VOXZOGO 0.4mg vosoritide Kit — NDC 68135-082-36 (Billing 68135-0082-36)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics NPR-B Binding Activity Biomarker and Bone Metabolism Biomarker An increase in urinary cyclic guanosine monophosphate (cGMP) concentrations from pre-dose baseline were observed within the first four hours post-dose, with a maximum level at 2 hours post-dose, after VOXZOGO administration to pediatric patients with achondroplasia. Daily administration of VOXZOGO also led to the increase from baseline in serum collagen type X marker (CXM), an endochondral ossification biomarker and remains elevated beyond 24 months.

In subjects aged 5 - 14 years old at screening, exposure-response analyses showed that vosoritide activity measured by urinary cGMP was near saturation at the dose of 15 mcg/kg once daily, while maximal increase in growth plate activity indicated by CXM was achieved at this dose. Cardiac Electrophysiology At the maximum approved recommended dose, VOXZOGO does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics The area under the concentration-time curve (AUC) and peak concentration (C max ) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg. The pharmacokinetics of vosoritide were evaluated in 58 subjects aged 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg once daily for 52 weeks. The mean (± SD) C max and area under the concentration-time curve from time zero to the last measurable concentration (AUC 0-t ) observed across 52 weeks of treatment ranged from 4.71 (± 2.32) to 7.18 (± 9.65) ng/mL, and 161 (± 98.1) to 290 (± 235) ng-min/mL, respectively.

No drug accumulation was observed following 15 mcg/kg once daily dosing. The exposure of vosoritide increased with the duration of treatment. The mean AUC 0-t at week 52 increased approximately 20% compared to that at day 1.

Absorption Absolute bioavailability for vosoritide following subcutaneous injection was not determined. Vosoritide was absorbed with a median T max of 15 minutes after dosing. Distribution The mean (± SD) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) mL/kg.

Elimination The mean (± SD) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) mL/min/kg. The mean (± SD) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes. Metabolism The metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids.

Specific Populations No clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.4 to 15 years), sex or race. The effect of hepatic or renal impairment on the pharmacokinetics… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics The area under the concentration-time curve (AUC) and peak concentration (C max ) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg. The pharmacokinetics of vosoritide were evaluated in 58 subjects aged 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg once daily for 52 weeks. The mean (± SD) C max and area under the concentration-time curve from time zero to the last measurable concentration (AUC 0-t ) observed across 52 weeks of treatment ranged from 4.71 (± 2.32) to 7.18 (± 9.65) ng/mL, and 161 (± 98.1) to 290 (± 235) ng-min/mL, respectively.

No drug accumulation was observed following 15 mcg/kg once daily dosing. The exposure of vosoritide increased with the duration of treatment. The mean AUC 0-t at week 52 increased approximately 20% compared to that at day 1.

Absorption Absolute bioavailability for vosoritide following subcutaneous injection was not determined. Vosoritide was absorbed with a median T max of 15 minutes after dosing. Distribution The mean (± SD) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) mL/kg.

Elimination The mean (± SD) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) mL/min/kg. The mean (± SD) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes. Metabolism The metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids.

Specific Populations No clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.4 to 15 years), sex or race. The effect of hepatic or renal impairment on the pharmacokinetics of vosoritide is unknown. Body weight Population pharmacokinetic analyses indicated that body weight is a significant covariate for vosoritide clearance and volume of distribution.

The apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (5 to 74.5 kg). Drug Interaction Studies In vitro assessment of drug-drug interactions In vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Based on in vitro studies, vosoritide is considered unlikely to inhibit the human drug uptake or efflux transporters such as OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP at clinically relevant concentrations and therefore, no effect of vosoritide is anticipated on concomitantly administered drugs that are substrates of these transporters.

In vivo assessment of drug-drug interactions No clinical studies evaluating the drug-drug interaction potential of vosoritide have been conducted.

