Vosoritide

VOXZOGO contains vosoritide, a human C type natriuretic peptide (CNP) analog. Vosoritide is a 39 amino acid peptide. Its amino acid sequence includes the 37 C terminal amino acids of the human CNP53 sequence plus Pro Gly on the N terminus to convey resistance to neutral endopeptidase (NEP) degradation. Vosoritide is manufactured from Escherichia coli using recombinant DNA technology. Vosoritide has a chemical formula of C 176 H 290 N 56 O 51 S 3 with a molecular weight of 4.1 kDa. Vosoritide has the structural formula shown in Figure 1. Figure 1 VOXZOGO (vosoritide) for injection, is a sterile, preservative-free white-to-yellow lyophilized powder, for subcutaneous administration after reconstitution with Sterile Water for Injection, USP. VOXZOGO is provided as a single-dose vial containing 0.4 mg, 0.56 mg, or 1.2 mg of vosoritide per vial. A pre-filled syringe containing Sterile Water for Injection, USP for use as a diluent is also provided. The contents of each single dose vial are summarized by strength in Table 4. The product contains no preservative. Table 4: Contents of VOXZOGO Strength Inactive Ingredients per Vial Trehalose dihydrate and D-Mannitol are used as isotonic agent. Citric acid monohydrate and sodium citrate dihydrate are used as buffering agent. VOXZOGO 0.4 mg Citric acid monohydrate (0.14 mg), mannitol (7.5 mg), methionine (0.36 mg), polysorbate 80 (0.025 mg), sodium citrate dihydrate (0.54 mg) and trehalose dihydrate (29.01 mg). After reconstitution with 0.5 mL Sterile Water for Injection USP, the resulting concentration is 0.4 mg/0.5 mL of vosoritide and the nominal deliverable volume is 0.4 mL. VOXZOGO 0.56 mg Citric acid monohydrate (0.20 mg), mannitol (10.50 mg), methionine (0.51 mg), polysorbate 80 (0.035 mg), sodium citrate dihydrate (0.76 mg) and trehalose dihydrate (40.61 mg). After reconstitution with 0.7 mL Sterile Water for Injection USP, the resulting concentration is 0.56 mg/0.7 mL of vosoritide and the nominal deliverable volume is 0.6 mL. VOXZOGO 1.2 mg Citric acid monohydrate (0.17 mg), mannitol (9 mg), methionine (0.44 mg), polysorbate 80 (0.030 mg), sodium citrate dihydrate (0.65 mg) and trehalose dihydrate (34.81 mg). After reconstitution with 0.6 mL Sterile Water for Injection USP, the resulting concentration is 1.2 mg/0.6 mL of vosoritide and the nominal deliverable volume is 0.5 mL. Chemical Structure

VOXZOGO is indicated to increase linear growth in pediatric patients 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). VOXZOGO is a C type natriuretic peptide (CNP) analog indicated to increase linear growth in pediatric patients with achondroplasia with open epiphyses. 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 VOXZOGO for injection is a white to yellow lyophilized powder for reconstitution and is provided as a co-pack which includes ten: Sterile, single-dose 2 mL glass vials containing VOXZOGO Diluent (Sterile Water for Injection, USP) in a single-dose prefilled syringe Diluent transfer needles (23 gauge) Single-dose administration syringes (30 gauge) both with needle retraction safety devices Strength (mg) Diluent (mL) Co-pack NDC Number Flip Cap Color 0.4 0.5 NDC 68135-082-36 White 0.56 0.7 NDC 68135-119-66 Magenta 1.2 0.6 NDC 68135-181-93 Grey The following items to be obtained separately; alcohol aseptic wipes, gauze, bandages and sharps container. Storage Refrigerate VOXZOGO vials and prefilled diluent syringes at 2°C to 8°C (36°F to 46°F). Do not freeze. VOXZOGO can be stored at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) for 90 days. Do not return VOXZOGO to the refrigerator once stored at room temperature. After reconstitution, VOXZOGO can be held in the vial at room temperature 20°C to 25°C (68°F to 77°F) for a maximum of 3 hours [see Dosage and Administration (2.4) ] . Record the starting date of room-temperature storage clearly on the unopened product carton. Do not use beyond expiration date on the label. Store in the original package to protect from light. Handling Reconstituted VOXZOGO must be administered within 3 hours of reconstitution [see Dosage and Administration (2.4) ] .

Ensure adequate food and fluid intake prior to administration. ( 2.1 ) Recommended dosage is based on patient's actual body weight. Administer VOXZOGO subcutaneously once daily. ( 2.2 ) Reconstitute prior to use. Injection volume is based on both patient's weight and concentration of reconstituted VOXZOGO. ( 2.2 ) Monitor growth and adjust dosage according to actual body weight. Permanently discontinue upon closure of epiphyses. ( 2.3 ) See full prescribing information for reconstitution, dilution, and administration instructions. ( 2.4 ) 2.1 Important Instructions Prior to Administration of VOXZOGO To reduce the risk of low blood pressure and its associated signs and symptoms, instruct the caregiver and patient that the patient should [see Warnings and Precautions (5.1) ] : Have adequate food intake prior to VOXZOGO administration. Drink approximately 240 to 300 mL of fluid in the hour prior to VOXZOGO administration. 2.2 Recommended Dosage and Administration The recommended dosage of VOXZOGO is based on the patient's actual body weight (see Table 1 ). VOXZOGO is administered by subcutaneous injection once daily [see Dosage and Administration (2.4) ] . Inject VOXZOGO at approximately the same time each day, if possible. The volume of VOXZOGO to be administered (injection volume) is based on the patient's actual body weight and the concentration of reconstituted VOXZOGO (0.8 mg/mL or 2 mg/mL) (see Table 1 ). VOXZOGO must be reconstituted prior to use [see Dosage and Administration (2.4) ] . Table 1: Recommended VOXZOGO Daily Dosage and Injection Volume Actual Body Weight Intermediate body weights that fall within these weight bands should be rounded to the nearest whole number. Dose Injection Volume Vial Strength for Reconstitution The concentration of vosoritide in reconstituted 0.4 mg vial and 0.56 mg vial is 0.8 mg/mL. The concentration of vosoritide in reconstituted 1.2 mg vial is 2 mg/mL. 3 kg 0.096 mg 0.12 mL 0.4 mg 4 kg 0.12 mg 0.15 mL 0.4 mg 5 kg 0.16 mg 0.2 mL 0.4 mg 6 to 7 kg 0.2 mg 0.25 mL 0.4 mg 8 to 11 kg 0.24 mg 0.3 mL 0.4 mg 12 to 16 kg 0.28 mg 0.35 mL 0.56 mg 17 to 21 kg 0.32 mg 0.4 mL 0.56 mg 22 to 32 kg 0.4 mg 0.5 mL 0.56 mg 33 to 43 kg 0.5 mg 0.25 mL 1.2 mg 44 to 59 kg 0.6 mg 0.3 mL 1.2 mg 60 to 89 kg 0.7 mg 0.35 mL 1.2 mg ≥ 90 kg 0.8 mg 0.4 mL 1.2 mg Missed dose If a dose of VOXZOGO is missed, it can be administered within 12 hours of the scheduled time of administration. Beyond 12 hours, skip the missed dose and administer the next daily dose according to the usual dosing schedule. 2.3 Growth Monitoring Monitor and assess patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust the dosage according to the patient's actual body weight [see Dosage and Administration (2.2) ] . Permanently discontinue VOXZOGO upon confirmation of no further growth potential, indicated by closure of epiphyses. 2.4 Preparation and Administration Reconstitute VOXZOGO before administration using the provided diluent syringe containing Sterile Water for Injection, USP (see Reconstitution Instructions below). Caregivers may inject VOXZOGO subcutaneously after proper training by a healthcare professional on the preparation and administration of VOXZOGO [see Instructions for Use ]. Reconstitution Instructions Select the correct VOXZOGO vial strength (co-packaged with prefilled syringe with Sterile Water for Injection diluent) based on the patient's actual body weight [see Dosage and Administration (2.2) ] . Remove VOXZOGO vial and prefilled diluent syringe from the refrigerator and allow the vial and prefilled diluent syringe to reach room temperature before reconstituting VOXZOGO. Attach the diluent needle provided with ancillary supplies to the diluent prefilled syringe. Inject the entire diluent prefilled syringe volume into the vial (see Table 2 ). Gently swirl the diluent in the vial until the white powder is completely dissolved. Do not shake. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Once reconstituted VOXZOGO is a clear, colorless to yellow liquid. The solution should not be used if discolored or cloudy, or if particles are present. The concentration of reconstituted solution is 0.8 mg/mL or 2.0 mg/mL (see Table 2 ). After reconstitution, VOXZOGO can be held in the vial at a room temperature 20°C to 25°C (68°F to 77°F) for a maximum of 3 hours. For administration, extract the required dose volume from the vial using the supplied administration syringe [see Dosage and Administration (2.2) ] . Table 2: Dilution Requirements for VOXZOGO Prior to Administration Vial Strength Reconstitution Volume Reconstituted Concentration 0.4 mg 0.5 mL 0.8 mg/mL 0.56 mg 0.7 mL 0.8 mg/mL 1.2 mg 0.6 mL 2 mg/mL Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications. Instructions for Subcutaneous Administration See the Instructions for Use document for detailed, illustrated instructions. Ensure patients have had adequate food and fluid intake prior to VOXZOGO administration [see Dosage and Administration (2.1) ] . Slowly withdraw the dosing volume of the reconstituted VOXZOGO solution from the single-dose vial into a syringe. Rotate sites for subcutaneous injections. The recommended injection sites for VOXZOGO are: the front middle of the thighs, the lower part of the abdomen at least 2 inches (5 centimeters) away from the navel, top of the buttocks or the back of the upper arms. The same injection area should not be used on two consecutive days. Do not inject VOXZOGO into sites that are red, swollen, or tender.

