Elamipretide

Barth Syndrome is a rare, X-linked, recessive, genetic disorder and is not likely to affect females. Therefore, there are no data with elamipretide use in pregnant women to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes occurred at any dose tested (see Data). Elamipretide contains benzyl alcohol as a preservative. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Barth Syndrome is a rare, X-linked, recessive, genetic disorder and is not likely to affect females. Therefore, there is no data to evaluate the presence of elamipretide in human milk, the effect on the breastfed infant, or the effects on milk production.

Elamipretide contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating female, benzyl alcohol exposure in the breastfed infant is unlikely. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for elamipretide and any potential adverse effects on the breastfed infant from elamipretide or from the underlying maternal condition.

Carcinogenicity studies have not been conducted with elamipretide.

Elamipretide was negative in an in vitro bacterial reverse mutation assay, a chromosomal aberration assay in Chinese hamster ovary cells, and an in vivo rat bone marrow micronucleus assay.

Subcutaneous doses of elamipretide in rats of up to 20 mg/kg/day, approximately 5-times the clinical exposure at the MRHD of 40 mg, did not adversely affect fertility or reproductive performance.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 elamipretide clinical development program, 12 male patients aged 12 to 35 years with genetically-confirmed Barth syndrome received treatment with daily subcutaneous injections of 40 mg elamipretide. Eleven of these 12 patients were Caucasian.

Patients first participated in a double-blind, placebo-controlled crossover trial where they were randomized to one of two sequences:

• 12 weeks of elamipretide in Period 1 then a 4-week washout followed by 12 weeks of placebo in Period 2 or
• 12 weeks of placebo in Period 1 then a 4-week washout followed by 12 weeks of elamipretide in Period 2

Ten patients completed the randomized trial and entered the open-label extension period where they received elamipretide once daily. Eight of these patients received elamipretide for 168 weeks, three of whom received elamipretide for a total of 192 weeks.

Adverse reactions occurring more commonly on elamipretide than on placebo include injection site reactions such as injection site erythema, pain, induration, pruritus, bruising, and urticaria (table).

Summary of Adverse Drug Reactions in the Placebo-Controlled Crossover Study, Barth Safety Population:

Eosinophilia

Increases in absolute eosinophil counts were noted frequently in studies where duration of administration of elamipretide was 30 days or greater. Eosinophil counts generally peaked around 90 days after initial exposure (mean increase from baseline ~0.5 to 0.6 × 10³/uL) and returned to baseline levels after 6 to 12 months of continuous exposure or after discontinuation of elamipretide. The elevation in eosinophils was not associated with clinical manifestations or changes in other laboratory parameters.