CLINICAL PHARMACOLOGY
Mechanism 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.
Pharmacodynamics
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.
Pharmacokinetics
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
PK Parameter |
Voxelotor 1,500 mg Geometric Mean (%CV) |
Plasma PK |
AUC0-24h (μg•hr/mL) |
246 (27.7) |
Cmax (μg/mL) |
12.6 (24.8) |
Half-life (hours) |
35.5 (25) |
Whole Blood PK |
AUC0-24h (μg•hr/mL) |
3820 (35) |
Cmax (μg/mL) |
179 (33.1) |
Absorption
The median plasma and whole blood Tmax 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 Cmax by 45% in whole blood relative to AUC and Cmax in the fasted state. Similarly, AUC increased by 42% and Cmax 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 Cmax 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 Cmax 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.
Clinical Studies
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/beta0-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*
 |
*Approximately 82% 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 4).
Table 4: 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 |
Hemoglobin |
1.14 g/dL (0.13) |
-0.08 g/dL (0.13) |
< 0.001 |
Indirect Bilirubin |
-29.08 % (3.48) |
-3.16 % (3.52) |
< 0.001 |
Percent Reticulocyte Count |
-19.93 % (4.60) |
4.54 % (4.60) |
< 0.001 |