None None. ( 4 )

Risk of Low Blood Pressure : Transient decreases in blood pressure have been reported. Instruct patients to be well-hydrated and have adequate food intake prior to administration of VOXZOGO ( 5.1 ) 5.1 Risk of Low Blood Pressure Transient decreases in blood pressure were observed in clinical studies of VOXZOGO. Subjects with significant cardiac or vascular disease and patients on anti-hypertensive medicinal products were excluded from participation in VOXZOGO clinical trials. To reduce the risk of a decrease in blood pressure and associated symptoms (dizziness, fatigue and/or nausea), instruct patients to be well hydrated and have adequate food intake prior to administration of VOXZOGO [see Dosage and Administration (2.1) and Adverse Reactions (6.1) ].

Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Preparation and Administration Instruct caregivers on proper preparation and administration of VOXZOGO. Ensure caregivers have demonstrated the ability to perform a subcutaneous injection [see Dosage and Administration (2.4) ] . Instruct caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct caregivers to dispose needles and syringes in a puncture-resistant container. Risk of Low Blood Pressure Inform caregivers and patients that VOXZOGO may lower blood pressure after administration. Instruct caregivers and patients that prior to VOXZOGO administration, the patient should have adequate food intake and within the hour prior to administration, the patient should drink approximately 8-10 ounces (240-300 mL) of fluid [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ] .

Long term carcinogenicity studies and genotoxicity studies with vosoritide have not been performed. In a fertility and reproductive study in male and female rats at doses up to 540 mcg/kg/day (15-times the exposure at the MRHD), vosoritide had no effect on mating performance, fertility, or litter characteristics.

Risk Summary There are no available data on vosoritide use 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, there was no evidence of embryo-fetal toxicity or congenital malformations when pregnant rats and rabbits were administered vosoritide subcutaneously at doses equivalent to 14-times and 200-times, respectively, the exposure at the maximum recommended human dose (MRHD) (see Data ). The estimated background risk of major birth defects for the indicated population is higher than the general population. The estimated background risk of 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 estimated 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 embryofetal developmental toxicity study in rats, vosoritide was administered at 90, 270, 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis from gestation day (GD) 6 – 17. There were no effects on maternal animals or on embryofetal development at the highest dose administered (14-times the exposure at the MRHD). In an embryofetal developmental toxicity study in rabbits, vosoritide was administered at 45, 135, 240 mcg/kg once daily by subcutaneous injection during the period of major organogenesis (GD 7 – 19). No effects were observed in maternal animals or on embryofetal development at the highest dose administered (200-times the exposure at the MRHD). In a pre- and postnatal toxicity study in rats, vosoritide was administered at 90, 270, and 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis and continuing to weaning (GD 6 through postpartum day 20). There were no effects on maternal animals, including maintenance of pregnancy, parturition, or care of offspring, and no effects were noted on offspring growth and development or ability to reproduce at the highest dose (14-times the exposure at the MRHD).

