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Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
Miller, Timothy; Cudkowicz, Merit; Shaw, Pamela J; Andersen, Peter M; Atassi, Nazem; Bucelli, Robert C; Genge, Angela; Glass, Jonathan; Ladha, Shafeeq; Ludolph, Albert L; Maragakis, Nicholas J; McDermott, Christopher J; Pestronk, Alan; Ravits, John; Salachas, François; Trudell, Randall; Van Damme, Philip; Zinman, Lorne; Bennett, C Frank; Lane, Roger; Sandrock, Alfred; Runz, Heiko; Graham, Danielle; Houshyar, Hani; McCampbell, Alexander; Nestorov, Ivan; Chang, Ih; McNeill, Manjit; Fanning, Laura; Fradette, Stephanie; Ferguson, Toby A.
Afiliação
  • Miller T; 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
  • Cudkowicz M; 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
  • Shaw PJ; 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
  • Andersen PM; 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
  • Atassi N; 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
  • Bucelli RC; 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
  • Genge A; 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
  • Glass J; 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
  • Ladha S; 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
  • Ludolph AL; 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
  • Maragakis NJ; 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
  • McDermott CJ; 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
  • Pestronk A; 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
  • Ravits J; 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
  • Salachas F; 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
  • Trudell R; 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
  • Van Damme P; 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
  • Zinman L; 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
  • Bennett CF; 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
  • Lane R; 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
  • Sandrock A; 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
  • Runz H; 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
  • Graham D; 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
  • Houshyar H; 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
  • McCampbell A; 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
  • Nestorov I; 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
  • Chang I; 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
  • McNeill M; 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
  • Fanning L; 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
  • Fradette S; 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
  • Ferguson TA; 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
N Engl J Med ; 383(2): 109-119, 2020 07 09.
Article em En | MEDLINE | ID: mdl-32640130
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 31 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.).
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Oligonucleotídeos Antissenso / Superóxido Dismutase-1 / Esclerose Lateral Amiotrófica Tipo de estudo: Clinical_trials Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Oligonucleotídeos Antissenso / Superóxido Dismutase-1 / Esclerose Lateral Amiotrófica Tipo de estudo: Clinical_trials Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Ano de publicação: 2020 Tipo de documento: Article