LEROCHOL Solution for injection Ref.[116114] Active ingredients: Lerodalcibep

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 LEROCHOL subcutaneously every 4 weeks [see Clinical Studies (14)]. 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 LEROCHOL-treated patients and more frequently than in placebo-treated patients are shown in Table 1. Adverse reactions led to treatment discontinuation in 4% of LEROCHOL-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 LEROCHOL-treated group compared to placebo-treated patients (1% vs. 0%).

Table 1. Adverse Reactions Occurring in ≥2% of LEROCHOL-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 LEROCHOL subcutaneously every 4 weeks [see Clinical Studies (14)]. Adverse reactions reported in at least 2% of LEROCHOL-treated patients, and more frequently than in placebo-treated patients are shown in Table 2.

Table 2. Adverse Reactions Occurring in ≥2% LEROCHOL-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

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of lerodalcibep-liga or of other lerodalcibep products.

During the 52-week treatment period in Trial 1 and Trial 2, 15.1% (180/1,195) of LEROCHOL-treated patients at the recommended dosage with evaluable assessments were ADA positive, of whom 22.8% (41/180) had neutralizing antibodies (NAb). During the 24-week treatment period in Trial 3, 11.3% (36/318) of LEROCHOL-treated patients at the recommended dosage with evaluable assessments were ADA positive, of whom 55.6% (20/36) had NAb [see Clinical Studies (14)].

There was no identified clinically significant effect of ADA and NAb on the pharmacokinetics, pharmacodynamics (free PCSK9), safety, or effectiveness (LDL-C) of LEROCHOL over the treatment period of 52 weeks.

Risk Summary

Discontinue LEROCHOL when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. LEROCHOL 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, LEROCHOL may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. 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 LEROCHOL 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-liga 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.

Data

Animal Data

In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when lerodalcibep-liga was dosed during organogenesis and through parturition at 30 and 100 mg/kg subcutaneously once weekly (exposures up to 119-fold the MRHD by AUC). An assessment of immune function in the infants showed no treatment-related adverse effects. Measurable lerodalcibep-liga serum concentrations were observed in the infant monkeys with infant serum concentrations approximately 2 to 7% of maternal serum concentrations on postnatal days 14, 21 and 28, indicating that lerodalcibep-liga has the potential to be transmitted from the mother to the developing fetus.

Risk Summary

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-liga was present in the milk of lactating monkeys (see Data). 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 LEROCHOL and any potential adverse effects on the breastfed infant from LEROCHOL or from the underlying maternal condition.

Data

Low concentrations of lerodalcibep-liga were measured in milk samples collected from monkeys on post-partum day (PPD) 7 and PPD 14, when lerodalcibep-liga was dosed during organogenesis through parturition at 30 and 100 mg/kg subcutaneously once weekly (exposures up to 119-fold the MRHD by AUC). There is no information regarding whether lerodalcibep-liga ingested with milk transfers to neonatal or infant monkey circulation.

The safety and effectiveness of LEROCHOL in pediatric patients have not been established. Clinical trials of LEROCHOL in pediatric patients with HeFH have not been conducted. Effectiveness of LEROCHOL was not demonstrated in a 24-week, randomized, open-label, active-controlled trial (NCT04034485) in 19 pediatric patients aged 10 to 17 years with homozygous familial hypercholesterolemia (HoFH).

Of the 1,631 patients treated with LEROCHOL 300 mg in clinical trials, 687 (42%) patients were 65 years of age and older, while 198 (12%) patients were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

No dose adjustment is necessary in patients with mild to moderate renal impairment [estimated glomerular filtration rate (eGFR) ≥30 to <90 mL/min] [see Clinical Pharmacology (12.3)]. LEROCHOL has not been studied in patients with severe renal impairment (eGFR <30 mL/min) or end-stage renal disease.

No dose adjustment is necessary in patients with mild (total bilirubin 1.0 to 1.5 upper limit of normal or aspartate aminotransaminase > upper limit of normal) or moderate (total bilirubin 1.5 to 3.0 upper limit of normal) hepatic impairment [see Clinical Pharmacology (12.3)]. LEROCHOL has not been studied in patients with severe hepatic impairment.