12.2Pharmacodynamics NPR-B Binding Activity Biomarker and Bone Metabolism Biomarker An increase in urinary cyclic guanosine monophosphate (cGMP) concentrations from pre-dose baseline were observed within the first four hours post-dose, with a maximum level at 2 hours post-dose, after VOXZOGO administration to pediatric patients with achondroplasia. Daily administration of VOXZOGO also led to the increase from baseline in serum collagen type X marker (CXM), an endochondral ossification biomarker and remains elevated beyond 24 months.

In subjects aged 5 - 14 years old at screening, exposure-response analyses showed that vosoritide activity measured by urinary cGMP was near saturation at the dose of 15 mcg/kg once daily, while maximal increase in growth plate activity indicated by CXM was achieved at this dose. Cardiac Electrophysiology At the maximum approved recommended dose, VOXZOGO does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Pediatric Patients 5 Years of Age and Older The safety and effectiveness of VOXZOGO in patients with achondroplasia were assessed in one 52-week, multi-center, randomized, double-blind, placebo-controlled, phase 3 study - Study 1 (NCT03197766). Study 1 was conducted in 121 subjects with genetically-confirmed achondroplasia, who were randomized to either VOXZOGO (N=60) or placebo (N=61). The dosage of VOXZOGO was 15 mcg/kg administered subcutaneously once daily.

Baseline standing height, weight Z-score, body mass index (BMI) Z-score, and upper to lower body ratio were collected for at least 6 months prior to randomization. Subjects with limb-lengthening surgery in the prior 18 months or who planned to have limb-lengthening surgery during the study period were excluded. The study included a 52-week placebo-controlled treatment phase followed by an open-label treatment extension study period in which all subjects received VOXZOGO.

The primary efficacy endpoint was the change from baseline in annualized growth velocity (AGV) at Week 52 compared with placebo. 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 subjects had a mean baseline height standard deviation score (SDS) of -5.13. Treatment with VOXZOGO for 52 weeks resulted in a treatment difference in the change from baseline in AGV of 1.57 cm/year after 52 weeks of treatment (Table 5).

Table 5: Annualized Growth Velocity (cm/year) at Week 52 in Subjects 5 Years of Age and Older with Achondroplasia - Study 1 Placebo (N=61 All randomized subjects. Two patients in the VOXZOGO group discontinued from the study before Week 52. The values for these 2 patients were imputed assuming baseline growth rate for the period with missing data. ) VOXZOGO 15 mcg/kg Daily (N=60 ) Abbreviations: AGV, annualized growth velocity; 95% CI, 95% confidence interval; LS, least-square; SD, standard deviation Baseline mean (SD) Baseline AGV was based on standing height at least 6 months prior to enrollment into the study.

4.06(1.20) 4.26 (1.53) Change from baseline LS means were estimated from the ANCOVA (analysis of covariance) model, which included treatment, stratum defined by sex and Tanner stage, baseline age, baseline AGV and baseline height Z-score. -0.17

1.40Difference in change of VOXZOGO – Placebo (95% CI) 1.57 (1.22, 1.93) 2-sided p-value <0.0001 for superiority. The improvement in AGV in favor of VOXZOGO was consistent across all predefined subgroups analyzed including sex, age group, Tanner stage, baseline height Z-score, and baseline AGV. Height Standard Deviation Score (SDS) The LS mean change from baseline to Week 52 in height SDS was -0.02 in the placebo group and 0.26 in the VOXZOGO group.

The difference in LS mean change from baseline was 0.28 (95% CI 0.17, 0.39; p<0.0001) in favor of VOXZOGO. The LS mean change from baseline to Week 52 in upper to lower body segment ratio was -0.02 in the placebo group and -0.03 in the VOXZOGO group. The difference in LS mean change from baseline was -0.01 (95% CI -0.05, 0.02; p=0.5).

Open-label extension After the 52 week double blind, placebo-controlled, phase 3 study, Study 1, 58 subjects initially randomized to VOXZOGO enrolled into an open-label extension. Among the subjects who had 2 years of follow-up since randomization, the improvement in AGV was maintained.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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.