Navepegritide

YUVIWEL ® is indicated to increase linear growth in pediatric patients 2 years of age and older with achondroplasia with open epiphyses. This indication is approved under accelerated approval based on an improvement in annualized growth velocity [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). YUVIWEL is a C-type natriuretic peptide (CNP) analog indicated to increase linear growth in pediatric patients 2 years of age and older with achondroplasia with open epiphyses. ( 1 ) This indication is approved under accelerated approval based on an improvement in annualized growth velocity . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )

For injection: 1.3 mg, 2.8 mg, and 5.5 mg of CNP(89-126) as a white to off-white lyophilized powder in a single-dose vial for reconstitution. For injection: 1.3 mg, 2.8 mg, and 5.5 mg as a lyophilized powder in single-dose vial for reconstitution. ( 3 )

None. None. ( 4 )

Risk of Low Blood Pressure : Transient decreases in blood pressure have been reported with a once daily CNP analog. Advise patients to contact their healthcare provider if they experience symptoms of decreased blood pressure while being treated with YUVIWEL. ( 5.1 )

5.1 Risk of Low Blood Pressure Transient decreases in blood pressure have been reported with a once daily CNP analog. Subjects with hemodynamically significant cardiovascular disease were excluded from participation in navepegritide clinical trials. Advise patients to contact their healthcare provider if they experience symptoms of decreased blood pressure (e.g., dizziness, fatigue and/or nausea) while being treated with YUVIWEL.

Most common adverse reactions (≥ 5%): vomiting, injection-site reaction, pain in extremity, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascendis Pharma at 1-844-442-7236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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 YUVIWEL 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) [see Clinical Studies (14) ] . 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 listed in Table 1. 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 Table 2. Table 2: 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 Adverse Reaction NAVEPEGRITIDE 0.1 mg /kg/week N = 68 n (%) Placebo N = 42 n (%) Vomiting 14 (21) 6 (14) Injection-site reaction 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 . 13 (19) 6 (14) Pain in extremity 8 (12) 3 (7) Nausea 4 (6) 0 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.

Renal Impairment : Not recommended for patients with moderate or severe renal impairment (eGFR < 60 mL/min/1.73 m 2 ). ( 8.6 )

8.1 Pregnancy Risk Summary There are no available data on the use of YUVIWEL 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) (see Data ) . 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. Data Animal Data In an embryo-fetal developmental toxicity study in pregnant rats, navepegritide was administered subcutaneously during the period of organogenesis (gestation day 6 to 20) at doses from 0.45 to 1.3 mg/kg/day. There was no effect on embryo-fetal survival, fetal toxicity, or embryo-fetal development up to the highest dose tested, corresponding to 10-fold the exposure at the MRHD [based on area under the curve (AUC)]. In an embryo-fetal developmental toxicity study in pregnant rabbits, navepegritide was administered subcutaneously during the period of organogenesis (gestation day 7 to 27) at doses from 0.3 to 0.9 mg/kg/every fourth day. There was no effect on embryo-fetal survival, fetal toxicity, or congenital malformations up to the highest dose tested, corresponding to 7-fold the exposure at the MRHD (based on AUC).

8.2 Lactation Risk Summary 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 YUVIWEL and any potential adverse effects on the breastfed infant from YUVIWEL or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of YUVIWEL to increase linear growth have been established in pediatric patients aged 2 years and older with achondroplasia with open epiphyses. Use of YUVIWEL for this indication is supported by evidence from a 52-week, randomized, placebo-controlled trial in 84 pediatric patients with achondroplasia [see Adverse Reactions (6.1) , Clinical Studies (14) ] . The safety and effectiveness of YUVIWEL in pediatric patients less than 2 years of age have not been established.

8.6 Renal Impairment YUVIWEL is not recommended for patients with moderate or severe renal impairment (eGFR < 60 mL/min/1.73 m 2 ). The recommended dosage for patients with mild renal impairment (eGFR ≥ 60 mL/min/1.73 m 2 ) is the same as the recommended dosage for patients with normal renal function [see Clinical Pharmacology (12.3) ] .

CNP released from navepegritide has the same receptor binding affinity and activity as endogenous CNP. CNP binds to natriuretic peptide receptor-B (NPR-B), which inhibits the mitogen activated protein kinase signaling (MAPK) pathway. Achondroplasia is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 (FGFR3) leading to overactive downstream signaling. The overly active FGFR3 inhibits endochondral ossification leading to short stature and skeletal dysplasia. Like endogenous CNP, CNP released from navepegritide binds to NPR-B, stimulating an increase in cyclic guanosine monophosphate (cGMP) and signaling through protein kinase G, resulting in an inhibition of the MAPK signaling pathway and thereby antagonizing the overactive FGFR3 signaling in achondroplasia. CNP promotes chondrocyte differentiation and proliferation, thereby stimulating skeletal bone growth in patients with achondroplasia.