Etranacogene dezaparvovec

Experience with use of etranacogene dezaparvovec in patients receiving hepatotoxic medications or using hepatotoxic substances is limited. Safety and efficacy of etranacogene dezaparvovec in these circumstances have not been established.

Before administering etranacogene dezaparvovec to patients receiving potentially hepatotoxic medicinal products or using other hepatotoxic agents (including alcohol, potentially hepatotoxic herbal products and nutritional supplements) and when deciding on the acceptability of such agents after treatment with etranacogene dezaparvovec, physicians should consider that they may reduce the efficacy of etranacogene dezaparvovec and increase the risk for more serious hepatic reactions, particularly during the first year following etranacogene dezaparvovec administration.

Agents that may reduce or increase the plasma concentration of corticosteroids (e.g. agents that induce or inhibit cytochrome P450 3A4) can decrease the efficacy of the corticosteroid regimen or increase their side effects.

In patients with Haemophilia B with preexisting risk factors for thromboembolic events, such as a history of cardiovascular or cardiometabolic disease, arteriosclerosis, hypertension, diabetes, advanced age, the potential risk of thrombogenicity may be higher.

No immunocompromised patients, including patients undergoing immunosuppressive treatment within 30 days before etranacogene dezaparvovec infusion, were enrolled in clinical studies with etranacogene dezaparvovec. Safety and efficacy of etranacogene dezaparvovec in these patients have not been established. Use in immunocompromised patients is based on healthcare professional’s judgment, taking into account the patient’s general health and potential for corticosteroid use post-etranacogene dezaparvovec treatment.

Experience regarding the use of this medicinal product during pregnancy is not available. Animal reproduction studies have not been conducted with etranacogene dezaparvovec. It is not known whether this medicinal product can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Etranacogene dezaparvovec should not be used during pregnancy.

It is unknown whether etranacogene dezaparvovec is excreted in human milk. A risk to the newborns/infants cannot be excluded. Etranacogene dezaparvovec should not be used during breast feeding.

Women of childbearing potential

No dedicated animal fertility/embryofoetal studies have been conducted to substantiate whether the use in women of childbearing potential and during pregnancy could be harmful for the newborn child (theoretical risk of viral vector integration in foetal cells through vertical transmission).

No data are available to recommend a specific duration of contraceptive measures in women of childbearing potential. Therefore, etranacogene dezaparvovec is not recommended in women of childbearing potential.

Contraception after administration in males

In clinical studies, after administration of etranacogene dezaparvovec, transgene DNA was temporarily detectable in semen.

For 12 months after administration of etranacogene dezaparvovec treated patients of reproductive potential and their female partners of childbearing potential must prevent or postpone pregnancy using barrier contraception.

Males treated with etranacogene dezaparvovec must not donate semen to minimise the potential risk of paternal germline transmission.

Fertility

Effects on male fertility have been evaluated in animal studies with mice. No adverse impact on the fertility was observed.

Infusion of etranacogene dezaparvovec may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as temporary dizziness, fatigue, and headache that have occurred shortly after etranacogene dezaparvovec administration, patients should be advised to use caution when driving and operating machinery until they are certain that this medicinal product does not adversely affect them.

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) in clinical studies with etranacogene dezaparvovec were headache (very common; 31.6% of patients), ALT elevations (very common; 22.8% of patients), AST elevations (very common; 17.5% of patients), and influenza-like illness (very common; 14% of patients).

Tabulated list of adverse reactions

The Table 1 shows the overview of ADRs from clinical trials with etranacogene dezaparvovec in 57 patients. The ADRs are classified according the MedDRA System Organ Class and frequency. The ADRs are listed based on the following convention for frequency categories: 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), and not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing frequency.

Table 1. Adverse drug reactions obtained from clinical studies with etranacogene dezaparvovec:

^* The frequency results from pooled infusion related reactions of similar medical concept. Individual infusion reactions occurred in 1 to 2 subjects with common frequency (incidence of 1.8 to 3.5%).

Hepatic laboratory Abnormalities

Table 2 describes hepatic laboratory abnormalities following administration of etranacogene dezaparvovec. ALT increases are further characterised, as they may be accompanied by decreased Factor IX activity and may indicate the need to initiate corticosteroid treatment.

Table 2. Hepatic laboratory abnormalities in patients administered 2 × 10¹³ gc/kg body weight etranacogene dezaparvovec in clinical studies:

Abbreviations: ULN = Upper Limit of Normal; CTCAE = Common Terminology Criteria for Adverse Events
^a Highest post-dose CTCAE Grades of values are presented
^b Not all patients with laboratory abnormality >ULN reached CTCAE Grade 1 due to elevated baseline levels
^c CTCAE Grade 1
^d CTCAE Grade 2
^e CTCAE Grade 3

Description of selected adverse reactions

Infusion related reactions

In the clinical studies with etranacogene dezaparvovec, infusion-related reactions of mild to moderate severity have been observed in 7/57 (12.3%) subjects. The infusion was temporarily interrupted in 3 patients and resumed at a slower infusion rate upon treatment with antihistamines and/or corticosteroids. In 1 patient, infusion was stopped and not resumed.

Immune-mediated transaminitis

In the clinical studies, treatment-emergent adverse reactions of ALT increases occurred in 13/57 (22.8%) patients. The onset of ALT elevations ranged from day 22 to 787 post-dose. Nine of the 13 patients with ALT elevations received a tapered course of corticosteroid. The mean corticosteroid treatment duration for those patients was 81.4 days. Nine of the 13 patients with ALT elevations also experienced AST elevations. All treatment-emergent adverse events of elevated ALTs were non-serious and resolved within 3 to 127 days.

Immunogenicity

In the clinical studies with etranacogene dezaparvovec, no Factor IX inhibitor development was observed.

An expected sustained humoral immune response to the infused AAV5 capsid was observed in all patients treated with etranacogene dezaparvovec. Anti-AAV5 antibody levels raised above the upper limit of quantification of 1:8748 by week 3 post-dose and remained elevated above the upper limit of quantification, as measured at month 24 post-dose.