M.; Pedersen Lomholt, T.; Nilsson, S.; Salvesen, L.; Skov, P.; Svenstrup, K.; Clarencon, F.; Guimaraes Costa, R.; Hesters, A.; Kermorvant, H.; Lacomblez, L.; Le Forestier, N.; Lenglet, T.; Retail, M.; Del Mar Amador, M.R.; Shotar, E.; Sourour, N.; Dorst, J.; Froehlich, E.; Fromm, A.; Kandler, K.; Langer, E.; Leichtle, S.; Ludolph, A.; Mayer, K.; Michels, S.; Raubold, S.; Schuster, J.; Weiland, U.; Wiesenfarth, M.; Witzel, S.; Calvo, A.; Canosa, A.; Casale, F.; Fuda, G.; Grassano, M.; Marchese, G.; Moglia, C.; Palumbo, F.; Salamone, P.; Ajiki, T.; Akasaka, A.; Ando, M.; Arata, H.; Asuka, K.; Baba, K.; Bekku, G.; Chiba, T.; Date, Y.; Eriko, T.; Hashiguchi, A.; Hatatori, R.; Hayano, E.; Hayashi, Y.; Higashi, K.; Higuchi, E.; Hiramatsu, Y.; Horikawa, R.; Ikenaka, K.; Ishiura, H.; Ito, D.; Kawai, S.; Kikuchi, J.; Kuzuyama, H.; Li, X.; Matsumoto, C.; Matsuura, E.; Michizono, K.; Mitsui, J.; Mitsutake, A.; Mochizuki, H.; Nagamatsu, A.; Nagano, S.; Nakamura, T.; Naruse, H.; Ogasawara, A.; Okada, K.; Okamoto, Y.; Okuno, T.; Oyama, S.; Ozono, T.; Sakiyama, Y.; Sakuishi, K.; Seki, M.; Shibata, S.; Shimizu, M.; Takahata, K.; Takahito, Y.; Takashima, H.; Takeichi, H.; Tashiro, Y.; Toda, T.; Tomizu, Y.; Tomoya, W.; Ujiakira, N.; Yashita, D.; Alix, J.; Bangalore, P.; Blackburn, D.; Chiwera, T.; Clegg, R.; Collins, A.; Cooper-Knock, J.; Emery, A.; Franklin, J.; Green, L.; Harvey, C.; Hobson, E.; Islam, M.; Jenkins, T.M.; Kazoka, M.; Kelly, G.; Korley, M.; Madarshahaian, D.; Mayl, K.; Radford, A.; Shaw, C.; Sidebottom, J.; Smart, L.; Sreedharan, J.; Stone, B.; Tsironis, T.; Tuddenham, L.; Verber, N.; Wollff, H.; Young, S.; Zis, P.; Adamo, A.; Ahmed, A.; Ajroud-Driss, S.; Alameda, G.; Arcila-Londono, X.; Baird, C.; Bazan, T.; Berry, J.; Bordeau, J.; Bradford, W.; Brook, N.; Brown, L.; Buckner, K.; Budler, M.W.; Burba, L.; Burke, K.; Calhoun, A.D.; Campbell, S.; Carey, J.; Caristo, I.B.; Carty, S.; Chan, E.; Chaudhry, V.; Chen, R.; Chow, S.; Clawson, L.L.; Clemens, M.; Cloninger, S.E.; Coleman-Wood, K.; Cooper, T.N.; Cummings, A.; Daniels, J.; DeSaro, P.; DeWitt, M.; Dedi, B.; Dempsey, D.; Denny, C.; Doherty, J.; Doherty, L.; Donahue, M.; Doyle, M.; Duncan, J.; Elman, L.; M. Eloge, C.; Echiti, D.R.; Ferrey, D.; Fournier, C.; Fukumura, Y.; Gallagher, K.; Garaycoa, J.; Garrett, M.; Gibson, R.L.; Gifford, R.; Gogol, D.; Golden, S.; Gonzalez, A.; Goodman, I.; Goolsby, C.; Goslin, K.; Goulbourne, M.; Granit, V.; Grignon, A.