Improving Care for ‘Patients of All Ages’ Is GBT’s Goal, Exec Says

Global Blood Therapeutics (GBT) is currently focused on expanding the use of Oxbryta (voxelotor) to children, ages 4–11, with sickle cell disease (SCD). But research into its use with younger children, as well as studies into other potential SCD therapies, are also underway.

“Sickle cell disease patients of all ages worldwide need improved care now; we are stepping up to the challenge,” Kim Smith-Whitley, MD, GBT’s executive vice-president and head of research and development, said in an emailed statement to Sickle Cell Disease News.

“GBT is committed to transforming sickle cell disease into a well-managed disease,” a GBT spokesperson added.

Oxbryta was conditionally approved in the U.S. in 2019 as the first disease-modifying therapy for SCD patients, ages 12 and older, and is currently under regulatory review in Europe for the same patient group. Its reported U.S. list price is about $10,417 per month, or $125,000 each year.

Given once daily as a 1,500-mg tablet, the therapy works by increasing hemoglobin’s affinity to oxygen, thereby preventing its clumping, or polymerization, and the resulting sickling and destruction of red blood cells — SCD’s underlying cause. Hemoglobin is the protein inside red blood cells that is responsible for oxygen transport.

“GBT has focused on sickle cell disease since the company’s founding ten years ago,” Smith-Whitley said, adding that its research team started by actively looking “for ways to modify sickle hemoglobin to target polymerization.”

“The approval of Oxbryta less than a decade after discovery is a testament to the GBT research team’s hard work and the breakthrough therapeutic innovation that it represents,” she said. Smith-Whitley, a pediatric hematologist, was an investigator for several Oxbryta trials conducted at Children’s Hospital of Philadephia.

Oxbryta’s pediatric expansion

Now, GBT’s goal is “to make Oxbryta available to all people in the United States and around the world who might benefit, including younger children,” and on plans to soon request Oxbryta’s use be expanded to children as young as age 4, Smith-Whitley said.

This request will be based on upcoming one-year data from the global Phase 2 HOPE-KIDS 1 trial (NCT02850406). The study is assessing the therapy’s safety, pharmacokinetics (movement into, through, and out of the body), and early effectiveness in up to 155 children, ages 9 months to 17 years, with SCD.

Latest results concerned the first 45 children, ages 4–11, given weight-based doses of Oxbryta for at least six months. In these young patients, Oxbryta led to rises in hemoglobin levels and reductions in red blood cell destruction (hemolysis) similar to those observed in older patients given the therapy’s approved dose.

Findings in these children “were consistent with outcomes in people 12 years of age and older in the Phase 3 HOPE study,” Smith-Whitley said.

HOPE (NCT03036813), whose six-month data supported the therapy’s current approval in the U.S., also highlighted Oxbryta’s sustained benefits, with no evidence of a waning, or reduction, of its effects over nearly 1.5 years of treatment.

Notably, HOPE-KIDS 1, which is still enrolling, will also evaluate Oxbryta in up to 30 infants and young children, ages 9 months to 3 years; information for contacts and sites in the U.S., U.K., and Lebanon can be found here.

“We know that disease complications can begin early in life, so extending the treatment to this very young group is essential for reducing risk of poor outcome,” 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.

Weight-based doses of Oxbryta will also be tested in up to 224 children, ages 2–14, with SCD and a slightly higher risk of stroke — as measured by brain blood flow velocity — in the international Phase 3 HOPE-KIDS 2 trial (NCT04218084).

Due to increased blood flow in certain brain arteries, children with SCD have “a 300-fold increased risk of stroke compared to a child without sickle cell” and this risk “is highest in those with the more severe anemia,” said Brown, who is also a principal investigator of HOPE-KIDS 2 and the director of sickle cell clinical research at Children’s Healthcare.

This study will investigate whether Oxbryta is superior to a placebo at reducing the children’s risk of stroke — as assessed through a non-invasive ultrasound procedure that detects changes in brain blood flow — after about six months of treatment.

Serving as a confirmatory trial for the therapy’s full approval in the U.S., HOPE-KIDS 2 is recruiting eligible children at 42 sites across the U.S., Africa, and in Europe, and is expected to conclude in March 2026.

“This trial is being conducted primarily in Africa. GBT has committed to providing Oxbryta to patients post-study as part of our goal of figuring out ways to ensure treatment access for lower-resource countries,” Smith-Whitley said.

Daily life gains

While Oxbryta’s blood-related benefits are generally well-established, its effects on patients’ quality of life and daily life activities remain somewhat unclear.

Brown hopes that HOPE-KIDS 2’s exploratory quality of life and patient-reported outcome measures, as well as data from the Phase 4 ActIVe study (NCT04400487) will help in pinpointing Oxbryta’s daily life gains in this patient population.

ActIVe is evaluating whether nearly six months of treatment with Oxbryta improves daily physical activity and sleep quality, as measured by a validated smartwatch, in up to 50 SCD patients, ages 12 and older. U.S. enrollment is underway, and top-line data are expected by November 2022.

Looking ahead

GBT is also working on other potential SCD therapies, with the most advanced being inclacumab for the prevention of vaso-oclusive crises (VOCs), and GBT021601, a second-generation sickle hemoglobin polymerization suppressor.

Inclacumab, initially developed by Roche, works by blocking the activity of P-selectin, a protein that helps increase the stickiness of sickled red blood cells, so as to lower the risk of blood vessel obstruction.

As such, the therapy is expected to reduce the frequency of VOCs — painful crises caused by blood vessel blockage — and hospital re-admissions post-VOC among SCD patients. Two global Phase 3 trials, in patients 12 and older, are now opening in this potential therapy.

The first study (NCT04927247) will enroll up to 280 patients with a recent “index” VOC (one requiring facility admission and treatment with a parenteral pain medication, like opioids) and between two and 10 VOCs in the previous year, for a single inclacumab (30 mg/kg) or placebo infusion. It aims to determine how many patients are readmitted due to a VOC within 90 days. Contact information is here.

The second trial (NCT04935879) runs for 48 weeks, and plans to enroll up to 240 patients — with two to 10 VOCs over the previous year — who will be randomized to either inclacumab at 30 mg/kg or a placebo, both given every 12 weeks (three months). Its main goal is to measure the rate of VOCs throughout its near yearlong run. Contact information is available here.

Previous preclinical studies also suggest that inclacumab may be a best-in-class therapy, as it showed longer and more pronounced effects than Adakveo (crizanlizumab), the first P-selectin inhibitor approved to lower the frequency of VOCs.

The investigational therapy may require only four doses per year, which could improve patient adherence and access to treatment, a GBT spokesperson noted.

With the same mechanism of action as Oxbryta, GBT021601 may become its successor, as it is reported to have shown greater efficacy at significantly lower doses in a mouse model of SCD.

Having finished dosing in a healthy volunteer study of GBT021601, GBT plans to launch a Phase 1 trial to assess the therapy’s safety and tolerability in SCD patients later this year.

“GBT has done a great job in establishing that … hemoglobin S polymerization is a good target for this disease,” Brown said, adding that Oxbryta has now “created a platform where we’ll start to see other agents being developed that will have some of the same effects, or additive effects, like [those] we’ve seen with hydroxyurea and Oxbryta.”