Navepegritide

There are no available data on the use of navepegritide in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of navepegritide during the period of organogenesis in pregnant rats and rabbits resulted in no impact on embryo-fetal survival or congenital malformations at doses up to 10- and 7-fold, respectively, the exposure at the maximum recommended human dose (MRHD).

Achondroplasia is an autosomal dominant genetic disorder with 100% penetrance. Therefore, there is a 50% risk for a parent with achondroplasia to have a child with achondroplasia. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the 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 available regarding the presence of navepegritide in human milk or regarding the potential effects on milk production or on the breastfed newborn/infant. High molecular weight therapeutic compounds, including navepegritide, are expected to have low passage into human milk. Further, no or low anticipated oral absorption of navepegritide will limit any systemic bioavailability in the breastfed newborn/infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for navepegritide and any potential adverse effects on the breastfed infant from navepegritide or from the underlying maternal condition.

Carcinogenesis and Mutagenesis

Long-term animal studies to address the carcinogenic potential of navepegritide have not been conducted.

Navepegritide was not genotoxic in an in vitro bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

In fertility studies, navepegritide was administered by subcutaneous injection at 0.5, 1.0, and 2.0 mg/kg/week to male and female rats. Navepegritide had no effect on mating performance, fertility, litter characteristics or early embryo-fetal development up to the highest dose tested corresponding to 3-fold the MRHD in male rats (based on body surface area) and 4-fold exposure in female rats (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.

The safety of navepegritide was evaluated in pediatric patients with achondroplasia in two randomized, placebo-controlled trials of navepegritide. Trial 1 included a 52-week, randomized, double-blind, placebo-controlled period, followed by a 52-week, single-arm, open-label extension (OLE) period. In Trial 1, 84 pediatric participants with achondroplasia (mean age 5.7 years; range: 2 to 12 years) were randomized to subcutaneous navepegritide 0.1 mg/kg/week (n=57) or placebo (n=27). Trial 2 included a randomized, double-blind, placebo-controlled dose-finding period. In Trial 2, 57 pediatric participants with achondroplasia (mean age 5.9 years; range: 2 to 10 years) were randomized 3:1 to subcutaneous navepegritide 0.006, 0.02, 0.05, or 0.1 mg/kg or placebo for 52 weeks. At Week 52, all participants transitioned to an OLE period during which they received navepegritide 0.1 mg/kg/week for 104 weeks.

The adverse reaction rates for navepegritide were derived from pediatric participants with achondroplasia who received navepegritide 0.1 mg/kg/week or placebo during the double-blind period of Trials 1 and 2. Of the dosages evaluated in Trials 1 and 2, 0.1 mg/kg/week is most similar to the approved weight-based dosage.

Adverse reactions reported in the placebo-controlled pooled periods of Trials 1 and 2 in ≥5% of navepegritide-treated patients and at an incidence at least 2% greater than with placebo are presented in the following table.

Adverse Reactions Reported in ≥5% of Participants Treated with Navepegritide 0.1 mg/kg/week and ≥2% Higher Than Placebo During the Placebo-Controlled Period of Trials 1 and 2:

^* Includes injection-site swelling, injection-site erythema, injection-site bruising, injection-site reaction, injection-site pruritus, injection-site discoloration, injection-site hemorrhage, injection-site pain, injection-site vesicles, and injection-site edema.

Injection-Site Reactions

During the 52-week double-blind period of Trials 1 and 2, 13 of 68 (19%) participants receiving navepegritide 0.1 mg/kg/week experienced a total of 25 events of injection-site reactions, while 6 of 42 (14%) participants receiving placebo experienced a total of 6 events of injection site reactions, corresponding to 0.4 events per person year exposure and 0.2 events per person year exposure, respectively.

Other Adverse Reactions from Trials 1 and 2 (Pooled)

Hypertrichosis

Hypertrichosis was reported in 2 of 68 patients (3%) receiving navepegritide 0.1 mg/kg/week compared to none receiving placebo in the double-blind periods of Trials 1 and 2. Cases presented as localized hair growth at injection sites or generalized increased body hair growth affecting limbs, back, or shoulders. To reduce the risk of local skin changes, rotate the site of injection with each dose.