Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy
| Autor: | Francis Fonyuy Tukov, John W. Day, Richard S. Finkel, Kevin A. Strauss, Deepa H. Chand, Jerry R. Mendell, Aaron Kleyn, Sitra Tauscher-Wisniewski, Sandra P. Reyna, Eugenio Mercuri |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Thrombotic microangiopathy Prednisolone Postmarketing surveillance Physical examination Toxicology Intracardiac injection Muscular Atrophy Spinal Mice Internal medicine medicine Animals Humans Pharmacology (medical) Original Research Article Adverse effect Pharmacology Biological Products Clinical Trials as Topic medicine.diagnostic_test business.industry Genetic Therapy medicine.disease Clinical trial Concomitant Chemical and Drug Induced Liver Injury business medicine.drug |
| Zdroj: | Drug Safety |
| ISSN: | 1179-1942 0114-5916 |
| Popis: | Introduction This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. Objective We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. Methods 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. Results 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. Conclusions 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. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01107-6. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink