SCD medical experts discuss Oxbryta and appropriate patient cases

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.

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. Santosh Saraf. I’m an adult hematologist who cares for approximately 150 patients with sickle cell disease.

Welcome to this video, where we will discuss the efficacy and safety results from the Phase 3 HOPE and Phase 2a HOPE-KIDS 1 trials.

The efficacy and safety of Oxbryta in adult and pediatric sickle cell disease patients 12 years and older was evaluated in HOPE, a phase 3, randomized, double-blind, placebo-controlled, multicenter trial.

The primary endpoint in the HOPE trial was the percentage of patients who achieved a greater than 1 gram per deciliter increase in hemoglobin from baseline to week 24.

This graph illustrates the change in hemoglobin from baseline at week 24 for each individual patient 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 in the intent-to-treat population who received the 1,500-milligram dose of Oxbryta achieved a greater than 1 gram per deciliter increase in hemoglobin, compared with 7% of patients who received placebo.

The intent-to-treat patients included all randomized patients.

Among the per-protocol population, 59% receiving Oxbryta achieved a >1 gram per deciliter increase in hemoglobin (compared with baseline) vs 10% in the placebo group.

The per-protocol population included randomized patients who completed 24 weeks and adhered to the defined trial protocols. This represented approximately 83% of the intent-to-treat population.

Oxbryta demonstrated an observed hemoglobin response vs. placebo regardless of baseline hydroxyurea use.

Now let’s take a look at the response observed in the HOPE trial. 42% of patients who received Oxbryta achieved a greater than 1.5 gram per deciliter increase in hemoglobin, compared with 3% in the placebo group.

Additionally, 27% of patients who received Oxbryta therapy achieved a greater than 2 grams per deciliter 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 gram per deciliter mean increase in hemoglobin at week 24…..

…..and a 1.0 gram per deciliter 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 grams per deciliter at week 24, and 0.9 grams per deciliter at week 72.

For those who were not on background hydroxyurea therapy, Oxbryta conferred a mean increase in hemoglobin of 1.1 grams per decliter 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 milligrams achieved a greater than 26% reduction in indirect bilirubin at both weeks 24 and 72.

Patients who received Oxbryta 1,500 milligrams 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 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.

The graph on the right 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.

Now, let’s take a look at the Phase 2a HOPE-KIDS 1 Clinical Trial.

The efficacy and safety of Oxbryta tablets for oral suspension in patients 4 to <12 years of age with sickle cell disease was evaluated in HOPE-KIDS 1, an open-label, multicenter, phase 2a trial.

The primary endpoint analysis in the Phase 2a HOPE-KIDS 1 trial was the percentage of patients who achieved a greater than 1 gram per deciliter increase in hemoglobin from baseline to week 24.

This graph illustrates the change in hemoglobin from baseline at week 24 for each individual patient who completed 24 weeks of therapy. As you can see, Oxbryta tablets for oral suspension increased hemoglobin levels in most patients in the Phase 2a HOPE-KIDS 1 trial.

36% of patients in the intent-to-treat population and who received Oxbryta tablets for oral suspension achieved a >1.0 gram per deciliter increase in hemoglobin from baseline at 24 weeks with a 95% confidence interval of 21.6%-49.5%.

The intent-to-treat population included all patients who enrolled and received at least 1 dose of study drug regardless of adherence to defined trial protocols.

Looking at the per-protocol population, 47% of patients receiving Oxbryta tablets for oral suspension achieved a >1 gram per deciliter increase in hemoglobin at week 24 compared with baseline.

The per-protocol population comprised patients who completed 24 weeks of the study drug and had a hemoglobin measurement available at week 24.

Now let’s take a look at the response observed in the HOPE-KIDS 1 trial. 35% of patients receiving Oxbryta tablets for oral suspension achieved a >1.5 grams per deciliter increase in hemoglobin from baseline.

21% of patients receiving Oxbryta tablets for oral suspension achieved a >2.0 gram per deciliter increase in hemoglobin from baseline.

The hemoglobin response with Oxbryta in the HOPE-KIDS 1 trial was rapid and sustained.

53% of the patients receiving Oxbryta tablets for oral suspension achieved or maintained absolute hemoglobin levels of ≥10.0 grams per deciliter at week 24.

Now, let’s take a look at the clinical safety data of Oxbryta from the Phase 3 HOPE and Phase 2a HOPE-KIDS 1 trials.

The table on the left illustrates the adverse reactions that were observed 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 at Week 72 in the HOPE trial. These reactions included headache, diarrhea, abdominal pain, nausea, rash, and pyrexia.

Serious adverse reactions that occurred in 3% or (3/88) of patients receiving Oxbryta 1,500 milligrams included headache, drug hypersensitivity, and pulmonary embolism, occurring in 1 patient each.

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

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

The table on the right illustrates the adverse reactions that were observed in pediatric patients aged 4 to <12 years who received Oxbryta tablets for oral suspension in the HOPE-KIDS 1 trial. These reactions included pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache.

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

There were no discontinuations of Oxbryta tablets for oral suspension related to vomiting, rash, abdominal pain, diarrhea, or headache.

Dose modifications may be warranted to manage adverse events.

Throughout the entirety of the HOPE trial, 48% of adult and pediatric patients 12 years of age and older 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 2 patients who received Oxbryta 1,500 milligrams included diarrhea and rash.

In the HOPE trial, patients needing a temporary modification based on physician discretion or adverse reaction severity could be lowered to 1,200 milligrams/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 milligrams per day.

5% of patients permanently discontinued therapy due to an adverse reaction (Grades 1-4).

In the Phase 3 HOPE Trial, there were no discontinuations due to diarrhea, headache, rash, fatigue, arthralgia, or pyrexia.

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

Patients experiencing a 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 there is no impairment of tissue oxygenation for Oxbryta. However, additional clinical studies need to be conducted to confirm 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.

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

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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 >>

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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

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