ITVISMA Solution for injection Ref.[116806] Active ingredients: Onasemnogene abeparvovec

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Reasons to postpone treatment

Due to the risk of serious immune response, it is recommended that patients are clinically stable in their overall health status (e.g. hydration and nutritional status, absence of infection, respiratory status) prior to injection. Itvisma should be postponed in patients with infection, either acute (e.g. respiratory) or chronic uncontrolled, until the infection has resolved and the patient is clinically stable. Clinical signs or symptoms of infection should not be evident at the time of injection.

Pre-existing immunity against AAV9

In Itvisma clinical studies, patients were required to have baseline serum anti-AAV9 antibody titres ≤1:50. The safety and efficacy of Itvisma in patients with elevated anti-AAV9 antibody titres have not been evaluated in humans.

Hepatotoxicity

Hepatotoxicity, which generally manifested as elevated ALT and/or AST levels, has occurred with onasemnogene abeparvovec intrathecal injection (see section 4.8). In order to mitigate potential aminotransferase elevations, a systemic corticosteroid should be administered to all patients before and after intrathecal injection. Immune-mediated hepatotoxicity may require adjustment of the immunomodulatory regimen including longer duration, increased dose, or prolongation of the corticosteroid taper (see section 4.2).

Patients with pre-existing hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. Patients with elevated liver function tests have not been studied in clinical studies with onasemnogene abeparvovec intrathecal injection.

Prior to onasemnogene abeparvovec intrathecal injection, liver function of all patients should be assessed by clinical examination and laboratory testing. Liver function should be monitored for at least 3 months after onasemnogene abeparvovec intrathecal injection administration, and at other times as clinically indicated. AST, ALT and total bilirubin should be assessed weekly for the first month after onasemnogene abeparvovec intrathecal injection administration and during the corticosteroid taper period. If the patient is clinically stable with unremarkable findings at the end of the corticosteroid taper period, liver function should continue to be monitored every two weeks for another month. Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than 2 × ULN (see section 4.2).

Patients with worsening liver function test results and/or signs or symptoms of acute illness should be promptly clinically assessed and monitored closely. In case hepatic injury is suspected, further testing is recommended (e.g. albumin, prothrombin time, PTT and INR). Prompt consultation with a gastroenterologist or hepatologist is recommended, as necessary.

Thrombocytopenia

Transient decreases in platelet counts were typically observed within the first week after onasemnogene abeparvovec intrathecal injection administration. In most cases, platelet counts were ˃75 × 10⁹/L and returned to baseline two weeks following onasemnogene abeparvovec intrathecal injection.

Platelet counts should be obtained before onasemnogene abeparvovec intrathecal injection and should be monitored on a regular basis afterwards, at least weekly for the first month and as clinically indicated until platelet counts return to baseline.

Thrombotic microangiopathy

Thrombotic microangiopathy (TMA) may occur. TMA is characterised by thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury. Concurrent immune system activation (e.g. infections, vaccinations) may be a contributing factor.

Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes.

Thrombocytopenia is a key feature of TMA, therefore platelet counts should be monitored on a regular basis following onasemnogene abeparvovec intrathecal injection, as well as signs and symptoms of TMA, such as hypertension, bruising easily, seizures or decreased urine output. In case these signs and symptoms occur in the presence of thrombocytopenia, further diagnostic evaluation for haemolytic anaemia and renal dysfunction should be promptly undertaken. If clinical signs, symptoms and/or laboratory findings consistent with TMA occur, a haematologist and/or nephrologist should be consulted immediately to manage TMA as clinically indicated. Patients and caregivers should be informed about signs and symptoms of TMA and should be advised to seek urgent medical care if such symptoms occur.

Peripheral sensory neuropathy

Peripheral sensory neuropathy has occurred with onasemnogene abeparvovec intrathecal injection. Administration of onasemnogene abeparvovec intrathecal injection may result in sensory symptoms (e.g. numbness, tingling, prickling or pain in the arms, hands, legs and/or feet), with onset seen at approximately three weeks post-injection in clinical studies. Symptoms requiring management with additional therapies may persist, but can also gradually improve over time (see section 4.8). Sensory symptoms suggestive of peripheral sensory neuropathy may also occur as part of the natural course of SMA.

Complete neurological evaluation and other testing and/or symptom management should be considered based on the patient's clinical presentation. Patients and caregivers should be informed about the signs and symptoms of peripheral sensory neuropathy and be advised to notify their physician promptly if such symptoms occur.

Risk of tumourigenicity as a result of vector integration

There is a theoretical risk of tumourigenicity due to potential integration of the AAV vector DNA of onasemnogene abeparvovec into the host genome.

Onasemnogene abeparvovec intrathecal injection is composed of a non-replicating AAV9 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumourigenicity.

