SCD medical experts discuss Oxbryta and appropriate patient cases

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.

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

Welcome to this video, where we’ll discuss a hypothetical patient case, Maria.

Maria is a 30-year-old Hispanic female with sickle cell disease genotype SS. She is quite busy with her two children and full-time work at a bank.

Maria has reported that over the past 2 months, she has been experiencing an increasing amount of shortness of breath. The workup included having an echocardiogram, which did show that she had an elevated TRV, or tricuspid regurgitant jet velocity, of over 3 meters per second. They followed up appropriately with a right heart catheterization and confirmed the diagnosis of pulmonary hypertension. In addition to that, Maria has had two blood transfusions and three vaso-occlusive crises in the past year.

She is on maximum tolerated dose of hydroxyurea. And she’s been on a dose that’s been titrated and is taking this as directed. In addition to her hydroxyurea, Maria’s also taking folic acid.

Now, Maria’s labs show that her hemoglobin is 7.0 grams per deciliter. Her electrophoresis shows that her hemoglobin F is at 15%, a very good response to hydroxyurea, with a mean corpuscular volume of 110 fluid ounces. Her white blood cell count shows that she’s just a little bit myelosuppressed with hydroxyurea, which is, again, a good response, and an indication that we’re pushing her to be at the maximum tolerated dose of hydroxyurea. Her white blood cell count is at 6,000. Her absolute neutrophil count is 2,500.

But her reticulocyte count is still at 12%. And her absolute reticulocyte count is at 371,000. Her total bilirubin and indirect bilirubin are also still elevated, at 8 and 7.5 milligrams per deciliter, respectively. So Maria still has a fair amount of hemolysis despite being on maximum tolerated dose treatment with hydroxyurea.

So, would Maria be a candidate for Oxbryta?

Yes, I think Maria may benefit from taking Oxbryta for three main reasons.

First, her sickle cell genotype is SS, which was one of the eligible genotypes in the HOPE study.

Second, I also think that she may be a good candidate for Oxbryta because her hemoglobin is 7.0 grams per deciliter while on a maximum tolerated dose of hydroxyurea. This showed that Maria needs additional interventions to increase her hemoglobin.

In the HOPE study, eligible patients, similar to Maria, who were on a stable dose of hydroxyurea for at least 90 days were allowed to stay on hydroxyurea throughout the study. And the results showed that Oxbryta provided an additional benefit on top of hydroxyurea.

And, finally, based on her elevated reticulocyte count and indirect bilirubin, we know she is experiencing a fair amount of hemolysis.

In the Phase 3 HOPE study, Oxbryta significantly reduced hemolysis as demonstrated by a decrease in indirect bilirubin and percent reticulocyte count.

Considering these three reasons, I think it would be appropriate to have a discussion with Maria about the convenient, once-daily oral dosing, efficacy, and safety of Oxbryta.

Now that we have talked about Maria, we can shift to discussing clinical safety of Oxbryta.

Here, we have the safety data from the Phase 3 HOPE and Phase 2a HOPE-KIDS 1 trials…..

The safety profile observed in pediatric patients 12 to <17 years of age treated with Oxbryta was similar to that seen in adult patients.

The overall safety profile for Oxbryta tablets for oral suspension in pediatric patients 4 to <12 years was similar to that seen in adult and pediatric patients (≥12 years) of age.

Since our hypothetical patient case is Maria and she's an adult, let’s focus on the adverse events from the adult and pediatric patients 12 years of age and older.

This table illustrates the adverse reactions that were seen in at least 10% of adult and pediatric patients 12 years of age and older, and with a difference of more than 3% in the Oxbryta vs placebo arms through Week 72 in the Phase 3 HOPE Trial.

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

Serious adverse reactions that occurred in 3% of patients receiving 1,500 milligrams of Oxbryta included headache, drug hypersensitivity, and pulmonary embolism, occurring in one patient each.

Seventy-four patients received 1,500 milligrams of Oxbryta once daily for ≥24 weeks, 65 patients for ≥48 weeks, and 63 patients completed the 72-week treatment period.

I hope this review of Maria’s case helps you identify patients that may be appropriate for Oxbryta therapy in your patient population. Please see important safety information at the end of this video.

INDICATION AND IMPORTANT SAFETY INFORMATION

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.

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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
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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

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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

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