Oxbryta in HOPE-KIDS Meeting ‘Urgent Need’ of Children, Ages 4-11

In children with sickle cell disease (SCD), ages 4–11, weight-based doses of Oxbryta (voxelotor) result in similar rises in hemoglobin levels and reductions in red blood cell destruction (hemolysis) to those observed in older patients at the approved dose, six-month data from the ongoing Phase 2 HOPE-KIDS 1 trial suggest.

“The hematologic [blood-related] responses for these children closely follows the response found in adults receiving Oxbryta,” Robert Clark Brown, MD, PhD, a pediatric hematologist and the trial’s principal investigator at its Children’s Healthcare of Atlanta site, said in an interview with Sickle Cell Disease News.

The therapy also “seems to be very [well] tolerated in the younger population, as it is in adults,” added Brown, who is also director of sickle cell clinical research at Children’s Healthcare.

“The impact of the sickling and destruction of red blood cells, which drive anemia and hemolysis, starts to take a toll on people with SCD from an early age — even if there are no outward symptoms at first, the cumulative damage can have a devastating effect over time,” Kim Smith-Whitley, MD, executive vice-president and head of research and development Global Blood Therapeutics (GBT), Oxbryta’s developer, said in an emailed statement.

“There is an urgent need for improved therapies for younger children and we’re encouraged by the findings … supporting the use of Oxbryta in children ages 4 to 11,” Smith-Whitley added.

If confirmed at one year of treatment, these positive, comparable results are expected to support GBT’s planned request to expand Oxbryta’s current U.S. label, covering SCD patients ages 12 and older, to include children as young as 4.

Oxbryta is the first approved therapy targeting SCD’s underlying cause: the polymerization, or clumping, of hemoglobin — the protein inside red blood cells that is responsible for oxygen transport — and subsequent red blood cell sickling.

Given once daily as an oral tablet, the therapy works by increasing hemoglobin’s affinity to oxygen, thereby preventing its clumping and the resulting red blood cell sickling and destruction.

The global Phase 2 HOPE-KIDS 1 study (NCT02850406) is evaluating the safety, pharmacokinetics (movement into, through, and out of the body), and early effectiveness of Oxbryta in up to 155 children, ages 9 months to 17 years, with SCD.

The study comprises four parts (A to D), each involving children of different ages assigned to receive single or multiple doses of the therapy.

For children under 12, weight-based dosing criteria were developed to provide “equivalent levels of medication in proportion to their weight,” a GBT spokesperson said.

Weight-based doses are being given through a dispersible tablet formulation developed by GBT for this pediatric population.

Results from HOPE-KIDS 1, recently presented at the European Hematology Association 2021 Virtual Congress, concerned the first 45 children, ages 4–11, receiving Oxbryta for at least six months in group C (which ranges in ages from 4 to 17). Data were collected through Sept. 30, 2020.

These 45 patients, with a median age of 7, weighed at least 10 kg (about 22 pounds) and were given a daily dose of either 600 mg, 900 mg, or the approved 1,500 mg, depending on their weight.

Six-month data showed that 47.1% of them achieved a hemoglobin response, similar to the 51% of patients ages 12 and older given Oxbryta (1,500 mg) in the Phase 3 HOPE trial (NCT03036813), which supported the therapy’s conditional approval for this patient population in the U.S.

In the children, a hemoglobin response, defined as a hemoglobin raise of at least 1 gram per deciliter (g/dL), was observed as early as two weeks of treatment, and was sustained through six months.

Some participants achieved hemoglobin levels between 12 and 13 g/dL, which are among the highest levels Brown has observed in pediatric SCD patients. Higher hemoglobin levels are associated with fewer long-term health complications and better survival, the pediatric hematologist added.  

The children also showed a mean hemoglobin increase of 1 g/dL and a 26% hemoglobin occupancy, defined as the percentage of hemoglobin bound by Oxbryta. These data were consistent with the 1.1 g/dL hemoglobin raise and the 26.5% hemoglobin occupancy seen in HOPE at the therapy’s approved dose.

Children given weight-based doses of Oxbryta “have the same hemoglobin response, but also roughly the same percent hemoglobin occupancy by the [therapy] as what we saw in the adult population,” Brown said.

Markers of hemolysis were also reduced in this pediatric population after six months of treatment, as in older patients who participated in HOPE.

Notably, children receiving hydroxyurea at a maximum tolerated dose, in addition to Oxbryta, achieved similar benefits, highlighting Oxbryta’s potential to improve their health beyond the standard approach to treatment.

This agrees with Brown’s and GBT’s view of the future therapeutic landscape for SCD, which both expect will involve a combination of treatments with different mechanisms of action.

“We know that there’s a lot of good physiological targets for sickle cell disease and a combination of therapy to address as many targets as possible makes sense,” Brown said, adding such combinations will likely become the standard for SCD in the next three to five years.

Importantly, trial data so far suggest that Oxbryta and hydroxyurea have “an additive effect,” targeting “different parts of the defective sickle red blood cell,” Brown said.

GBT estimates that “roughly a third of people taking Oxbryta are [currently] on some sort of combination therapy.”

Oxbryta was generally well-tolerated, with no new safety concerns identified and the most common treatment-related adverse events being temporary and resolving on their own.

HOPE-KIDS 1 is still enrolling children and adolescents for its part C, and has recently started recruitment for its part D, which Smith-Whitley said will evaluate Oxbryta in 30 infants and young children, ages 9 months to 3 years. More information on sites and contacts can be found here.

“As a pediatric hematologist, it is this young group that I’m particularly interested in,” Brown said, noting that he expects Oxbryta will also show favorable safety and effectiveness profiles in these younger patients, despite some biological differences — such as higher fetal hemoglobin levels in children up to around 12 to 18 months of age.

GBT has also open the international Phase 3 HOPE-KIDS 2 trial (NCT04218084) to serve as a confirmatory trial for Oxbryta’s full approval in the U.S. The study is currently recruiting children, ages 2–14 years old, with SCD at sites across the U.S., Africa, and in Europe.

Enrollment is also ongoing in a Phase 4 study, called ActIVe (NCT04400487), evaluating Oxbryta’s effects on daily physical activity and sleep quality, as measured by a validated wrist-worn device, in SCD patients, ages 12 and older, living in the U.S.