Enlicitide

Discontinue enlicitide when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Alternatively, consider the ongoing therapeutic needs of the individual patient. Enlicitide increases LDL-C uptake and lowers LDL-C levels in the circulation, thus decreasing cholesterol and possibly other biologically active substances derived from cholesterol; therefore, enlicitide may cause fetal harm when administered to pregnant patients based on the mechanism of action.

There are insufficient data on the use of enlicitide in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Consider the benefits and risks of enlicitide when prescribing enlicitide to pregnant women.

In animal reproduction studies, no adverse embryofetal developmental effects were observed in pregnant rats and rabbits administered enlicitide subcutaneously during organogenesis (up to 58- and 51-fold, respectively, the human exposure at the recommended human dose (RHD), based on AUC). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

There is no information on the presence of enlicitide in human milk, the effects on the breastfed infant, or the effects on milk production. Enlicitide was detected at low concentrations in the plasma of nursing pups from lactating rats administered subcutaneous enlicitide.

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

Carcinogenesis

In a 26-week study in RasH2Tg mice, enlicitide was administered daily both by subcutaneous and oral routes at subcutaneous/oral dosages of 2.5/1, 10/2 or 30/4 mg/kg/day. Enlicitide was not carcinogenic in rasH2 transgenic mice up to the highest dose tested, corresponding to 59-fold the human exposure at the RHD, based on AUC.

Based on a comprehensive assessment of the available toxicology data and the PCSK9-specific target, enlicitide is not expected to be carcinogenic in humans.

Mutagenesis

Enlicitide was not mutagenic or genotoxic in a standard battery of genotoxicity tests that included a microbial mutagenicity assay, an in vitro chromosome aberration assay and an in vivo micronucleus assay in rats.

Impairment of Fertility

In fertility and early embryonic-development studies, male or female rats were administered enlicitide subcutaneously at doses of 1, 5, or 10 mg/kg/day for 14 days (female) or 15 days (male) prior to cohabitation, during cohabitation, until the day prior to scheduled sacrifice (male) or through GD 7 (female). There were no adverse effects on fertility, mating performance or early embryonic development up to the highest dose tested, corresponding to 45-fold the human exposure at the RHD, based on AUC

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.

Adverse Reactions in Adults with Hypercholesterolemia

The safety of enlicitide was evaluated in Trial 1 (CORALreef Lipids, NCT05952856), a 52-week, multicenter, double-blind, randomized, placebo-controlled trial in 2,904 patients with hypercholesterolemia (including those with and without HeFH) and a history of a major atherosclerotic cardiovascular disease (ASCVD) event or increased risk for development of a first major ASCVD event. In Trial 1, the frequencies of adverse reactions in adults with hypercholesterolemia were similar between those treated with enlicitide and those receiving placebo. Similar proportions of enlicitide-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction.

Adverse Reactions in Adults with HeFH

The safety of enlicitide was evaluated in Trial 2 (CORALreef HeFH, NCT05952869), a 52-week multicenter, double-blind, randomized, placebo-controlled trial in 303 patients with HeFH. In Trial 2, the most common adverse reactions in adults with HeFH treated with enlicitide that occurred at higher frequencies compared to placebo were diarrhea (enlicitide 7%, placebo 2%) and dizziness (enlicitide 9%, placebo 4%). Similar proportions of enlicitide-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. The safety profile observed in adults with HeFH in Trial 2 was otherwise generally consistent with that observed in adults with hypercholesterolemia in Trial 1.