Plozasiran

There are insufficient data on plozasiran use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with FCS are at risk for pancreatitis during pregnancy because of defects in lipid metabolism and increased triglyceride levels.

In animal reproduction studies, no adverse drug-related developmental effects were observed in pregnant rats or rabbits with subcutaneous administration of plozasiran during organogenesis up to 23 and 140 times, respectively, the maximum recommended human dose (MRHD).

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 is no information regarding the presence of plozasiran in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Oligonucleotide-based products typically have poor oral bioavailability. Therefore, it is considered that if plozasiran is present in breastmilk, it is unlikely to lead to clinically relevant levels in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for plozasiran and any potential adverse effects on the breastfed infant from plozasiran or from the underlying maternal condition.

Carcinogenesis

In a 26-week study in RasH2Tg mice, plozasiran was administered subcutaneously once every 8 weeks at dose levels of 30, 60, and 120 mg/kg. Plozasiran was not carcinogenic up to the highest tested dose of 120 mg/kg (23-times MRHD based on BSA).

Mutagenesis

Plozasiran was not mutagenic or clastogenic in a standard battery of genetic toxicity assays, including a bacterial mutation (Ames) assay, and in vitro and in vivo mouse micronucleus assays.

Impairment of Fertility

In a fertility and early embryonic-development study, male and female rats were administered subcutaneously with vehicle or plozasiran at the doses of 12.5, 25 or 50 mg/kg or rat specific surrogate at 25 mg/kg. Males were treated once weekly before and throughout cohabitation, while females received treatment either once every 3 days or once weekly before and through mating until gestation day 6. There were no adverse effects on mating and fertility in males or females up to 50 mg/kg corresponding to 19-times the MRHD, based on BSA.

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

The safety of plozasiran was evaluated in 75 patients with FCS enrolled in Trial 1 (NCT05089084). In this trial, patients received at least one dose of plozasiran 25 mg (N=26) or 50 mg of plozasiran (N=24) and 25 patients received placebo. Plozasiran 50 mg is not an approved dosage regimen for FCS. Across treatment groups, the mean age was 46 years and 49% of patients were male. Seventy-three percent (73%) of patients were White, 21% were Asian, and 5% were reported as other races; 3% identified as Hispanic or Latino ethnicity. Fifty (50) patients were exposed to plozasiran for a median of 11.6 months; 26 patients were treated with plozasiran 25 mg every 3 months for a median of 11.8 months.

Adverse reactions led to discontinuation of treatment in 3 (6.0%) of plozasiran-treated patients and 0% of placebo-treated patients. The reasons for plozasiran treatment discontinuation were hyperglycemia and urticaria. Adverse reactions occurring in greater than or equal to 10% of plozasiran-treated patients and greater than 5% more frequently than in placebo-treated patients are listed below in the following table.

Adverse Reactions Occurring in Greater than or Equal to 10% of Plozasiran-treated Patients and Greater than 5% More Frequently than with Placebo in Trial 1:

¹ Grouped terms composed of several similar terms

Laboratory Tests

Increase in Glucose

Mean increases from baseline in HbA1c (up to 0.36%) and fasting glucose (up to 9 mg/dL) were observed over time in the 25 mg plozasiran group. The incidence of hyperglycemia (defined as adverse events consistent with diabetes mellitus or hyperglycemia, new antidiabetic medication, or laboratory values) was higher in 25 mg plozasiran-treated patients without a medical history of diabetes at baseline (40%) compared to placebo-treated patients (20%).

Increase in Liver Enzymes

Increases from baseline liver enzymes within the normal range were observed with plozasiran treatment in the FCS population. These increases occurred within the first 3 months of treatment and stabilized.

Increase in LDL-cholesterol

Increases in low-density lipoprotein cholesterol (LDL-C) and total apolipoprotein B (apoB) were observed in the FCS population treated with plozasiran compared to those treated with placebo. Despite increases in the LDL-C, the average LDL-C value at Month 12 was less than 50 mg/dL in the 25 mg plozasiran group.