Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The safety information was observed in 3 open-label clinical studies in which eladocagene exuparvovec was administered to 30 AADC-deficient patients aged 19 months to 8.5 years at the time of dosing. Patients were followed for a median duration of 59.3 months (minimum of 11.8 months to a maximum of 5.7 years). Twenty-six patients treated in the clinical studies enrolled in a long-term follow-up study. The duration of follow-up from the time of gene therapy ranged from 27.2 to 126.5 months (approximately 2 to 10.5 years).
The most common adverse reaction was dyskinesia; it was reported in 26 (86.7%) patients and was prevalent during the first 2 months post-treatment.

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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 = 30)
System organ class                       Very common                   Common Metabolism and nutrition disorders                                     Feeding disorders Psychiatric disorders                    Initial insomnia              Irritability Nervous system disorders                 Dyskinesia
Gastrointestinal disorders                                             Salivary hypersecretion 
Table 2         Neurosurgery-related adverse reactions occurring in ≥ 2 patients in 3 open-label clinical studies (n=30)
Adverse reaction category                                 Very common Blood and lymphatic system disorders                      Anaemia
Nervous system disorders                                  Cerebrospinal fluid leakagea 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=30)
Adverse reaction category                  Very common               Common Infections and infestations                Pneumonia                 Gastroenteritis Metabolism and nutrition disorders         Hypokalaemia
Psychiatric disorders                      Irritability
Nervous system disorders                                             Dyskinesia Cardiac disorders                                                    Cyanosis Vascular disorders                         Hypotension               Hypovolemic shock Respiratory, thoracic and mediastinal                                Respiratory failure disorders
Gastrointestinal disorders                 Upper gastrointestinal    Mouth ulceration haemorrhage, Diarrhoea
Skin and subcutaneous tissue               Decubitus ulcer           Dermatitis diaper, Rash disorders
General disorders and administration       Pyrexia                   Hypothermia site conditions                            Breath sounds abnormal
Surgical and medical procedure                                       Tooth extraction 
Description of selected adverse reactions

Dyskinesia
Events of dyskinesia were reported in 26 (86.7%) subjects (see section 4.4).
Of the 37 events of dyskinesia, 35 events were mild to moderate and 2 were severe. The majority of events resolved in approximately 2 months, and all resolved within 7 months from symptom onset.
The mean time to onset of events of dyskinesia was 25 days after receiving gene therapy. Events of dyskinesia were managed with routine medical care, such as anti-dopaminergic treatment.



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Immunogenicity
Patients with titres of anti-AAV2 antibodies <1:1200 were allowed to participate in the clinical studies. However, 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.

Cerebrospinal fluid leaks
Three patients who received eladocagene exuparvovec in clinical studies experienced CSF leaks.
One patient reported two separate events as serious adverse events potentially related to the surgical procedure whereas all other events were nonserious.

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 .