The safety and effectiveness of VOXZOGO have been established in pediatric patients for the improvement in linear growth in patients with achondroplasia with open epiphyses. Use of VOXZOGO for this indication is supported by evidence from an adequate and well-controlled study in 121 pediatric patients aged 5 to 15 years with achondroplasia, pharmacokinetic data in pediatric patients aged 4.5 months to 15 years, and additional safety data in pediatric patients aged 4.4 months to <5 years [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Low Blood Pressure [see Warnings and Precautions (5.1) ] Most common adverse reactions (>10%) are injection site erythema, injection site swelling, rash, vomiting, injection site urticaria, arthralgia, decreased blood pressure, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, 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. Pediatric Patients 5 Years of Age and Older VOXZOGO was studied in a 52-week, randomized, double-blind, placebo-controlled trial in 121 subjects with achondroplasia (Study 1) [see Clinical Studies (14) ] . The subjects' ages ranged from 5.1 to 14.9 years with a mean of 8.7 years. Sixty four (53%) subjects were male and 57 (47%) were female. Overall, 86 (71%) subjects were White, 23 (19%) were Asian, 5 (4%) were Black or African American, and 7 (6%) were classified as "multiple" race. The demographic and baseline characteristics were balanced between treatment groups. The subjects received either VOXZOGO 15 mcg/kg, or placebo administered subcutaneously once daily. Table 3 shows adverse reactions that occurred in ≥5% of patients treated with VOXZOGO and at a percentage greater than placebo. Table 3: Adverse Reactions that Occurred in ≥5% of Patients Treated with VOXZOGO and at a Percentage Greater than Placebo in Study 1 Includes adverse reactions occurring more frequently in the vosoritide arm and with a risk difference of ≥5% (i.e., difference of >2 subjects) between treatment arms Adverse Reaction Placebo (N=61) n (%) VOXZOGO (N=60) n (%) Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects with the adverse reaction; %, percent of subjects with the adverse reaction. Injection site erythema 42 (69%) 45 (75%) Injection site swelling 22 (36%) 37 (62%) Vomiting 12 (20%) 16 (27%) Injection site urticaria 6 (10%) 15 (25%) Arthralgia 4 (7%) 9 (15%) Decreased blood pressure 3 (5%) 8 (13%) Gastroenteritis Includes the preferred terms: gastroenteritis and gastroenteritis, viral 5 (8%) 8 (13%) Diarrhea 2 (3%) 6 (10%) Dizziness Includes the preferred terms: dizziness, presyncope, procedural dizziness, vertigo 2 (3%) 6 (10%) Ear pain 3 (5%) 6 (10%) Influenza 3 (5%) 6 (10%) Fatigue Includes the preferred terms: fatigue, lethargy, malaise 2 (3%) 5 (8%) Seasonal allergy 1 (2%) 4 (7%) Dry skin 0 3 (5%) Laboratory Abnormalities Increase in Alkaline Phosphatase More VOXZOGO-treated patients had an increase in alkaline phosphatase levels during the study compared to placebo (17% vs 7%). Discussion of Selected Adverse Reactions Decreased blood pressure Eight (13%) of 60 subjects treated with VOXZOGO had a total of 11 events of transient decrease in blood pressure compared to 3 (5%) of 61 subjects on placebo, identified predominantly during periods of frequent monitoring at clinical visits after dosing over a 52-week treatment period. The median time to onset from injection was 31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes in VOXZOGO-treated subjects. Two out of 60 (3%) VOXZOGO-treated subjects each had one symptomatic episode of decreased blood pressure with vomiting and/or dizziness compared to 0 of 61 (0%) subjects on placebo. Injection site reactions Injection site reactions occurred in 51 (85%) subjects receiving VOXZOGO and 50 (82%) subjects receiving placebo over a 52 week period of treatment. Injection site reactions included the preferred terms injection site erythema, injection site reaction, injection site swelling, injection site urticaria, injection site pain, injection site bruising, injection site pruritus, injection site hemorrhage, injection site discoloration, and injection site induration. Over a 52 week period, 51 (85%) of 60 subjects receiving VOXZOGO experienced a total of 6983 events of injection site reactions, while 50 (82%) of 61 subjects receiving placebo experienced a total of 1776 events of injections site reactions, representing 120.4 events per person/year exposure and 29.2 per person/year exposure, respectively. One injection site reaction event could have been associated with one or more injection site reaction symptoms (e.g., injection site swelling, injection site erythema, injection site urticaria, etc.). Two subjects in the VOXZOGO arm discontinued treatment due to adverse reactions of pain and anxiety with injections. Pediatric Patients <5 Years The safety of VOXZOGO in pediatric patients <5 years with achondroplasia was evaluated in a 52-week randomized, double blind, placebo-controlled study (Study 2) . In this study, 64 patients from 4.4 months to <5 years of age were randomized to receive either a daily vosoritide dose with similar exposure to that characterized to be safe and effective in children with ACH aged ≥5 years old, or placebo. An additional 11 patients received open-label treatment as part of this study. Subjects received 30 mcg/kg while they were <2 years of age. The daily dose for subjects was adjusted to 15 mcg/kg immediately following their 2 year birthday. The most common adverse reactions (>10%) reported in pediatric patients <5 years were injection site reactions (86%) and rash (28%). The overall safety profile of VOXZOGO in pediatric patients <5 years was similar to that seen in older pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of VOXZOGO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: hypertrichosis (includes the preferred terms: hair growth abnormal and hypertrichosis).