Navepegritide

1 INDICATIONS AND USAGE 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 )

12.1 Mechanism of Action 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.

2 DOSAGE AND ADMINISTRATION Administer once-weekly by subcutaneous injection. Dosage is based on body weight. ( 2.1 ) Periodically monitor growth and adjust dose according to body weight. Discontinue when no further growth potential, as indicated by epiphyseal closure. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.3 , 2.4 ) 2.1 Recommended Dosage and Administration The recommended once-weekly dosage of YUVIWEL is based on the patient´s body weight (see Table 1 ). YUVIWEL is administered by subcutaneous injection. YUVIWEL must be reconstituted prior to use [see Dosage and Administration (2.3) ]. Table 1: Recommended YUVIWEL Weekly Dosage and Injection Volume Patient Body weight Weekly Dose Injection Volume Vial Strength for Reconstitution The concentration of navepegritide is 2.2 mg/mL in a reconstituted 1.3 mg vial; 4.6 mg/mL in a reconstituted 2.8 mg vial; and 5.5 mg/mL in a reconstituted 5.5 mg vial. 8 to 9.9 kg 0.88 mg 0.4 mL 1.3 mg 10 to 13.4 kg 1.2 mg 0.55 mL 13.5 to 17.5 kg 1.6 mg 0.35 mL 2.8 mg 17.6 to 23 kg 2.1 mg 0.45 mL 23.1 to 30.5 kg 2.8 mg 0.6 mL 30.6 to 41.2 kg 3.6 mg 0.65 mL 5.5 mg 41.3 to 55.9 kg 5 mg 0.9 mL 56 to 73.5 kg 6.6 mg 1.2 mL (use 2 Kits) Administer 0.6 mL from each Kit 73.6 to 90 kg 8.8 mg 1.6 mL (use 2 Kits) Administer 0.8 mL from each Kit Switching from Daily C-type Natriuretic Peptide (CNP) Analog Start once-weekly YUVIWEL on the day after completing the last dose of daily CNP therapy. 2.2 Monitor Growth Periodically monitor the patient's growth and adjust the dosage according to the actual body weight [see Dosage and Administration (2.1) ] . Discontinue YUVIWEL upon confirmation of no further growth potential, indicated by closure of the epiphyses. 2.3 Preparation of YUVIWEL for Administration Patients and caregivers who will administer YUVIWEL should receive appropriate training by a healthcare provider prior to use. Refer to the Instructions for Use for complete preparation and administration instructions with illustrations. Before administration, reconstitute YUVIWEL using the provided prefilled diluent syringe containing Sterile Water for Injection as described below. Needles and syringes supplied with YUVIWEL are for single use only. If the product was refrigerated, allow the YUVIWEL vial and the prefilled diluent syringe to reach room temperature (about 30 minutes) before reconstitution. Screw a preparation needle onto the prefilled diluent syringe and inject the entire diluent volume into the vial. Shake the vial up and down for 15 seconds. Do not swirl or roll. The reconstituted YUVIWEL vial should stand at room temperature for 5 minutes after shaking. Dispose the diluent syringe with attached preparation needle immediately after injecting the diluent into the vial. YUVIWEL should be visually inspected for particles or discoloration prior to administration, whenever solution and container permit. Once reconstituted, YUVIWEL is a clear and colorless solution. Do not use the solution if it is discolored, cloudy or contains visible particles. Air bubbles may be seen, and this is normal. Screw a new preparation needle onto the injection syringe and withdraw the prescribed injection volume from the reconstituted vial. Remove air from the withdrawn dose volume before continuing and ensure the withdrawn dose volume is correct after removing any air. Remove and dispose the preparation needle from the injection syringe. Screw the injection needle onto the injection syringe before administration. Two Kits are needed to achieve a complete dose for patients with body weight 56 kg or greater, where the prescribed injection volume is greater than 1 mL. Reconstituted YUVIWEL can be stored at room temperature up to 30°C (86°F) for up to 4 hours. 2.4 Administration Instructions Refer to the Instructions for Use for complete administration instructions with illustrations. Using the prepared syringe, administer the prescribed injection volume [see Dosage an

6 ADVERSE REACTIONS 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.

5 WARNINGS AND PRECAUTIONS 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.

4 CONTRAINDICATIONS None. None. ( 4 )