David Michelson1, Emma Ciafaloni1, Stephen Ashwal1, Elliot Lewis1, Pushpa Narayanaswami1, Maryam Oskoui1, Melissa J Armstrong1. 1. From the Department of Pediatrics, Division of Child Neurology (D.M., S.A.), Loma Linda University School of Medicine, CA; Department of Neurology (E.C.), University of Rochester Medical Center, NY; Beth Israel Deaconess Medical Center (P.N.), Harvard Medical School, Boston, MA; Department of Pediatrics and Neurology & Neurosurgery (M.O.), McGill University, Montreal, Canada; and Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville.
Abstract
OBJECTIVE: To identify the level of evidence for use of nusinersen to treat spinal muscular atrophy (SMA) and review clinical considerations regarding use. METHODS: The author panel systematically reviewed nusinersen clinical trials for patients with SMA and assigned level of evidence statements based on the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. RESULTS: Four published clinical trials were identified, 3 of which were rated above Class IV. There is Class III evidence that in infants with homozygous deletions or mutations of SMN1, nusinersen improves the probability of permanent ventilation-free survival at 24 months vs a well-defined historical cohort. There is Class I evidence that in term infants with SMA and 2 copies of SMN2, treatment with nusinersen started in individuals younger than 7 months results in a better motor milestone response and higher rates of event-free survival than sham control. There is Class I evidence that in children aged 2-12 years with SMA symptom onset after 6 months of age, nusinersen results in greater improvement in motor function at 15 months than sham control. Nusinersen was safe and well-tolerated. CLINICAL CONTEXT: Evidence of efficacy is currently highest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. While approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use.
OBJECTIVE: To identify the level of evidence for use of nusinersen to treat spinal muscular atrophy (SMA) and review clinical considerations regarding use. METHODS: The author panel systematically reviewed nusinersen clinical trials for patients with SMA and assigned level of evidence statements based on the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. RESULTS: Four published clinical trials were identified, 3 of which were rated above Class IV. There is Class III evidence that in infants with homozygous deletions or mutations of SMN1, nusinersen improves the probability of permanent ventilation-free survival at 24 months vs a well-defined historical cohort. There is Class I evidence that in term infants with SMA and 2 copies of SMN2, treatment with nusinersen started in individuals younger than 7 months results in a better motor milestone response and higher rates of event-free survival than sham control. There is Class I evidence that in children aged 2-12 years with SMA symptom onset after 6 months of age, nusinersen results in greater improvement in motor function at 15 months than sham control. Nusinersen was safe and well-tolerated. CLINICAL CONTEXT: Evidence of efficacy is currently highest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. While approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use.
Authors: Lauren Elman; Bora Youn; Crystal M Proud; Margaret R Frey; Senda Ajroud-Driss; M Eileen McCormick; David Michelson; Michael S Cartwright; Terry Heiman-Patterson; Joseph M Choi; Aastha Chandak; Artak Khachatryan; Marta Martinez; Angela D Paradis Journal: J Neuromuscul Dis Date: 2022
Authors: Hamish W Y Wan; Kate A Carey; Arlene D'Silva; Nadine A Kasparian; Michelle A Farrar Journal: Orphanet J Rare Dis Date: 2019-04-02 Impact factor: 4.123
Authors: Ivana Jedličková; Anna Přistoupilová; Lenka Nosková; Filip Majer; Viktor Stránecký; Hana Hartmannová; Kateřina Hodaňová; Helena Trešlová; Michaela Hýblová; Peter Solár; Gabriel Minárik; Mária Giertlová; Stanislav Kmoch Journal: Mol Genet Genomic Med Date: 2020-04-26 Impact factor: 2.183
Authors: Kathrin Kizina; Benjamin Stolte; Andreas Totzeck; Saskia Bolz; Michael Fleischer; Christoph Mönninghoff; Nika Guberina; Denise Oldenburg; Michael Forsting; Christoph Kleinschnitz; Tim Hagenacker Journal: Front Neurol Date: 2019-11-05 Impact factor: 4.003