Navepegritide

YUVIWEL for injection contains navepegritide, a C-type natriuretic peptide (CNP) analog. Navepegritide is a prodrug of active CNP consisting of a CNP moiety transiently conjugated to two branched 20 kDa methoxy polyethylene glycol (mPEG) moieties via a proprietary TransCon ® Linker. The amino acid sequence of the CNP moiety is identical to the 38 amino acid sequence of residues 89-126 of human CNP. The structural formula of navepegritide is as follows: The molecular formula is C 231 H 386 N 64 O 67 S 5 + 4 × (C 2 H 4 O)n, where n is between 200 and 250. The average molecular weight is approximately 45 kDa. YUVIWEL is provided as a sterile, lyophilized white to off-white powder for reconstitution to a colorless solution with Sterile Water for Injection, USP (diluent). The diluent for reconstitution of YUVIWEL is provided in a prefilled syringe. The compositions of YUVIWEL are shown in Table 3. Table 3: Content of YUVIWEL Strength Composition of YUVIWEL (gross content per vial) An overfill is included in the vial to compensate for loss in the vial and during transfer. CNP(89-126) Concentration After Reconstitution 1.3 mg/vial Navepegritide equivalent to 1.9 mg CNP(89-126), succinic acid (1.0 mg), trehalose dihydrate (72.2 mg), tromethamine and hydrochloric acid (q.s. for adjustment to pH 5.0) 2.2 mg/mL 2.8 mg/vial Navepegritide equivalent to 4.0 mg CNP(89-126), succinic acid (1.0 mg), trehalose dihydrate (66.7 mg), tromethamine and hydrochloric acid (q.s. for adjustment to pH 5.0) 4.6 mg/mL 5.5 mg/vial Navepegritide equivalent to 6.9 mg CNP(89-126), succinic acid (1.5 mg), trehalose dihydrate (91.9 mg), tromethamine and hydrochloric acid (q.s. for adjustment to pH 5.0) 5.5 mg/mL Chemical Structure

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 )

How Supplied YUVIWEL (navepegritide) for injection is supplied as a lyophilized white to off-white powder in a vial, in three strengths: 1.3 mg, 2.8 mg, and 5.5 mg (see Table 5 ). Each YUVIWEL carton contains 4 Kits with 1 Prescribing Information, and 1 Instructions for Use. Table 5: YUVIWEL Strengths and Contents of Each Kit Strength Contents of Each Kit (4 Kits in each carton) Carton NDC 1.3 mg vial One 1.3 mg single-dose vial of YUVIWEL for injection with yellow cap One 0.8 mL Sterile Water for Injection, USP (clear, colorless prefilled diluent syringe) 2 single use preparation needles (21 gauge) 1 single use injection syringe 1 single use injection needle (30 gauge) 73362-201-01 2.8 mg vial One 2.8 mg single-dose vial of YUVIWEL for injection with blue cap One 0.8 mL Sterile Water for Injection, USP (clear, colorless prefilled diluent syringe) 2 single use preparation needles (21 gauge) 1 single use injection syringe 1 single use injection needle (30 gauge) 73362-202-01 5.5 mg vial One 5.5 mg single-dose vial of YUVIWEL for injection with violet cap One 1.1 mL Sterile Water for Injection, USP (clear, colorless prefilled diluent syringe) 2 single use preparation needles (21 gauge) 1 single use injection syringe 1 single use injection needle (30 gauge) 73362-203-01 Only use the vial, needles, and syringes that are in the Kits for handling of YUVIWEL [see Dosage and Administration (2.3) ] and do not use the components for other medicinal products. Storage and Handling Store YUVIWEL refrigerated between 2°C to 8°C (36°F to 46°F). Store in the original packaging until time of use to protect from light. Do not freeze. YUVIWEL can also be stored at room temperature up to 30°C (86°F) for up to 6 months and can be returned to refrigeration within the 6 months. Do not use YUVIWEL beyond the expiration date or 6 months after the date it was first removed from refrigeration (whichever is earlier). Reconstituted YUVIWEL can be stored at room temperature up to 30°C (86°F) for up to 4 hours. Discard unused reconstituted solution.

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 and Administration (2.1 , 2.3) ] . Administer YUVIWEL subcutaneously in the abdominal region (2 inches from the belly button) or thighs. If a caregiver is administering YUVIWEL, subcutaneous injection in the buttocks or back of the upper arm is also acceptable. Rotate injection sites. Do not give an injection into sites other than described above. Avoid injecting where the skin is red, swollen, or scarred. Administer YUVIWEL once weekly on the dosing day, at any time of day. All YUVIWEL components are for single use only. Do not draw up more than one injection volume, as specified in Table 1, from a vial. For injection volumes greater than 1 mL, use two Kits to achieve a complete dose. The two injections must be given one after the other, using different injection sites. Discard the unused reconstituted solution. 2.5 Missed Dose If a dose of YUVIWEL is missed, administer the missed dose as soon as possible but not more than 2 days after the missed dosing day. To avoid missed doses, YUVIWEL can be taken up to 2 days before or 2 days after the scheduled dosing day. Resume once-weekly dosing for the next dose at the previously scheduled dosing day. If more than 2 days have passed from the dosing day, skip the missed dose and administer the dose on the next regularly scheduled day. At least 5 days should elapse between doses.

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.

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Administration Instructions Provide appropriate instructions for injection to the patient/caregiver based on the YUVIWEL Instructions for Use (available at www.Yuviwel.com). Patients/caregivers and healthcare providers may also call the Ascendis Pharma Customer Support toll-free number at 1-844-442-7236 (1-844-44ASCENDIS) for assistance or additional training, if needed. Advise patients/caregivers to refer to the Instructions for Use that accompanies YUVIWEL for complete reconstitution and administration instructions with illustrations [see Dosage and Administration (2.3 , 2.4) ] . Advise patients/caregivers to administer YUVIWEL once weekly on the dosing day, at any time of day. Advise patients and caregivers to rotate the site of injection to reduce the risk of injection site reactions [see Dosage and Administration (2.4) ]. Missed Dose [see Dosage and Administration (2.5) ] Advise patients/caregivers that to avoid missed doses, YUVIWEL can be taken up to 2 days before or 2 days after the scheduled dosing day. If a dose is missed and more than 2 days have passed from the scheduled day, advise patients/caregivers to skip the missed dose and administer the next dose on the regularly scheduled day. To change the regular dosing day to a different day of the week, advise patients/caregivers to ensure that at least 5 days will elapse between the last dose and the newly established regular dosing day. Risk of Low Blood Pressure Advise patients and/or caregivers 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 [see Warnings and Precautions (5.1) ] .

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).

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).

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.

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.