OXBRYTA Voxelotor 500 mg Tablet, Film Coated, 90-count — NDC 72786-101-01 (Billing 72786-0101-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

12.2Pharmacodynamics The pharmacodynamic effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure. The pharmacodynamic effect of voxelotor treatment also demonstrated a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes). Cardiac Electrophysiology At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent.

12.3Pharmacokinetics Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs.

Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD. Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood Based on the 72-week population pharmacokinetic analysis. PK Parameter Voxelotor 1,500 mg Geometric Mean (%CV) Plasma PK AUC 0-24h (μg∙hr/mL) 278 (28.4) C max (µg/mL) 14 (24.5) Half-life (hours) 38.7 (30.2) Whole Blood PK AUC 0-24h (μg∙hr/mL) 3,830 (33.5) C max (µg/mL) 180 (31) In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole.

Absorption The median plasma and whole blood T max of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration. Effect of Food A high-fat, high-calorie meal increased voxelotor AUC by 42% and C max by 45% in whole blood relative to AUC and C max in the fasted state.

Similarly, AUC increased by 42% and C max increased by 95% in plasma. Distribution Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 L and

72.3L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD. Elimination The geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as

6.1L/h in plasma in patients with SCD. Metabolism In vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase I (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase I and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9.

Excretion Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min). Pediatric… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

12.3Pharmacokinetics Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs.

Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD. Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood Based on the 72-week population pharmacokinetic analysis. PK Parameter Voxelotor 1,500 mg Geometric Mean (%CV) Plasma PK AUC 0-24h (μg∙hr/mL) 278 (28.4) C max (µg/mL) 14 (24.5) Half-life (hours) 38.7 (30.2) Whole Blood PK AUC 0-24h (μg∙hr/mL) 3,830 (33.5) C max (µg/mL) 180 (31) In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole.

Absorption The median plasma and whole blood T max of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration. Effect of Food A high-fat, high-calorie meal increased voxelotor AUC by 42% and C max by 45% in whole blood relative to AUC and C max in the fasted state.

Similarly, AUC increased by 42% and C max increased by 95% in plasma. Distribution Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 L and

72.3L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD. Elimination The geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as

6.1L/h in plasma in patients with SCD. Metabolism In vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase I (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase I and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9.

Excretion Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min). Pediatric Patients The pharmacokinetic exposures of voxelotor in whole blood and plasma were similar between pediatric patients 4 to <17 years and adults following the recommended dosage [see Dosage and Administration (2) ] .

Patients with Renal Impairment There was no clinically significant effect of renal function on the excretion of voxelotor. Following a single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m 2 ) were 25% lower compared to healthy controls. The unbound plasma concentrations were comparable.

OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis. Patients with Hepatic Impairment The voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh A and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function. Patients with HbSC Genotype Voxelotor steady state whole blood AUC and C max were 50% and 45% higher in HbSC genotype patients (n=11) compared to HbSS genotype (n=… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The pharmacodynamic effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure. The pharmacodynamic effect of voxelotor treatment also demonstrated a dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and % reticulocytes). Cardiac Electrophysiology At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Adults and Pediatric Patients 12 Years and Older The efficacy and safety of OXBRYTA in SCD was evaluated in HOPE, a Phase 3 randomized, double-blind, placebo-controlled, multicenter trial [NCT 03036813]. In this study, 274 patients were randomized to daily oral administration of OXBRYTA 1,500 mg (N=90), OXBRYTA 900 mg (N=92), or placebo (N=92). Patients were included if they had from 1 to 10 vasoocclusive crisis (VOC) events within 12 months prior to enrollment and baseline hemoglobin (Hb) ≥5.5 to ≤10.5 g/dL.

Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. Randomization was stratified by patients already receiving hydroxyurea (yes, no), geographic region (North America, Europe, Other), and age (12 to <17 years, 18 to 65 years). The trial excluded patients who received red blood cell (RBC) transfusions within 60 days and erythropoietin within 28 days of enrollment, had renal insufficiency, uncontrolled liver disease, were pregnant, or lactating.

The majority of patients had HbSS or HbS/beta 0 -thalassemia genotype (90%) and were receiving background hydroxyurea therapy (65%). The median age was 24 years (range: 12 to 64 years); 46 (17%) patients were 12 to <17 years. Median baseline Hb was 8.5 g/dL (5.9 to 10.8 g/dL).

One hundred and fifteen (42%) had 1 VOC event and 159 (58%) had 2 to 10 events within 12 months prior to enrollment. In the OXBRYTA 1,500 mg group, 63 (70%) patients completed the study through Week 72. Efficacy was based on Hb response rate defined as a Hb increase of >1 g/dL from baseline to Week 24 in patients treated with OXBRYTA 1,500 mg versus placebo.

The response rate for OXBRYTA 1,500 mg was 51.1% (46/90) compared to 6.5% (6/92) in the placebo group (p < 0.001). No outlier subgroups were observed. The distribution of Hb change from baseline for individual patients completing 24 weeks of treatment with OXBRYTA 1,500 mg or placebo is depicted in Figure 1.

Figure 1: Subject-level Change from Baseline in Hemoglobin at Week 24 in Patients Who Completed 24 Weeks of Treatment Approximately 83% of all randomized patients completed 24 weeks of treatment. Additional efficacy evaluation included change in Hb and percent change in indirect bilirubin and percent reticulocyte count from baseline to Week 24 (Table 6). Table 6: Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of Hemolysis OXBRYTA 1,500 mg QD (N=90) Placebo (N=92) P Value QD = once daily; SE = standard error Hemoglobin 1.1 g/dL (0.1) -0.1 g/dL (0.1) < 0.001 Indirect Bilirubin -29.1% (3.5) -2.8% (3.5) < 0.001 Percent Reticulocyte Count -18.0% (4.7) 6.8% (4.7) < 0.001 Figure 1

14.2Pediatric Patients 4 to <12 Years The efficacy and safety of OXBRYTA in patients 4 to <12 years with SCD was evaluated in an open-label, multi-center, Phase 2 trial [NCT 02850406]. In this study, 45 patients 4 to <12 years and 11 patients 12 to <17 years received OXBRYTA. Patients 4 to <12 years received tablets for oral suspension based on body weight at baseline.

OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients were included if their baseline hemoglobin (Hb) was ≤10.5 g/dL.

Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. The trial excluded patients who had a VOC event within 14 days prior to enrollment, received red blood cell (RBC) transfusions within 30 days of enrollment, and had renal insufficiency or uncontrolled liver disease. All patients had HbSS or HbS/beta 0 -thalassemia genotype (100%) and most were receiving background hydroxyurea therapy (80%).

The median age was 8 years (range: 4 to 15 years); 45 (80%) patients were 4 to <12 years. In this age group, mea… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Voxelotor was not carcinogenic in a 26-week study in RasH2 transgenic mice at oral doses of 30, 150, or 500 mg/kg/day. Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay. In a fertility and early embryonic development study, voxelotor was administered orally to rats at 15, 50, and 250 mg/kg/day.

Males were dosed 28 days prior to mating through cohabitation and females were dosed 14 days prior to mating through gestation Day 7. Voxelotor had no effect on fertility or reproductive function. Sperm motility was decreased and changes in sperm morphology occurred at 250 mg/kg/day (approximately 5-times the human exposure at 1,500 mg/day).