Lerodalcibep

Discontinue lerodalcibep when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Lerodalcibep 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, lerodalcibep may cause fetal harm when administered to pregnant patients based on the mechanism of action. In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia for most patients.

Available data from clinical trials on lerodalcibep use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

In animal reproduction studies, there were no adverse developmental effects observed when pregnant monkeys were administered lerodalcibep subcutaneously during organogenesis and through to parturition at doses up to 100 mg/kg/week [up to 119-fold the exposure at the maximum recommended human dose (MRHD) of 300 mg every month].

The 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 are no data on the presence of lerodalcebip-liga in human milk, the effects on the breastfed infant, or the effects on milk production. In animal reproduction studies, lerodalcibep was present in the milk of lactating monkeys. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lerodalcibep and any potential adverse effects on the breastfed infant from lerodalcibep or from the underlying maternal condition.

Carcinogenicity studies have not been performed with lerodalcibep.

The mutagenic potential of lerodalcibep has not been evaluated; however, proteins are not expected to directly interact with DNA or chromosomes.

Fertility studies were not performed. However, in a chronic 6-month toxicology study in sexually mature cynomolgus monkeys, no adverse lerodalcibep-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) were observed when lerodalcibep was administered subcutaneously at 30 and 100 mg/kg once weekly. The highest dose tested corresponds to 138-fold the recommended human dose of 300 mg every month based on serum 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 Primary Hypercholesterolemia

Adverse Reactions in Two Pooled 52-week Controlled Trials

In two pooled 52-week, double-blind, randomized, placebo-controlled trials (Trials 1 and 2), 1,229 patients received 300 mg of lerodalcibep subcutaneously every 4 weeks. The mean age was 64 years (range 25 to 90 years), 52% were 65 years of age or older, 37% female, 79% White, 18% Black or African American, 4% Asian; 7% identified as Hispanic or Latino ethnicity. At baseline, 9% of patients had a diagnosis of HeFH, 74% had established atherosclerotic cardiovascular disease (ASCVD), and 26% were at increased risk for ASCVD. Adverse reactions reported in at least 2% of lerodalcibep-treated patients and more frequently than in placebo-treated patients are shown in Table 1. Adverse reactions led to treatment discontinuation in 4% of lerodalcibep-treated patients and placebo-treated patients. The most frequent adverse reaction leading to treatment discontinuation was injection site reactions, with a higher frequency in the lerodalcibep-treated group compared to placebo-treated patients (1% vs. 0%).

Table 1. Adverse Reactions Occurring in ≥2% of Lerodalcibep-treated Patients with Hypercholesterolemia and >1% More Frequently than Placebo-treated Patients in Two Pooled 52-Week Trials (Trials 1 and 2):

^a Grouped terms composed of several similar terms

Adverse Reactions in a 24-Week Controlled Trial

In a 24-week, double-blind, randomized, placebo-controlled trial (Trial 3), 318 patients with HeFH received 300 mg of lerodalcibep subcutaneously every 4 weeks. Adverse reactions reported in at least 2% of lerodalcibep-treated patients, and more frequently than in placebo-treated patients are shown in Table 2.

Table 2. Adverse Reactions Occurring in ≥2% Lerodalcibep-treated Patients with HeFH and >1% More Frequently than Placebo-treated Patients at 24 Weeks (Trial 3):

^a Grouped terms composed of several similar terms