SCD medical experts discuss Oxbryta and appropriate patient cases

Understanding the HOPE Trial

Dr. Santosh L. Saraf explores the Phase 3 HOPE trial, including the trial’s design, study endpoints, and baseline demographics.

INDICATIONS AND USAGE

Oxbryta is indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients.

Hello. My name is Dr. Santosh Saraf. I’m an adult hematologist that cares for people with sickle cell disease. We’ll be discussing the HOPE clinical trial design and baseline patient characteristics.

The phase 3 HOPE trial was a multicenter, randomized, double-blind, placebo-controlled trial with 274 enrolled patients.

The key inclusion criteria were patients aged 12 to 65 with confirmed sickle cell disease, baseline hemoglobin between 5.5 and 10.5, and 1 to 10 VOCs in the 12 months prior to enrollment. Patients were allowed to continue hydroxyurea therapy if they had been on stable doses for at least 90 days prior to enrollment.

Among excluded individuals were those who had received red blood cell transfusions within 60 days prior to enrollment, or those who received erythropoietin within 28 days prior to enrollment. Individuals with renal insufficiency or uncontrolled liver disease were also excluded, as were those who were pregnant or lactating.

Patients were randomized in a 1:1:1 manner to receive either the 1,500 mg approved dose of Oxbryta, 900 mg Oxbryta, or placebo.

Randomization was stratified by hydroxyurea use, age, and geographic region. Patients were enrolled in the trial after a 28 to 35 day screening period, and then received 72 weeks of treatment.

The primary endpoint and key secondary endpoints occurred at 24 weeks, which we will discuss in greater detail on the next slide.

The primary endpoint in the HOPE trial was the percentage of patients who achieved a greater than 1 g/dL increase in hemoglobin from Baseline to Week 24.

Key secondary endpoints included changes from Baseline at Week 24 in hemoglobin levels, and changes in laboratory markers of hemolysis, specifically indirect bilirubin and percentage of reticulocytes.

Baseline demographics were balanced between the Oxbryta 1,500 mg arm and placebo with respect to age, sex, hemoglobin concentration, frequency of vasoocclusive crises, hydroxyurea use, and geographic region.

Patients in this trial ranged from 12 to 64 years of age. The range for baseline hemoglobin concentration was between 5.9 and 10.8 g/dL.

Additional baseline demographics that were balanced between the Oxbryta 1,500 mg arm and placebo included race or ethnicity, and hemoglobin genotype. Among hemoglobin genotypes observed in the study were SS, SC, S/beta-0 thalassemia, S/beta+ thalassemia, and others.

I hope this provides a useful overview of the HOPE study design and baseline characteristics to provide context for the clinical trial results. Please see important safety information at the end of the video.

Important Safety Information and Indication

INDICATIONS AND USAGE

Oxbryta is indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older.

This indication is approved under accelerated approval based on increase in hemoglobin.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Serious hypersensitivity reactions after administration of Oxbryta have occurred in <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia.

If hypersensitivity reactions occur, discontinue Oxbryta and administer appropriate medical therapy. Do not reinitiate Oxbryta in patients who experience these symptoms with previous use.

Laboratory Test Interference

Oxbryta administration may interfere with measurement of hemoglobin subtypes A, S, and F by HPLC. If precise quantitation of hemoglobin species is required, chromatography should be performed when the patient is not receiving Oxbryta therapy.

ADVERSE REACTIONS

Clinical Trials Experience

Serious adverse reactions occurred in 3% (3 out of 88) of patients receiving Oxbryta 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each.

Adverse Reactions (≥10%) in patients receiving Oxbryta with a difference of >3% compared to placebo: Headache (26% vs. 22%), Diarrhea (20% vs. 10%), Abdominal Pain (19% vs. 13%), Nausea (17% vs. 10%), Fatigue (14% vs. 10%), Rash (14% vs. 10%), and Pyrexia (12% vs.7%).

DRUG INTERACTIONS

Sensitive CYP3A4 Substrates

Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate). Avoid co-administration with sensitive CYP3A4 substrates with a narrow therapeutic index. If unavoidable, consider dose reduction of the CYP3A4 substrates.

Strong CYP3A4 Inhibitors or Fluconazole

Co-administration of strong CYP3A4 inhibitors or fluconazole may increase voxelotor plasma concentrations and may lead to increased toxicity. Avoid co-administration of strong CYP3A4 inhibitors or fluconazole. Decrease Oxbryta dosage if unavoidable.

Strong or Moderate CYP3A4 Inducers Co-administration of strong or moderate

CYP3A4 inducers may decrease voxelotor plasma concentrations and may lead to reduced efficacy. Avoid co-administration of strong or moderate CYP3A4 inducers. Increase the Oxbryta dosage if unavoidable. [1.

USE IN SPECIFIC POPULATIONS

Lactation

Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients not to breastfeed while taking Oxbryta and for at least 2 weeks after the last dose.

Recommended Dosage for Hepatic Impairment Severe hepatic impairment increases voxelotor exposures. Reduce dose to 1,000 mg orally once daily for severe hepatic (Child Pugh C) impairment.

Please see Full Prescribing Information for Oxbryta by clicking below for more information.

Additional Videos
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Other Videos:

How Oxbryta Works

Listen to Dr. Nirmish Shah discuss the mechanism of action of Oxbryta, how it was designed to target HbS polymerization, and its proposed effect on red blood cell morphology.

For more information about the Oxbryta MOA, watch an additional video How oxbryta intervenes
Go to Video >>

Understanding the HOPE Trial

Dr. Santosh L. Saraf explores the Phase 3 HOPE trial, including the trial’s design, study endpoints, and baseline demographics. Go to Video >>

Efficacy & Safety of Oxbryta in the HOPE Trial

Dr. Alan Anderson describes the safety and efficacy results from the pivotal Phase 3 HOPE trial, including the impact of Oxbryta on anemia and hemolysis at 72 weeks. Go to Video >>

Dosing and Management of Your Patient on Oxbryta Therapy

Dr. Santosh L. Saraf reviews the convenient, once-daily oral dosing of Oxbryta, dose adjustment protocols utilized during the Phase 3 HOPE trial, and topics to discuss with patients when initiating Oxbryta therapy. Go to Video >>

Managing Side Effects During Oxbryta Treatment

While not necessary for all patients, dose modifications may be appropriate to help manage adverse reactions in some cases. Watch Dr. Alan Anderson describe the dose adjustment protocols utilized during the Phase 3 HOPE trial. Go to Video >>

Maria, Age 30, Female With SCD Genotype HbSS

Dr. Nirmish Shah discusses Maria who has an Hb level of 7.0 g/dL, has had 3 VOCs in the past year, and complains of increasing shortness of breath. Go to Video >>

Henry, Age 50, Male With SCD Genotype HbSβ0-thalassemia

Dr. Santosh L. Saraf discusses Henry who has an Hb level of 6.5 g/dL and has had 3 VOCs and 2 episodes of acute chest syndrome in the past year. Go to Video >>

Jamie, Age 12, Female With SCD Genotype HbSS

Dr. Alan Anderson discusses Jamie who has an Hb level of 7.5 g/dL and has had 1 VOC in the past year. Go to Video >>

Gabriel, Age 14, Male With SCD Genotype HbSS

Dr. Alan Anderson discusses Gabriel who has an Hb level of 6.0 g/dL, has had 3 VOCs in the past year, has established microalbuminuria, and complains of yellowing eyes. Go to Video >>

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