{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:50:45Z","timestamp":1790214645795,"version":"4.1.0"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T00:00:00Z","timestamp":1652400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The long\u2010term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile\u2010onset spinal muscular atrophy (SMA). Steady\u2010state CSF trough (\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      ) levels, plasma phosphorylated neurofilament heavy chain (pNF\u2010H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      . PK\/pharmacodynamic (PK\/PD) models used nusinersen CSF\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      measurements, which were time\u2010matched with CHOP INTEND scores.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Higher nusinersen CSF exposure was associated with a greater decrease in pNF\u2010H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose\u2013response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4\u2010fold increase in nusinersen CSF levels with fewer loading doses. PK\/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5\u2010point increase in CHOP INTEND score beyond that observed with 12\u2009mg.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12\u2010mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2\/3 DEVOTE study (NCT04089566).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.51562","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T02:52:48Z","timestamp":1652496768000},"page":"819-829","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Scientific rationale for a higher dose of nusinersen"],"prefix":"10.1002","volume":"9","author":[{"given":"Richard S.","family":"Finkel","sequence":"first","affiliation":[{"name":"St. Jude Children's Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique M.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Royal Children's Hospital Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel Ignacio","family":"Pascual Pascual","sequence":"additional","affiliation":[{"name":"Pedi\u00e1trica Hospital Universitario La Paz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Day","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9851-5365","authenticated-orcid":false,"given":"Eugenio","family":"Mercuri","sequence":"additional","affiliation":[{"name":"Universit\u00e1 Cattolica del Sacro Cuore Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl C.","family":"De Vivo","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Foster","sequence":"additional","affiliation":[{"name":"Biogen Maidenhead Berkshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7357-0819","authenticated-orcid":false,"given":"Jacqueline","family":"Montes","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Gurgel\u2010Giannetti","sequence":"additional","affiliation":[{"name":"Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"MacCannell","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7987-5683","authenticated-orcid":false,"given":"Zdenek","family":"Berger","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60921-6"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1941310"},{"key":"e_1_2_8_4_1","unstructured":"SPINRAZA (nusinersen) injection for intrathecal use. Prescribing Information.2018. Accessed April 23 2018.www.spinraza.com\/content\/dam\/commercial\/specialty\/spinraza\/caregiver\/en_us\/pdf\/spinraza\u2010prescribing\u2010information.pdf"},{"key":"e_1_2_8_5_1","unstructured":"SPINRAZA (nusinersen).Summary of product characteristics.2018. Accessed April 23 2018.http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_\u2010_Product_Information\/human\/004312\/WC500229704.pdf"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.007"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31408-8"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702752"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(21)00100-0"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710504"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007527"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2020.08.265"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2020.08.263"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2020.08.257"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2020.08.253"},{"key":"e_1_2_8_16_1","unstructured":"CastroD FinkelRS TuliniusM et\u00a0al.Integrated analysis of annualized incidence of serious adverse events in infantile\u2010onset SMA treated with nusinersen. 16th International Congress on Neuromuscular Diseases 2021 May 21\u201322 & 28\u201329; Virtual meeting"},{"key":"e_1_2_8_17_1","unstructured":"SaitoK CastroD FinkelRS et\u00a0al.Integrated analysis of incidence of serious adverse events in nusinersen\u2010treated later\u2010onset SMA. 63rd Annual Meeting of the Japanese Society of Child Neurology 2021 May 27\u201029; Fukuoka Japan."},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.779"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-019-00656-w"},{"key":"e_1_2_8_20_1","first-page":"287","article-title":"Longer\u2010term safety data in individuals with later\u2010onset SMA support the favourable tolerability profile of nusinersen","volume":"28","author":"Farrar M","year":"2021","journal-title":"Eur J Neurol"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2021.02.014"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S172291"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1212\/WNL.94.15_supplement.1132","article-title":"Longer\u2010term experience with nusinersen in teenagers and young adults with spinal muscular atrophy: results from the CS2\/CS12 and SHINE studies","volume":"94","author":"Day JW","year":"2020","journal-title":"Neurology"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51562","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51562","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51562","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T15:48:17Z","timestamp":1727192897000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,13]]},"references-count":22,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1002\/acn3.51562"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51562","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,13]]},"assertion":[{"value":"2021-12-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}