Onasemnogene abeparvovec

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed in onasemnogene abeparvovec clinical trials. In most cases, the lowest platelet value occurred the first week following onasemnogene abeparvovec infusion. Platelet counts should be obtained before onasemnogene abeparvovec infusion and monitored on a regular basis afterwards, weekly for the first month and every other week for the second and third months until platelet counts return to baseline.

• Administration of AAV vector may result in transaminase elevations, which may be serious.
• Acute serious liver injury has occurred.
• Patients with pre-existing liver impairment or acute hepatic viral infection may be at higher risk of liver injury.
• Prior to infusion, liver function of all patients should be assessed by clinical examination and laboratory testing (e.g., hepatic aminotransferases AST and ALT, and total bilirubin.
• In order to mitigate potential transaminase elevations, a systemic corticosteroid should be administered to all patients before and after onasemnogene abeparvovec infusion.
• Liver function should be monitored for at least 3 months after infusion.
• The risks and benefits of infusion with onasemnogene abeparvovec in pre-existent hepatic impairment should be weighed carefully against the risks of not treating the patient.

AST/ALT/bilirubin should be assessed weekly for 30 days and every two weeks for an additional 60 days post administration of onasemnogene abeparvovec through to the end of the corticosteroid taper period, or longer if needed. Tapering of prednisolone should not be considered until AST/ALT are less than 2 × ULN.

Increases in cardiac troponin-I levels following infusion with onasemnogene abeparvovec were observed. Elevated troponin-I levels found in some patients may indicate potential myocardial tissue injury. Based on these findings and the observed cardiac toxicity in mice, troponin-I levels should be obtained before onasemnogene abeparvovec infusion and monitored for at least 3 months following onasemnogene abeparvovec infusion or until levels return to within normal reference range for SMA patients. Consider consultation with a cardiac expert as needed.

Human data on use during pregnancy are not available.

Human data on use during lactation are not available.

Animal fertility or reproduction studies have not been performed.

Onasemnogene abeparvovec has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reaction following administration was transient hepatic transaminase increase (12.4%) and vomiting (8.2%).

Tabulated list of adverse reactions

The adverse reactions identified with onasemnogene abeparvovec in all patients treated with intravenous infusion with a causal association to treatment are presented in Table 1. Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Tabulated list of adverse reactions to onasemnogene abeparvovec:

Description of selected adverse reactions

Hepatobiliary disorders

Elevated transaminases >2 × ULN were reported in up to 12% of patients treated at the recommended dose and were considered study-drug related. Two patients had AST and ALT elevations of >20 × ULN (one of these patients was experiencing a viral infection). These patients were clinically asymptomatic, did not exhibit jaundice or a clinically significant elevation of bilirubin and did not meet Hy’s Law criteria. Serum transaminase elevations resolved with prednisolone treatment, and patients recovered without clinical sequelae.

Outside of clinical trials, a case of acute serious liver injury was reported with onasemnogene abeparvovec where the patient was continuing treatment with nusinersen and had AST and ALT elevations of >3 × ULN before treatment with onasemnogene abeparvovec. The patient recovered with additional steroid therapy.

Transient thrombocytopenia

Transient decreases from baseline in mean platelet counts (4.1%) were observed at multiple time points post-dose and normally resolved within two weeks. Decreases in platelet counts were more prominent during the first week of treatment. No patients had clinical symptoms associated with decreased platelets.

Increases of troponin-I levels

Increases in cardiac troponin-I levels (3.1%) up to 0.2 mcg/L following onasemnogene abeparvovec infusion were observed. In the clinical trial program, there were no clinically apparent cardiac findings observed following administration of onasemnogene abeparvovec.

Immunogenicity

Pre- and post-gene therapy titres of anti-AAV9 antibodies were measured in the clinical studies. All patients that received onasemnogene abeparvovec had anti-AAV9 titres at or below 1:50 before treatment. Mean increases from baseline in AAV9 titre were observed in all patients at all but 1 time-point for antibody titre levels to AAV9 peptide, reflecting normal response to non-self viral antigen. Some patients experienced AAV9 titres exceeding the level of quantification, however most of these patients did not have potentially clinically significant adverse reactions. Thus, no relationship has been established between high anti-AAV9 antibody titres and the potential for adverse reactions or efficacy parameters.

In the AVXS-101-CL-101 clinical study, 16 patients were screened for anti-AAV9 antibody titre: 13 had titres less than 1:50 and were enrolled in the study; three patients had titres greater than 1:50, two of whom were retested following cessation of breast-feeding and their titres were measured at less than 1:50 and both were enrolled in the study. There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies. Patients all had less than or equal to 1:50 AAV9 antibody titre prior to treatment with onasemnogene abeparvovec and subsequently demonstrated an expected increase in anti-AAV9 antibody titres to at least 1:102,400 and up to greater than 1:819,200.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medicinal products and underlying disease.

No onasemnogene abeparvovec-treated patient demonstrated an immune response to the transgene.