OXBRYTA Film-coated tablet Ref.[9906] Active ingredients: Voxelotor

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.

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 3) 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 3. Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood:

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 increased by 95% in plasma.

Distribution

Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 338 L and 72.2 L in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 15:1 in patients with SCD.

Elimination

The geometric mean (CV) terminal elimination half-life of voxelotor in patients with SCD is 35.5 hours (25) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.7 L/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. Oxidation of voxelotor is mediated primarily by CYP3A4, with minor contribution from CYP2C19, CYP2B6, and CYP2C9.

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 parameters of voxelotor were similar in pediatric patients 12 to <17 years and adults.

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 m²) 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=220) patients and voxelotor steady state plasma AUC and C_max were 23% and 15% higher in HbSC genotype patients compared to HbSS genotype patients.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Strong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with ketoconazole is predicted to increase voxelotor AUC in patients by 42% to 83%.

Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor: concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 77%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 60%.

Effect of Fluconazole on Voxelotor: concomitant use of OXBRYTA with fluconazole, a moderate CYP3A4 inhibitor, a moderate CYP2C9 inhibitor and a strong CYP2C19 inhibitor, is predicted to increase voxelotor AUC in patients by 40% to 116%.

Effect of Acid Reducing Agents on Voxelotor: co-administration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure.

Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2-fold.

Effect of Voxelotor on P-gp: concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to a clinically relevant extent.

In Vitro Studies

CYP Enzymes: voxelotor is a reversible and time-dependent inhibitor as well as an inducer of CYP2B6.

Transporter Systems: voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP.

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).

The efficacy and safety of OXBRYTA in sickle cell disease (SCD) was evaluated in HOPE, a 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 of age. 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.

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^*:

Additional efficacy evaluation included change in Hb and percent change in indirect bilirubin and percent reticulocyte count from baseline to Week 24 (Table 4).

Table 4. Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of Hemolysis: