SCD medical experts discuss Oxbryta and appropriate patient cases

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.

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, my name is Dr. Alan Anderson. And I’m a pediatric hematologist who cares for over 450 individuals with sickle cell disease.

Welcome to this video, where we will review the hypothetical patient, Tiana. Tiana is an 8-year-old, African American female with sickle cell disease genotype SS. She enjoys dancing, but sometimes struggles to get through an entire class. She is here for a follow-up appointment for her recent hospitalization for acute chest syndrome. Aside from that hospitalization, Tiana has also suffered from two vaso-occlusive crises in the past year, which were managed at home. Tiana has a prior history of conditional transcranial dopplers, and she complains of ongoing constipation and sickle cell-related pain. She also suffers from asthma.

Tiana is currently receiving her maximally tolerated dose of hydroxyurea. She is also receiving folic acid, salbutamol, cholecalciferol, and is taking hydrocodone on an as-needed basis.

Tiana is anemic with a hemoglobin level of 7.9 gram per deciliter, even though she is on the maximally tolerated dose of hydroxyurea. You can see that she’s had a response from hydroxyurea by looking at her hemoglobin F at 20% and her elevated mean corpuscular volume of 109. Her white blood cell count at 5,500 per microliter and absolute neutrophil count of 2,000 further show that we have her titrated to a good dose. Tiana’s reticulocytes are at 8% and indirect bilirubin is 3.8 milligrams per deciliter, indicating that she is experiencing a fair amount of hemolysis despite hydroxyurea use.

After considering this patient case, would Oxbryta be an appropriate option for Tiana?

Yes. I think Tiana may benefit from taking Oxbryta, which was studied in patients similar to Tiana in terms of age and SS genotype in the Phase 2a HOPE-KIDS 1 trial.

Tiana’s hemoglobin of 7.9 grams per deciliter, showing that she has a fair amount of anemia to contend with even though she is receiving hydroxyurea. I believe Oxbryta can improve Tiana’s hemoglobin of 7.9 gram per deciliter as demonstrated in the HOPE-KIDS 1 study, where Oxbryta improved hemoglobin levels in pediatric patients similar to Tiana. The average increase seen in the hemoglobin was 1.0 gram per deciliter.

Additionally, 36% of patients aged 4 to <12 years in the Phase 2a HOPE-KIDS 1 trial in the intent-to-treat population and who received Oxbryta tablets for oral suspension achieved a >1.0 gram per deciliter increase in Hb from baseline at 24 weeks with a 95% confidence interval between 21.6% to 49.5%, and 47% of patients in the per-protocol population receiving Oxbryta tablets for oral suspension achieved a >1 gram per deciliter increase in hemoglobin at week 24 compared with baseline.

Increases in hemoglobin were observed as early as 2 weeks after starting Oxbryta and were maintained over 24 weeks.

Additionally, Tiana’s elevated reticulocytes and indirect bilirubin indicate that she is experiencing hemolysis. Both indirect bilirubin and percent reticulocyte count were also reduced at week 24 in the HOPE-KIDS 1 study. Given Oxbryta’s demonstrated efficacy in improving anemia and hemolysis, I feel confident about discussing Oxbryta with Tiana and her caregivers.

I would like to take a moment and mention Tiana’s weight here – she weighs 22.7 kilograms which is approximately 50 pounds.

This is important to consider in the context of Oxbryta’s dosing, since there are weight-based dosing recommendations for patients 4 to less than 12 years of age.

Tiana’s weight would place her in the category of 20 kilograms to less than 40 kilograms per the dosing recommendations for Oxbryta which would require three 300-milligram Oxbryta tablets for oral suspension.

Let’s take a closer look at the administration of Oxbryta. In this instance, if you were preparing a dose for a patient like Tiana, you would use the 900 milligram dose, or three 300-milligram Oxbryta tablets for oral suspension, in the minimum recommended volume of 3 teaspoons, or 15 milliliters.

Immediately before administration, the tablets should be dispersed in room temperature clear liquid before swallowing. In this case, let’s assume that Tiana’s favorite drink of choice is lemon-lime soda. After the tablets start to disintegrate, swirl the contents of the cup until the tablets are dispersed, wait 1 to 5 minutes, swirl the contents of the cup again, and then orally administer the contents of the cup. The tablets will not completely dissolve; there will still be small tablet clumps in the mixture. Resuspend any residue left in the cup in lemon-lime soda and administer. Repeat until no tablet residue is left in the cup.

Do not swallow whole, cut, crush, or chew the tablets for oral suspension.

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

The safety profile observed in pediatric patients aged 12 to less than 17 years treated with Oxbryta was similar to that seen in adult patients. The overall safety profile of Oxbryta tablets for oral suspension in pediatric patients 4 to less than 12 years was similar to that seen in adults and pediatric patients 12 years and older.

The table on the left illustrates the adverse reactions that were seen in at least 10% of patients 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 mg of Oxbryta included headache, drug hypersensitivity, and pulmonary embolism, occurring in one patient each.

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

The table on the right illustrates the safety of Oxbryta tablets for oral suspension in pediatric patients aged 4 to less than 12 years with sickle cell disease as evaluated in the open-label, Phase 2a HOPE-KIDS 1 study.

The most common adverse reactions through week 48 included pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache.

There were no discontinuations due to vomiting, rash, abdominal pain, diarrhea, or headache.

I hope this review of Tiana’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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Understanding the HOPE and HOPE-KIDS 1 Trials

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