Eplontersen

Eplontersen has not been studied in patients with severe renal impairment or end-stage renal disease.

Eplontersen has not been studied in patients with moderate or severe hepatic impairment.

Risk Summary

There are no available data on eplontersen use in pregnant women to inform drug-associated risk of adverse developmental outcomes. Eplontersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking eplontersen. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by eplontersen administration is unknown.

No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis [see Animal Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development.

There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for eplontersen and any potential adverse effects on the breast-fed infant from eplontersen or from the underlying maternal condition.

Carcinogenesis

Carcinogenicity studies have not been conducted with eplontersen.

Mutagenesis

Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and continuing in females throughout the period of organogenesis resulted in no adverse effects on fertility.

Clinical Trials Experience

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

In Study 1, a total of 144 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) were randomized to eplontersen and received at least one dose of eplontersen. Of these, 141 patients received at least 6 months of treatment and 107 patients received at least 12 months of treatment. The mean duration of treatment was 15 months (range: 1.9 to 19.4 months). The median patient age at baseline was 52 years and 69% of the patients were male. Seventy-eight percent of patients treated with eplontersen were White, 15% were Asian, 4% were Black, 2% were reported as other races, and <1% were multiple races. Fifty-nine percent of patients had the Val30Met variant in the transthyretin gene; the remaining patients had one of 19 other variants. At baseline, 80% of patients were in Stage 1 of the disease and 20% were in Stage 2 with a mean duration from polyneuropathy diagnosis of 47 months. The mean duration from onset of polyneuropathy symptoms was 68 months.

The following table lists the adverse reactions that occurred in at least 5% of patients treated with eplontersen in Study 1.

Adverse Reactions Reported in at least 5% of Patients Treated with Eplontersen (Study 1):

^* Vitamin A decreased includes vitamin A deficiency and vitamin A decrease.
^† Injection site reactions includes erythema, pain, and pruritis.

Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in eplontersen-treated patients, including 1 case of complete AV block.

Vitamin A Decrease

In Study 1, patients were instructed to take the recommended daily allowance of vitamin A. All patients treated with eplontersen had normal vitamin A levels at baseline, 95% of patients developed low vitamin A levels during the study. In some cases, the decreased vitamin A level was reported as an adverse reaction.