Eteplirsen

Risk Summary

There are no human or animal data available to assess the use of eteplirsen during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4% and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

Risk Summary

There are no human or animal data to assess the effect of eteplirsen on milk production, the presence of eteplirsen in milk, or the effects of eteplirsen on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for eteplirsen and any potential adverse effects on the breastfed infant from eteplirsen or from the underlying maternal condition.

Carcinogenesis

Carcinogenicity studies have not been conducted with eteplirsen.

Mutagenesis

Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Fertility studies in animals were not conducted with eteplirsen. No effects on the male reproductive system were observed following intravenous administration of eteplirsen (0, 5, 40, or 320 mg/kg) to male monkeys once weekly for 39 weeks. Plasma eteplirsen exposure (AUC) in monkeys at the highest dose tested was 20 times that in humans at recommended human dose (30 mg/kg).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the eteplirsen clinical development program, 107 patients received at least one intravenous dose of eteplirsen, ranging between 0.5 mg/kg (0.017 times the recommended dosage) and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 4 to 19 years. Most (89%) patients were Caucasian.

Eteplirsen was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1), followed by an open label extension (Study 2). In Study 1, 12 patients were randomized to receive weekly intravenous infusions of eteplirsen (n=8) or placebo (n=4) for 24 weeks. All 12 patients continued in Study 2 and received open-label eteplirsen weekly for up to 208 weeks.

In Study 1, 4 patients received placebo, 4 patients received eteplirsen 30 mg/kg, and 4 patients received eteplirsen 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6 patients received eteplirsen 30 mg/kg/week and 6 patients received eteplirsen 50 mg/kg/week.

Adverse reactions that occurred in 2 or more patients who received eteplirsen and were more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50 mg/kg groups are pooled). Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of eteplirsen is not recommended.

The most common adverse reactions were balance disorder and vomiting.

Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week¹ eteplirsen with Incidence at Least 25% More than Placebo (Study 1):

¹ 50 mg/kg/week = 1.7 times the recommended dosage

In the 88 patients who received ≥30 mg/kg/week of eteplirsen for up to 208 weeks in clinical studies, the following events were reported in ≥10% of patients and occurred more frequently than on the same dose in Study 1: vomiting, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection.

Hypersensitivity reactions have occurred in patients treated with eteplirsen.