Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy.
Journal
Drug safety
ISSN: 1179-1942
Titre abrégé: Drug Saf
Pays: New Zealand
ID NLM: 9002928
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
accepted:
03
08
2021
pubmed:
13
8
2021
medline:
21
4
2022
entrez:
12
8
2021
Statut:
ppublish
Résumé
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.
Identifiants
pubmed: 34383289
doi: 10.1007/s40264-021-01107-6
pii: 10.1007/s40264-021-01107-6
pmc: PMC8473343
doi:
Substances chimiques
Biological Products
0
Prednisolone
9PHQ9Y1OLM
Banques de données
ClinicalTrials.gov
['NCT02122952', 'NCT03306277', 'NCT03505099', 'NCT03461289', 'NCT03837184', 'NCT03421977', 'NCT04042025']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1109-1119Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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