-L.; GuhaRay, A.; Guide, D.; Betul Gundogdu, M.; Gutierrez, G.; Hastings, D.; Hayzen, C.; Herzog, H.; Holloway, R.; Jacobs, G.; Jacobsen, B.; James, V.; Jenkins, L.; Jockel-Balsarotti, J.; Carol Johnson, L.; Jose, S.; Joslin, B.; Karanja, E.; Katz, J.; Keener, A.; Kittle, G.; Klein, S.; Kreple, C.; Kuenzler, R.; Kusnir, J.; Labbe, K.; Lachica-Encinas, N.; Ladha, S.; Leimer, L.; Levy, M.; Levy, W.; Li, Y.; Likanje, M.-F.; Livigni, R.; Locatelli, E.; Luppino, S.; Malcolm, A.; Maragakis, N.; Marin, H.; Markowitz, C.; Markway, J.; McCaffrey, A.; McCoy, A.; McCoy Gross, K.; Mehta, K.; Meyer, R.; Milan, J.; Miller, R.G.; Morales, F.; Mosmiller, E.; Mott, D.; Moulton, K.; Murphy, C.A.; Negron, T.; Nelson, C.; Newman, D.S.; Nissinen, J.K.; Norman, A.; Ohkubo, T.; Olney, N.; Ortiz, N.; Oskarsson, B.; Pace, M.; Packard, K.; Padgett, D.; Paganoni, S.; Paredes, M.E.; Parker, E.; Partlow, A.; Pattee, G.L.; Paulett, J.; Pelot, A.; Pfeifer, K.M.; Pijanowski, O.; Pioro, E.; Polak, M.; Prakash, A.; Previte, R.; Pukenas, B.; Quinn, C.; Ravits, J.; Razavi, R.; Regan, T.; Riley, K.M.; Roth, H.; Sanders, D.; Scalia, J.; Schmidt, E.; Schwen, E.; Shah, J.; Shah, S.; Shefner, J.; Sheldon, D.; Simmons, K.; Singh, N.K.; Singleton, J.; Smiley, R.; Smith, W.B.; Smith, S.; Sotirchos, E.; Sorenson, E.; Staff, N.; Steele, J.; Steijlen, K.; Stirrat, T.; Stoica, G.S.; Strong, S.; Sufit, R.; Sultze, J.; Swartz, A.; Szymanski, A.; Tay, A.; Thakore, N.; Thiessen, D.; Thotala, S.; Trudell, R.G.; Turcotte, N.; Turner, M.; Uchil, A.; Upadhyay, V.; Usman, U.; Vallis, A.; Vaporean-Bussey, D.; Vladimirova, V.; Weber, H.; Winbigler, J.; Wojanowski, H.; Wulf, C.; Yasek, J.; Yoo, S.; Zivalic, H.; Cole, A.; File, G.; Foate, J.; Mason, D.; Newton, S.; Roberts, S.; Sellwood, C.D.; Swan, J.; Werno, A.; Zhong, C. |
| Publisher Information: |
American Medical Association (AMA) |
| Publication Year: |
2025 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
2168-6149 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/237142/1/jamaneurology_miller_2025_oi_250084_1769188938.09478.pdf; Miller, T.M., Cudkowicz, M.E., Shaw, P.J. et al. (428 more authors) (2025) Long-term tofersen in SOD1 amyotrophic lateral sclerosis. JAMA Neurology, 83 (2). ISSN: 2168-6149 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/237142/; https://eprints.whiterose.ac.uk/id/eprint/237142/1/jamaneurology_miller_2025_oi_250084_1769188938.09478.pdf |
| Rights: |
cc_by_nc_nd_4 |
| Accession Number: |
edsbas.F3216C34 |
| Database: |
BASE |