Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Timothy Miller; Merit Cudkowicz; Pamela J Shaw; Peter M Andersen; Nazem Atassi; Robert C Bucelli; Angela Genge; Jonathan Glass; Shafeeq Ladha; Albert L Ludolph; Nicholas J Maragakis; Christopher J McDermott; Alan Pestronk; John Ravits; François Salachas; Randall Trudell; Philip Van Damme; Lorne Zinman; C Frank Bennett; Roger Lane; Alfred Sandrock; Heiko Runz; Danielle Graham; Hani Houshyar; Alexander McCampbell; Ivan Nestorov; Ih Chang; Manjit McNeill; Laura Fanning; Stephanie Fradette; Toby A Ferguson

doi:10.1056/NEJMoa2003715

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.

Authors

Timothy Miller¹, Merit Cudkowicz¹, Pamela J Shaw¹, Peter M Andersen¹, Nazem Atassi¹, Robert C Bucelli¹, Angela Genge¹, Jonathan Glass¹, Shafeeq Ladha¹, Albert L Ludolph¹, Nicholas J Maragakis¹, Christopher J McDermott¹, Alan Pestronk¹, John Ravits¹, François Salachas¹, Randall Trudell¹, Philip Van Damme¹, Lorne Zinman¹, C Frank Bennett¹, Roger Lane¹, Alfred Sandrock¹, Heiko Runz¹, Danielle Graham¹, Hani Houshyar¹, Alexander McCampbell¹, Ivan Nestorov¹, Ih Chang¹, Manjit McNeill¹, Laura Fanning¹, Stephanie Fradette¹, Toby A Ferguson¹

Affiliation

¹ From the Washington University School of Medicine, St. Louis (T.M., R.C.B., A.P.); the Healey Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.C., N.A.), and Biogen, Cambridge (A.S., H.R., D.G., H.H., A.M., I.N., I.C., L.F., S.F., T.A.F.) - both in Massachusetts; the Sheffield Institute for Translational Neuroscience, University of Sheffield, and NIHR Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (P.J.S., C.J.M.), and Biogen, Maidenhead (M.M.) - both in the United Kingdom; the Department of Clinical Science, Neurosciences, Umeå University, Umea, Sweden (P.M.A.); Montreal Neurological Institute and Hospital, Montreal (A.G.), and Sunnybrook Research Institute, Toronto (L.Z.); Emory University, Atlanta (J.G.); Barrow Neurological Institute, Phoenix, AZ (S.L.); the University of Ulm, Ulm, Germany (A.L.L.); Johns Hopkins University School of Medicine, Baltimore (N.J.M.); the University of California San Diego, La Jolla (J.R.), and Ionis Pharmaceuticals, Carlsbad (C.F.B., R.L.) - both in California; Paris ALS Centre, Hôpital de la Salpêtrière, Paris (F.S.); the University of Tennessee Medical Center, Knoxville (R.T.); and KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.).

PMID: 32640130
DOI: 10.1056/NEJMoa2003715

Abstract

Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.

Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.

Results: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.

Conclusions: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amyotrophic Lateral Sclerosis / cerebrospinal fluid
Amyotrophic Lateral Sclerosis / drug therapy*
Amyotrophic Lateral Sclerosis / genetics
Disease Progression
Dose-Response Relationship, Drug
Double-Blind Method
Female
Headache / chemically induced
Humans
Injections, Spinal / adverse effects
Intermediate Filaments
Leukocytosis / chemically induced
Male
Middle Aged
Mutation
Oligonucleotides / administration & dosage*
Oligonucleotides / adverse effects
Oligonucleotides / pharmacokinetics
Oligonucleotides, Antisense / administration & dosage*
Oligonucleotides, Antisense / adverse effects
Oligonucleotides, Antisense / pharmacokinetics
Superoxide Dismutase-1 / cerebrospinal fluid*
Superoxide Dismutase-1 / genetics
Vital Capacity

Substances

Oligonucleotides
Oligonucleotides, Antisense
SOD1 protein, human
tofersen
Superoxide Dismutase-1

Supplementary concepts

Amyotrophic lateral sclerosis 1

Associated data

ClinicalTrials.gov/NCT02623699
EudraCT/2015-004098-33