Vosoritide

12.1 Mechanism of Action In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 ( FGFR3 ). Binding of vosoritide to natriuretic peptide receptor-B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) pathway at the level of rapidly accelerating fibrosarcoma serine/threonine protein kinase (RAF-1). As a result, vosoritide, like CNP, acts as a positive regulator of endochondral bone growth as it promotes chondrocyte proliferation and differentiation. In animal models with open growth plates, vosoritide administration resulted in the promotion of chondrocyte proliferation and differentiation that led to a widening of the growth plate and subsequent increase in skeletal growth. In the mouse models of FGFR3-related chondrodysplasia, a partial or complete normalization of the dwarfism phenotype was observed.

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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 m

6 ADVERSE REACTIONS 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 patient