SCD medical experts discuss Oxbryta and appropriate patient cases

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 am Dr. Nirmish Shah. I am a medicine and pediatric trained hematologist caring for approximately 350 patients with sickle cell disease.

Welcome to this video, where we will review a hypothetical patient, Max.

Max is a 6-year-old, African male with sickle cell disease genotype SS. He recently moved to the United States and has limited access to transportation, which makes it challenging to bring him in for frequent medical appointments.

Max presents complaining of scleral icterus and ongoing sickle cell-related pain. He experiences approximately one acute chest syndrome event per year. He also suffers from allergic rhinitis and vitamin D deficiency.

His doctor has discussed hydroxyurea for Max, but his family refuses it as a treatment option. He currently receives cetirizine, Singulair^®, hydrocodone, and cholecalciferol.

Max’s labs indicate that he has hemolytic anemia with a hemoglobin level of 7.1 grams per deciliter, reticulocyte count at 12%, and indirect bilirubin of 2.7 milligrams per deciliter.

Max weighs 17.5 kilograms which is approximately 38.5 pounds and is considered underweight. This is important to note since Oxbryta has weight-based dosing recommendations for patients aged 4 to 11 years of age.

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

Yes. I think Max may benefit from taking Oxbryta.

First of all, Max’s limited access to transportation precludes him from making frequent office visits. Oxbryta could be advantageous here since it does not require frequent laboratory monitoring.

I also think Max may benefit from taking Oxbryta since his hemoglobin is 7.1 grams per deciliter showing that he has a fair amount of anemia to contend with.

I believe Oxbryta can improve Max’s hemoglobin of 7.1 grams per deciliter as demonstrated in the Phase 2a HOPE-KIDS 1 study where Oxbryta improved hemoglobin levels in pediatric patients similar to Max. The average increase in hemoglobin levels 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 were receiving Oxbryta tablets for oral suspension achieved a >1.0 gram per deciliter increase in Hb from baseline at 24 weeks (95% CI: 21.6%-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 Hb at week 24 compared with baseline.

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

Now let’s come back to discussing Max’s case.

Max is experiencing significant hemolysis, as indicated by his elevated reticulocytes and indirect bilirubin levels as well as scleral icterus.

In the Phase 2a HOPE-KIDS 1 study, percent reticulocyte count and indirect bilirubin were reduced at week 24.

Given Oxbryta’s demonstrated efficacy in improving anemia and hemolysis, I feel confident in discussing Oxbryta with Max’s caregivers.

I would like to take a moment and mention Max’s weight here—he weighs 17.5 kilograms, which is approximately 38.5 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.

Max’s weight would place him in the category of 10 kilograms to less than 20 kilograms per the dosing recommendations for Oxbryta, which would require two 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 Max, you would use the 600 milligrams dose, or two 300-milligram Oxbryta tablets for oral suspension, in the minimum recommended volume of 2 teaspoons, or 10 milliliters.

Immediately before administration, the tablets should be dispersed in room temperature clear liquid before swallowing. In this case, let’s assume that Max’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 more lemon-lime soda and administer. Repeat until no tablet residue is left in the cup.

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

Now that we have talked about Max, we can shift our discussion to the clinical safety of Oxbryta.

The safety profile observed in pediatric patients aged 12 to less than 17 years of age 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 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 adults and pediatric patients 12 years of age and older, and a difference of more than 3% in the Oxbryta vs the 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 Oxbryta 1,500 milligrams once daily for ≥24 weeks, 65 patients for ≥48 weeks, and 63 patients actually 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 an 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 Max’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.