REDEMPLO Injection for solution Ref.[116088] Active ingredients: Plozasiran

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REDEMPLO 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 REDEMPLO was evaluated in 75 patients with FCS enrolled in Trial 1 (NCT05089084) [see Clinical Studies (14)]. In this trial, patients received at least one dose of REDEMPLO 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 [see Dosage and Administration (2.1)]. 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 REDEMPLO for a median of 11.6 months; 26 patients were treated with REDEMPLO 25 mg every 3 months for a median of 11.8 months.

Adverse reactions led to discontinuation of treatment in 3 (6.0%) of REDEMPLO-treated patients and 0% of placebo-treated patients. The reasons for REDEMPLO treatment discontinuation were hyperglycemia and urticaria. Adverse reactions occurring in greater than or equal to 10% of REDEMPLO-treated patients and greater than 5% more frequently than in placebo-treated patients are listed below in Table 1.

Table 1. Adverse Reactions Occurring in Greater than or Equal to 10% of REDEMPLO-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 REDEMPLO 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 REDEMPLO-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 REDEMPLO compared to those treated with placebo [see Clinical Studies (14)]. Despite increases in the LDL-C, the average LDL-C value at Month 12 was less than 50 mg/dL in the 25 mg REDEMPLO group.

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

In Trial 1, none of the 50 FCS-patients treated with REDEMPLO over a period of 12 months developed treatment-induced or treatment-boosted ADAs. Because ADAs were not observed in the limited number of REDEMPLO-treated patients, the effect of ADAs on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of REDEMPLO products is unknown.

Risk Summary

There are insufficient data on REDEMPLO 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 (see Clinical Considerations).

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) (see Data).

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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Triglyceride levels increase during the third trimester of pregnancy. In patients with underlying defects in lipid metabolism, such as FCS, severe gestational hypertriglyceridemia may occur, increasing the risk of acute pancreatitis during pregnancy.

Data

Animal Data

In an embryo-fetal development study, pregnant rats were administered plozasiran by subcutaneous injection at 0, 5, 15, or 60 mg/kg, or 60 mg/kg rat specific surrogate, once daily during the period of organogenesis (gestational days 6 to 17). There was no evidence of drug-related embryo-fetal toxicity or fetal malformations up to 60 mg/kg plozasiran [23 times the MRHD based on body surface area (BSA)]. At maternally toxic doses there were embryo-fetal toxicities including increases in post-implantation loss and mean number of late resorptions at 60 mg/kg (23 times the MRHD based on BSA), early deliveries, reduced fetal body weight, and fetal skeletal developmental variations at ≥15 mg/kg (6 times the MRHD based on BSA). No adverse embryo-fetal developmental effects were observed from a single subcutaneous administration of 50 mg/kg plozasiran (19 times the MRHD based on BSA) or the rat specific surrogate to pregnant rats on gestation day 10.

In an embryo-fetal development study in pregnant rabbits, plozasiran was administered by subcutaneous injection at 0, 30, 60, or 180 mg/kg/day once daily during the period of organogenesis (gestational days 7 to 19). No evidence (of embryo-fetal toxicity or developmental abnormalities) was observed up to 180 mg/kg (140 times the MRHD based on BSA).

In a rat pre- and post-natal development study, plozasiran was administered at 0, 8, 24, or 80 mg/kg by subcutaneous injection once a week from gestation day 6 through lactation day 17. Plozasiran increased the number of females with stillborn offspring and the increase in stillborn offspring per litter resulted in reductions in live birth index at 80 mg/kg (31 times the MRHD based on BSA). There were decreases in offspring body weight and offspring survival at ≥24 mg/kg (9 times the MRHD based on BSA). No adverse effects were noted on offspring development up to 80 mg/kg (31 times the MRHD based on BSA).

Risk Summary

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 REDEMPLO and any potential adverse effects on the breastfed infant from REDEMPLO or from the underlying maternal condition.

The safety and effectiveness of REDEMPLO in pediatric patients with FCS have not been established.

Of the 75 patients with FCS randomized in Trial 1, 9 (12%) were 65 years of age or older, including 2 (3%) patients who were 75 years of age or older. No overall differences in safety or effectiveness of REDEMPLO have been observed between patients 65 years of age and older and younger adult patients.

The recommended dosage of REDEMPLO in patients with mild or moderate renal impairment (eGFR ≥30 to <90 mL/min) is the same as those with normal renal function. The impact of severe renal impairment or end stage renal disease is not known [see Clinical Pharmacology (12.3)].

The recommended dosage of REDEMPLO in patients with mild hepatic impairment [total bilirubin ≤1 times the upper limit of normal (ULN) and AST >1 times ULN, or total bilirubin >1.0 to 1.5 times ULN and any AST] is the same as those with normal hepatic function. The impact of moderate or severe hepatic impairment is not known [see Clinical Pharmacology (12.3)].