SCD medical experts discuss Oxbryta and appropriate patient cases

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

INDICATIONS AND USAGE

Oxbryta is indicated for the treatment of sickle cell disease (SCD) in adults and pediatric patients 4 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).

CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia.

Hello, I’m Dr. Nirmish Shah. I’m a medicine and pediatric trained hematologist and I care for approximately 350 patients with sickle cell disease.

I’m here to talk about Oxbryta’s mechanism of action. First, let’s examine the pathophysiology of sickle cell disease.

Hemoglobin S polymerization is the root cause of sickle cell disease, as well as the first step in the disease pathway.

Hemoglobin S polymerization leads to sickling of the red blood cells…

…which then leads to hemolysis and anemia. And hemolysis is important because…

…it triggers the activation of neutrophils as well as platelets, and leads to a decrease in nitric oxide, which then subsequently results in impaired vasodilation.

All of this hemolysis, anemia, and vaso-occlusion leads to endothelial cell damage and tissue ischemia.

As the prior slide depicted, multiple pathophysiologic processes are involved with sickle cell disease, and there are treatment options that target some of the different processes.

This figure depicts various treatments for sickle cell disease. Hematopoietic stem cell transplant, Oxbryta, and hydroxyurea are similar in that they target hemoglobin S mutation or polymerization, as opposed to the other treatment options that are targeting downstream consequences of hemoglobin S polymerization.

Oxbryta has been specifically designed to intervene in the sickle cell disease cascade, attacking its root cause by inhibiting hemoglobin S polymerization. Let’s elaborate.

If you were to look at a blood smear of a patient with sickle cell disease, you would see sickled red blood cells and cells that have undergone hemolysis.

Now if you were to further zoom in on that red blood cell, you’d get a better idea of what’s really happening. Because hemoglobin S molecules have a mutation compared with wild-type hemoglobin…

…in that once they release oxygen…

…that mutation promotes the binding of hemoglobin molecules to one another, starting the polymerization process that forms long rigid rods, which then deform the red blood cell into the characteristic sickled shape.

Now, where does Oxbryta come in? Oxbryta binds to about 20% to 30% of those hemoglobin S molecules…

…which increases the oxygen-binding affinity, allowing the hemoglobin molecules to retain oxygen…

…which then inhibits hemoglobin S polymerization.

Preclinical studies suggest that Oxbryta may inhibit red blood cell sickling, improve deformability, and reduce whole blood viscosity.

Oxbryta allows for oxygen extraction by the tissues under low oxygen conditions.

And at the same time the red blood cell is migrating to the downstream tissues, releasing oxygen if and when it’s needed, and Oxbryta’s also helping to improve anemia and reduce hemolysis.

As you can see here in this “with and without Oxbryta” rendering of a blood smear, there is a difference in the number of hemolyzed cells, the number of sickled red blood cells, and the overall healthy appearance of the red blood cells.

Oxbryta improves the anemia as measured by the hemoglobin level as well as hemolysis as measured by reticulocyte and indirect bilirubin counts compared to red blood cells without Oxbryta.

And now that you’ve seen this illustrated, let’s take a look at the actual blood smears that came out of the double-blind, placebo-controlled phase 1/2 study of voxelotor, which used 2 independent, blinded readers to analyze the percentage of sickled red blood cells.

Oxbryta’s ability to improve red blood cell morphology is evident in these blood smears, where a difference is observed between patients who received Oxbryta and those who received placebo. This is demonstrated in this patient’s blood smears, where sickled red blood cells are present at baseline and persist at day 90.

However, when we examine the blood smears of patients who received Oxbryta therapy, we see a reduction in the presence of sickled red blood cells from baseline compared to day 90.

Oxbryta reduced the number of sickled red blood cells at day 90 in a phase 1/2 study and those who received Oxbryta achieved a greater than 70% reduction from baseline in the proportion of sickled red blood cells versus placebo.

So with that, I want to thank you very much for listening to this presentation.

I hope this provides a thorough review of the mechanism of action of Oxbryta. 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 (SCD) in adults and pediatric patients 4 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).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia.

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 Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC). If precise quantitation of Hb species is required, chromatography should be performed when the patient has not received Oxbryta therapy in the immediately preceding 10 days

ADVERSE REACTIONS

Clinical Trials Experience

Adults and Pediatric Patients 12 Years of Age and Older

Serious adverse reactions occurred in 3% (3/88) of patients receiving Oxbryta 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each. Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5% (4/88) of patients who received Oxbryta 1,500 mg.

The most common adverse reactions (≥10%) in patients receiving Oxbryta 1,500 mg with a difference of >3% compared to placebo: Headache (32% vs. 25%), Diarrhea (23% vs. 11%), Abdominal Pain (23% vs. 16%), Nausea (19% vs. 10%), Rash (15% vs. 11%), and Pyrexia (15% vs. 8%).

Pediatric Patients 4 to <12 Years

The safety of Oxbryta in pediatric patients 4 to <12 years with SCD was evaluated in an open‑label, Phase 2 study. In this study, 45 patients 4 to <12 years of age received doses of Oxbryta tablets for oral suspension based on weight at baseline. Thirty‑five patients received Oxbryta for 24 weeks and 26 patients for 48 weeks. The most common adverse reactions (>10%) reported in pediatric patients 4 to <12 years were pyrexia (36%), vomiting (33%), rash (20%), abdominal pain (18%), diarrhea (18%), and headache (18%).

The overall safety profile of Oxbryta in pediatric patients 4 to <12 years was similar to that seen in adults and pediatric patients 12 years and older.

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inducers

Coadministration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma and whole blood concentrations and may lead to reduced efficacy. Avoid coadministration of Oxbryta with strong or moderate CYP3A4 inducers. Increase the Oxbryta dosage when coadministration with a strong or moderate CYP3A4 inducer is unavoidable.

Sensitive CYP3A4 Substrates

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

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. For severe hepatic impairment (Child Pugh C) reduce dose to 1,000 mg orally once daily for adults and pediatric patients ≥12 years. Dose reduction for pediatric patients 4 to <12 years is dependent on body weight (please refer to Table 2 in the Full Prescribing Information).

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

Additional Videos
Show All Videos

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 and HOPE-KIDS 1 Trials

Dr. Santosh Saraf explores the Phase 3 HOPE trial, including the trial’s design, study endpoints, and baseline demographics, as well as the study design from the Phase 2a HOPE-KIDS 1 trial. Go to Video >>

Efficacy & Safety of Oxbryta in the HOPE and HOPE-KIDS 1 Trials

Dr. Santosh Saraf describes the safety and efficacy results from the pivotal Phase 3 HOPE trial and the Phase 2a HOPE-KIDS 1 trial. 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 and Phase 2a HOPE-KIDS 1 trials, 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. Nirmish Shah 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 >>

Max, Age 6, Male with SCD Genotype HbSS

Dr. Nirmish Shah discusses Max who has an Hb level of 7.1 g/dL and has an acute chest syndrome (ACS) episode approximately once a year. Go to Video >>

Tiana, Age 8, Female with SCD Genotype HbSS

Dr. Alan Anderson discusses Tiana who has an Hb level of 7.9 g/dL and has had 2 VOCs in the past year. Go to Video >>

Get the latest information about Oxbryta delivered to your inbox