An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
Summary
The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of tofersen in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation. The secondary objective of Parts A and B of this study is to evaluate the effects of tofersen on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of tofersen.
Timeline
- Start
- 2016-01-20
- Primary completion
- 2021-07-16
- Completion
- 2021-07-16
Outcome
Missed primary endpoint
registry p = 0.9689; least square (LS) mean difference 1.2 (95% CI -3.19 to 5.53); NCT02623699 ↗
paper but did not improve clinical end points PMID 36129998 ↗
release “In the Phase 3 VALOR study, the primary endpoint as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) did not reach statistical significance” biogen.com ↗
Publications
- Guise AJ, Sellon MT, Roemer SF, Monine M, Comfort Harris NT, Bartlett D, David E, Xu S, Jandreski L, Malek S, Garafalo S, Nestorov I, Ireland MD, King A, Bowser RP, Korobeynikov V, Ravits J, Shaw PJ, Highley JR, Ferguson TA, Fradette S, Graham DL, Sorenson EJ, Oskarsson B, Reichard RR, Dickson DW, Paganoni S, Babu S, Oakley DH, Frosch MP, Miller TM, Bucelli RC, Perrin RJ, Ly CV, Plowey ED. Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors. JAMA Neurol. 2026 Jul 6. doi: 10.1001/jamaneurol.2026.2195. Online ahead of print.
- Miller TM, Cudkowicz ME, Shaw PJ, Genge A, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, 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; VALOR and OLE Working Group. Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. JAMA Neurol. 2026 Feb 1;83(2):115-125. doi: 10.1001/jamaneurol.2025.4946.
- Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
- Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Tofersen | Antisense oligonucleotide | 10 mg | Intrathecal |
| Subject | Tofersen | Antisense oligonucleotide | 20 mg | Intrathecal |
| Subject | Tofersen | Antisense oligonucleotide | 40 mg | Intrathecal |
| Subject | Tofersen | Antisense oligonucleotide | 60 mg | Intrathecal |
| Subject | Tofersen | Antisense oligonucleotide | 100 mg | Intrathecal |