FDA Approves OXBRYTA (Voxelotor) for the Treatment of Sickle Cell Disease in Adults and Pediatric Patients 12 Years of Age and Older

FDA Approves OXBRYTA (Voxelotor) for the Treatment of Sickle Cell Disease in Adults and Pediatric Patients 12 Years of Age and Older

On November 25, 2019, the U.S. Food and Drug Administration (FDA) approved OXBRYTA (voxelotor) for the treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). The approved recommended dosage of OXBRYTA is 1,500 mg taken orally once daily with or without food. OXBRYTA may be given with or without hydroxyurea.

OXBRYTA is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Additional information regarding dosage and administration, laboratory test interference, and important warnings and precautions about hypersensitivity reactions can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Voxelotor is a hemoglobin S (HbS) polymerization inhibitor.
• General PK: Voxelotor exposures increased proportionally with either single or multiple doses 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. The geometric mean (%CV) AUC_0-24h and C_max of voxelotor in plasma were 246 (27.7) μg·hr/mL and 12.6 (24.8) µg/mL, respectively. The geometric mean (%CV) AUC_0-24h and C_max of voxelotor in whole blood were 3820 (35) μg·hr/mL and 179 (33.1) µg/mL, respectively.
• 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.
• 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. Voxelotor is distributed predominantly into RBCs due to its preferential binding to Hb; 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: Voxelotor is 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).
• PD: 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).

Drug Interactions

• Strong CYP3A4 Inhibitors or Fluconazole: Avoid co-administration of OXBRYTA with strong CYP3A4 inhibitors or fluconazole and replace these drugs with alternative drugs when possible. If co-administration is unavoidable, decrease the OXBRYTA dosage to 1,000 mg once daily. Co-administration of strong CYP3A4 inhibitors or fluconazole may increase voxelotor plasma concentrations and may lead to increased toxicity.
• Strong or Moderate CYP3A4 Inducers: Avoid co-administration of OXBRYTA with strong or moderate CYP3A4 inducers. If co-administration is unavoidable, increase the OXBRYTA dosage to 2,500 mg once daily. Co-administration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma concentrations and may lead to reduced efficacy.
• Sensitive CYP3A4 Substrate: Avoid co-administration of OXBRYTA with sensitive CYP3A4 substrates with a narrow therapeutic index. If co-administration is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s). Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate).
• Laboratory Test Interference: If precise quantitation of Hb species is required, chromatography should be performed when the patient is not receiving OXBRYTA therapy. OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography.

Use in 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 15-89 mL/min). OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis.

• Pediatric Patients: The pharmacokinetic parameters of voxelotor were similar in pediatric patients 12 to < 17 years and adults.
• Patients with Hepatic Impairment: The recommended dosage of OXBRYTA in patients with severe hepatic impairment (Child Pugh C) is 1,000 mg taken once daily with or without food. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment (Child Pugh A or B). 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.
• Lactation: Advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose.

Efficacy and Safety

Efficacy of OXBRYTA was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in patients with SCD. Efficacy was based on Hb response rate defined as a Hb increase of > 1 g/dL from baseline to Week 24. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence > 10%) are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia.

Full prescribing information is available at  https://go.usa.gov/xpVDK.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.