So far, no cases of malignancies associated with onasemnogene abeparvovec intrathecal injection treatment have been reported. In the event of a tumour, the marketing authorisation holder should be contacted for guidance on collecting patient samples for testing.

Blood, organ, tissue and cell donation

Patients treated with onasemnogene abeparvovec intrathecal injection should not donate blood, organs, tissues or cells for transplantation.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL dose, that is to say essentially 'sodium-free'.

No interaction studies have been performed.

Vaccinations

Where feasible, the patient's vaccination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec intrathecal injection. Seasonal respiratory syncytial virus (RSV) prophylaxis is recommended. Live vaccines, such as measles, mumps and rubella (MMR) and varicella, should not be administered to patients on an immunosuppressive steroid dose (i.e. ≥2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisolone or equivalent).

Pregnancy

There are no data from the use of onasemnogene abeparvovec in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). It is not known whether onasemnogene abeparvovec has the potential to be transferred to the foetus in humans. Therefore, women who are pregnant or may become pregnant should only be treated with Itvisma after a thorough benefit-risk evaluation.

Breast-feeding

There is no information available on the presence of onasemnogene abeparvovec in human milk, the effects on the breast-fed infant or the effects on milk production. A decision must be made whether to discontinue breast-feeding, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of onasemnogene abeparvovec on human fertility. In animal fertility studies, onasemnogene abeparvovec did not impact fertility in male or female mice at doses up to 1.1 × 10¹⁴ vg/kg administered intravenously (see section 5.3).

Onasemnogene abeparvovec intrathecal injection may have a minor influence on the ability to drive and use machines. Patients experiencing dizziness (see section 4.8) should avoid driving and using machines.

Summary of the safety profile

The safety data described in this section are from 127 patients from studies COAV101B12301, COAV101B12302 and COAV101A12102 over a 52-week follow-up period (see section 5.1). The most frequently reported adverse reactions following Itvisma administration were upper respiratory tract infection (41.7%), pyrexia (36.2%), vomiting (28.3%), headache (13.4%), and increased hepatic enzyme (9.4%). The most frequently reported serious adverse reactions were vomiting (2.4%), increased hepatic enzyme (1.6%), headache (1.6%) and pyrexia (1.6%). The adverse reactions reported were similar across studies.

Tabulated list of adverse reactions

The adverse reactions identified with Itvisma in patients treated with intrathecal injection at the recommended dose are presented in Table 2. 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Tabulated list of adverse reactions to Itvisma:

^a Upper respiratory tract infection includes upper respiratory tract infection, viral upper respiratory tract infection, rhinitis, and oropharyngeal pain.
^b Thrombocytopenia includes thrombocytopenia and platelet count decreased.
^c Adverse reactions considered related to the lumbar puncture procedure.
^d Peripheral sensory neuropathy includes peripheral sensory neuropathy and neuropathy peripheral.
^e Hepatic enzyme increased includes hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatitis, hypertransaminasaemia and hepatic function abnormal.

Description of selected adverse reactions

eripheral sensory neuropathy

In clinical studies, cases of peripheral sensory neuropathy (1.6%) have been observed within approximately three weeks following Itvisma administration. Patients presented with hypoaesthesia and paraesthesia. These cases required prolonged symptom management and some symptoms had not fully resolved at the end of the study (see section 4.4).

Hepatic laboratory abnormalities

In clinical studies, all patients received prophylaxis with corticosteroids. The majority of patients received the recommended immunomodulatory regimen with a median duration of approximately 60 days (see section 4.2). AST or ALT elevations >3 × ULN were observed in 4.7% of patients following Itvisma administration. Serum transaminase elevations resolved with prednisolone treatment and patients recovered without clinical sequelae.

Immunogenicity

In the clinical studies COAV101B12301 and COAV101B12302, following a one-time Itvisma injection, increases from baseline in serum anti-AAV9 antibody titres occurred in all patients. Median serum anti-AAV9 antibody titres at 12 months following Itvisma injection were ˃1:800 000 in both studies. No clear association between post-administration anti-AAV9 antibody level and safety findings or loss of efficacy was seen in the studied population over the follow-up period of 12 months post-dose.

During the 12-month period following Itvisma injection in studies COAV101B12301 and COAV101B12302, positive anti-SMN antibodies were observed in 5/75 (6.7%) and 2/27 (7.4%) Itvisma-treated patients, respectively. No clear association can be made between a positive anti-SMN antibody response and safety or efficacy of Itvisma over the follow-up period of 12 months post-dose.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Contact of the medicinal product with medical devices made of polyvinylchloride (PVC), bisphenol-A (BPA), bis(2-ethylhexyl) phthalate (DEHP) or latex must be avoided.