SCD medical experts discuss Oxbryta and appropriate patient cases

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.

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. Alan Anderson and I’m the medical director of a comprehensive lifespan sickle cell disease program and a practicing pediatric hematologist.

Welcome to this video, where we will discuss the efficacy and safety results from the HOPE trial.

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.

This graph illustrates the change in hemoglobin from Baseline at Week 24 for the patients who completed 24 weeks of therapy. As you can see, Oxbryta significantly increased hemoglobin levels in patients in the Phase 3 HOPE trial.

In fact, with regard to the primary endpoint, 51% of patients who received the 1,500 mg dose of Oxbryta achieved a greater than 1 g/dL increase in hemoglobin, compared with 7% of patients who received placebo.

Oxbryta demonstrated an observed hemoglobin response versus placebo regardless of age, hydroxyurea use, or geographic region.

42% of patients who received Oxbryta achieved a greater than 1.5 g/dL increase in hemoglobin, compared with 3% in the placebo group.

Additionally, 27% of patients who received Oxbryta therapy achieved a greater than 2 g/dL increase in hemoglobin compared with 1% in the placebo group.

The hemoglobin response with Oxbryta in the HOPE trial was rapid and sustained. Significant increases in the hemoglobin were observed within 2 weeks of treatment initiation and were sustained over 72 weeks.

Compared with Baseline, Oxbryta use resulted in a 1.1 g/dL mean increase in hemoglobin at Week 24, and a 1.0 g/dL increase at Week 72.

Oxbryta benefited patients regardless of baseline hydroxyurea use. In patients on background hydroxyurea therapy, Oxbryta conferred an incremental mean increase in hemoglobin of 1.1 g/dL at Week 24, and 0.9 g/dL at Week 72.

For those who were not on background hydroxyurea therapy, Oxbryta conferred a mean increase in hemoglobin of 1.1 g/dL at Week 24 and Week 72.

Oxbryta reduced hemolysis in the Phase 3 HOPE trial, as measured by indirect bilirubin and percent reticulocyte count. Patients who received Oxbryta 1,500 mg achieved a greater than 26% reduction in indirect bilirubin at both Weeks 24 and 72.

Patients who received Oxbryta 1,500 mg achieved a 24.8% reduction in the percent reticulocyte count at Week 24, and an 18.6% reduction at Week 72.

In preclinical studies with SS sickle blood, Oxbryta increased red blood cell deformability and reduced whole blood viscosity.

The graph on the left shows the amount of pressure needed to pass red blood cells through a polycarbonate filter at different flow rates under deoxygenated conditions. Unaffected AA red blood cells treated with vehicle are depicted in gray, SS red blood cells treated with vehicle are depicted in blue, and SS red blood cells treated with Oxbryta are depicted in red. Treatment with Oxbryta significantly reduced the amount of pressure needed to pass the red blood cells through the filter, indicating increased deformability.

The graph on the right shows blood viscosity for oxygenated and deoxygenated AA and SS red blood cells, as well as deoxygenated SS red blood cells incubated with Oxbryta.

Treatment with Oxbryta significantly decreased the viscosity of deoxygenated red blood cells so that it was similar to oxygenated red blood cells.

This table illustrates the adverse reactions that were observed in at least 10% of patients and with a difference of more than 3% in the Oxbryta vs placebo arms at Week 24 or Week 72.

These reactions included headache, diarrhea, abdominal pain, nausea, arthralgia, fatigue, rash, pyrexia, and back pain.

Serious adverse reactions that occurred in 3% of patients receiving 1,500 mg of Oxbryta included headache, drug hypersensitivity, and pulmonary embolism, occurring in one patient each at 24 weeks. No new events occurred after 24 weeks.

The safety profile observed in pediatric patients between the ages of 12 and 17 was similar to adult patients enrolled in the phase 3 trial through Weeks 24 and 72.

Clinically relevant adverse reactions occurring in <10% of patients through Week 24 included drug hypersensitivity. No new events occurred after 24 weeks.

Dose modifications may be warranted to manage adverse events.

41% of patients at Week 24 and 48% at Week 72 who received Oxbryta required a dose modification, as either a dose reduction or interruption.

The most frequent adverse reactions requiring dosage interruption occurring in more than 1 patient who received Oxbryta 1,500 mg included diarrhea, headache, rash, and vomiting.

In the HOPE trial, patients needing a temporary modification based on physician discretion or adverse reaction severity could be lowered to 1,200 mg/day, which was a reduction of 1 pill in the HOPE trial based on the clinical formulation at that time, until the event subsided and patients could return to the 1,500 mg/day.

During the first 24 weeks, 5% of patients permanently discontinued therapy due a to a treatment-related adverse reaction, with no additional discontinuations through Week 72.

There were no discontinuations due to diarrhea, headache, rash, fatigue, arthralgia, or pyrexia.

Most diarrhea events were reported were mild and self- limiting. The median time to onset was 15 days, and median time from onset to resolution was 30 days.

Patients experiencing Grade 1 or 2 rash were allowed oral antihistamines and/or topical steroids.

The laboratory measures of erythropoietin levels are indirect measures of tissue oxygenation preservation. And although no formal statistical testing was conducted, thus limiting the interpretation of these data, the finding that erythropoietin levels did not increase with Oxbryta treatment may suggest that there is no impairment of tissue oxygenation for Oxbryta.

However, additional clinical studies need to be conducted to confirm that Oxbryta preserves tissue oxygenation.

I hope this presentation provides a useful overview and may help you understand and discuss Oxbryta as a treatment option with your patients with sickle cell disease.

Please see important safety information at the end of this 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

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

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.

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 for more information.

Additional Videos
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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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