{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:31:50Z","timestamp":1778038310366,"version":"3.51.4"},"reference-count":46,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:p>Myostatin is a negative regulator of skeletal muscle and has become a therapeutic target for muscle atrophying disorders. Although previous inhibitors of myostatin offered promising preclinical data, these therapies demonstrated a lack of specificity toward myostatin signaling and have shown limited success in the clinic. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors. To support the clinical development of apitegromab, we present data from a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies confirmed the ability of apitegromab to inhibit the activation of promyostatin. Toxicology studies in monkeys for 4 weeks and in adult rats for up to 26\u00a0weeks showed that weekly intravenous administration of apitegromab achieved sustained serum exposure and target engagement and was well-tolerated, with no treatment-related adverse findings at the highest doses tested of up to 100\u00a0mg\/kg and 300\u00a0mg\/kg in monkeys and rats, respectively. Additionally, results from an 8-week juvenile rat study showed no adverse effects on any endpoint, including neurodevelopmental, motor, and reproductive outcomes at 300\u00a0mg\/kg administered weekly IV. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors. These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy (SMA).<\/jats:p>","DOI":"10.1177\/10915818211025477","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T18:46:51Z","timestamp":1626202011000},"page":"322-336","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease"],"prefix":"10.1177","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3211-9156","authenticated-orcid":false,"given":"Brian T.","family":"Welsh","sequence":"first","affiliation":[{"name":"ToxStrategies, Austin, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4596-9301","authenticated-orcid":false,"given":"Shaun M.","family":"Cote","sequence":"additional","affiliation":[{"name":"Scholar Rock, Inc, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Meshulam","sequence":"additional","affiliation":[{"name":"Scholar Rock, Inc, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Jackson","sequence":"additional","affiliation":[{"name":"Scholar Rock, Inc, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajai","family":"Pal","sequence":"additional","affiliation":[{"name":"Scholar Rock, Inc, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice","family":"Lansita","sequence":"additional","affiliation":[{"name":"ToxStrategies, Kennett Square, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashish","family":"Kalra","sequence":"additional","affiliation":[{"name":"Scholar Rock, Inc, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"bibr1-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206410109"},{"key":"bibr2-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-13-1435-3_8"},{"key":"bibr3-10915818211025477","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201797931"},{"key":"bibr4-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.05.019"},{"key":"bibr5-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.20.012103.135836"},{"key":"bibr6-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040933"},{"key":"bibr7-10915818211025477","doi-asserted-by":"publisher","DOI":"10.17987\/jcsm-cr.v2i1.37"},{"key":"bibr8-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12420"},{"key":"bibr9-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01486-4"},{"key":"bibr10-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0127"},{"key":"bibr11-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy382"},{"key":"bibr12-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2020.05.002"},{"key":"bibr13-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25268"},{"key":"bibr14-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13601"},{"key":"bibr15-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20524-9"},{"key":"bibr16-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1053\/ejpn.1999.0181"},{"key":"bibr17-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.12.001"},{"key":"bibr18-10915818211025477","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz268"},{"key":"bibr19-10915818211025477","volume-title":"Guidance for Industry: S6(R1) preclinical Safety evaluation of biotechnology-derived pharmaceuticals","author":"Food and Drug Administration","year":"2012"},{"key":"bibr20-10915818211025477","volume-title":"Annex I of the EMA Document Guideline on Development, Production, Characterisation and Specifications for Monoclonal Antibodies and Related Product, Adopted by the Committee for Medicinal Products for Human Use (CHMP)","author":"EMA","year":"2016"},{"key":"bibr21-10915818211025477","volume-title":"Points to consider in the manufacture and testing of monoclonal antibody products for human use","author":"Food and Drug Administration. 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Apitegromab, a novel high-affinity anti-promyostatin monoclonal antibody for treating spinal muscular atrophy: results of a phase 2 interim analysis. 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