Eladocagene exuparvovec

Based on the lack of systemic exposure and negligible biodistribution to the gonads, the risk for germline transmission is low.

There are no data from the use of eladocagene exuparvovec in pregnant women. Animal reproductive studies have not been conducted with eladocagene exuparvovec.

It is unknown whether eladocagene exuparvovec is excreted in human milk.

Eladocagene exuparvovec is not absorbed systemically following intraputaminal administration, and no effect on the breastfed newborns/infants are anticipated.

Fertility

There are no clinical or nonclinical data available regarding the effect of eladocagene exuparvovec on fertility.

Not relevant.

Summary of the safety profile

The safety information was observed in 3 open-label clinical studies in which eladocagene exuparvovec was administered to 28 AADC-deficient patients aged 19 months to 8.5 years at the time of dosing. Patients were followed for a median duration of 52.3 months (minimum of 3.1 months to a maximum of 9.63 years). The most common adverse reaction was dyskinesia; it was reported in 24 (85.7%) patients and was prevalent during the first 2 months post-treatment.

Tabulated list of adverse reactions

The adverse reactions are reported in Table 1. The adverse reactions are listed by system organ class and frequency using the following convention: 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).

Table 1. Adverse reactions occurring in ≥2 patients in 3 open-label clinical studies (n=28):

Table 2. Neurosurgery-related adverse reactions occurring in ≥2 patients in 3 open-label clinical studies (n=28):

^a May include pseudomeningocele

Table 3. Anaesthesia and postoperative related adverse reactions in ≥2 patients within ≤2 weeks after administration, in 3 open label clinical studies (n=28):

Description of selected adverse reactions

Dyskinesia

Events of dyskinesia were reported in 24 (85.7%) subjects. Of the 35 events of dyskinesia, 33 events were mild to moderate and 2 were severe. The majority of events resolved in approximately 2 months and all resolved within 7 months. The mean time to onset of events of dyskinesia was 25.8 days after receiving gene therapy. Events of dyskinesia were managed with routine medical care, such as anti-dopaminergic treatment.

Immunogenicity

Titres of anti-AAV2 antibodies were measured pre- and post-gene therapy in the clinical studies. All patients that received eladocagene exuparvovec had anti-AAV2 titres at or below 1:20 before treatment. Following treatment, most subjects (n=18) were positive for anti-AAV2 antibodies at least once within the first 12 months. In general, antibody levels stabilised or declined with time. There was no specific follow up program to capture potential immunogenicity reactions in any of the clinical studies, but presence of anti-AAV2 antibodies in the clinical studies was not reported to be associated with increase in severity, number of adverse reactions, or with decreased efficacy.

Experience with eladocagene exuparvovec in patients with anti-AAV2 antibody levels >1:20 prior to treatment is not available.

The immune response to the transgene and the cellular immune response were not measured.