Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

Abstract

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.

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

“…The longer-term effects of combined therapy however require evaluation. 20 Whilst transaminitis and thrombocytopaenia were observed across our cohort as seen in prior studies, 6,21 we observed a greater extent of liver and platelet dysfunction in children weighing ≥8 kg. We also observed a bimodal rise in liver enzymes with one peak occurring relatively acutely following therapy.…”

Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial

“…Hepatotoxicity events resolved over time with prednisolone treatment. Transient decreases in platelets (<75,000 cells/µL) were also observed after vector administration 16 . In the post-marketing setting, transient hepatotoxicity, including four cases of acute liver failure, was the most common adverse event (AE).…”

“…A recent analysis summarized onasemnogene abeparvovec safety data from seven clinical trials ( n = 102) as well as post-marketing reports ( n = 665) through 12 November 2020 16 . In clinical trials, liver transaminases increased transiently in 90 of 102 (90%) patients and, in some cases, exceeded three times the upper limit of normal (ULN) (9% mild ≥3× ULN to <5× ULN; 6% ≥5× to <20× ULN; and 5% ≥20× ULN) 17 .…”

“…In the post-marketing setting, transient hepatotoxicity, including four cases of acute liver failure, was the most common adverse event (AE). In addition, thrombotic microangiopathy (TMA) was observed in the post-marketing setting 16 . Although not observed clinically, cardiac thrombi and dorsal root ganglia toxicities were observed in nonclinical toxicology studies 16 .…”

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

“…Increased SMN protein expression following the treatment has successfully prevented the death of motor neurons with the improvement of neuromuscular functions in the affected children. The phase 3 trial provides promising outcomes and Onasemnogene abeparvovec (Zolgensma ® ) was approved by the FDA in 2019 [ 146 , 147 ]. Recently, a matching-adjusted indirect comparison study between Onasemnogene abeparvovec and Nusinersen found that, in terms of event-free survival, overall survival, and motor milestone achievement, Onasemnogene abeparvovec provides a continuous benefit compared to Nusinersen in 24 months follow-up [ 148 ].…”