Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of onasemnogene abeparvovec was evaluated in 99 patients who received onasemnogene abeparvovec at the recommended dose (1.1 x 1014 vg/kg) in 5 open-label clinical studies. The most frequently reported adverse reactions following administration were hepatic enzyme increased (24.2%), hepatotoxicity (9.1%), vomiting (8.1%), thrombocytopenia (6.1%), troponin increased (5.1%), and pyrexia (5.1%) (see section 4.4).

Tabulated list of adverse reactions
The adverse reactions identified with onasemnogene abeparvovec in all patients treated with intravenous infusion at the recommended dose with a causal association to treatment are presented in Table 3. Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived ZOL API APR24 V5                                        8                                  EU SmPC Mar2024 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 3      Tabulated list of adverse reactions to onasemnogene abeparvovec Adverse Reactions by MedDRA SOC/PT and Frequency
Blood and lymphatic system disorders
Common            Thrombocytopenia1)
Uncommon           Thrombotic microangiopathy2)3)
Gastrointestinal disorders
Common            Vomiting
Hepatobiliary disorders
Common            Hepatotoxicity4)
Uncommon           Acute liver failure2)3)
General disorders and administration site conditions
Common            Pyrexia
Investigations
Very common          Hepatic enzyme increased5)
Common            Troponin increased6)
1)
Thrombocytopenia includes thrombocytopenia and platelet count decreased.
2)
Treatment-related adverse reactions reported outside of pre-marketing clinical studies, including in the post-marketing setting.
3)
Includes fatal cases.
4)
Hepatotoxicity includes hepatic steatosis and hypertransaminasaemia.
5)
Hepatic enzyme increased includes: alanine aminotransferase increased, ammonia increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, liver function test increased and transaminases increased.
6)
Troponin increased includes troponin increased, troponin-T increased, and troponin-I increased (reported outside of clinical studies, including in the post-marketing setting).

Description of selected adverse reactions

Hepatobiliary disorders
In the clinical development program (see section 5.1), elevated transaminases > 2 × ULN (and in some cases > 20 × ULN) were observed in 31% of patients treated at the recommended dose. These patients were clinically asymptomatic and none of them had clinically significant elevations of bilirubin. Serum transaminase elevations usually resolved with prednisolone treatment and patients recovered without clinical sequelae (see sections 4.2 and 4.4).

In the post-marketing setting, there have been reports of children developing signs and symptoms of acute liver failure (e.g. jaundice, coagulopathy, encephalopathy) typically within 2 months of treatment with onasemnogene abeparvovec, despite receiving corticosteroids before and after infusion. Cases of acute liver failure with fatal outcome have been reported.

In a study (COAV101A12306) including 24 children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to 9 years; 21 discontinued previous SMA treatment) increased transaminases were observed in 23 out of 24 patients. The patients were asymptomatic and there were no elevations of bilirubin. The AST and ALT elevations were managed with the use of corticosteroids, typically with prolonged duration (at Week 26, 17 patients were continuing prednisolone, at Week 52, 6 patients were still receiving prednisolone) and/or a higher dose.

Transient thrombocytopenia
In the clinical development program (see section 5.1), transient thrombocytopenia, was 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. Post-marketing cases with transient decrease in platelet count to levels <25 x 109/L within three weeks of administration have been reported (see section 4.4).
ZOL API APR24 V5                                        9                                EU SmPC Mar2024 In a study (COAV101A12306) including 24 children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to 9 years), thrombocytopenia was observed in 20 out of 24 patients.

Increases in troponin-I levels
Increases in cardiac troponin-I levels up to 0.2 mcg/L following onasemnogene abeparvovec infusion were observed. In the clinical study program, there were no clinically apparent cardiac findings observed following administration of onasemnogene abeparvovec (see section 4.4).

Immunogenicity
Pre- and post-gene therapy titres of anti-AAV9 antibodies were measured in the clinical studies (see section 4.4).
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 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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/.