FDA Approval Sought for Oxbryta for Children Ages 4–11

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by Marta Figueiredo PhD |

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Oxbryta/sicklecellanemianews.com/GBT seeks FDA approval for treating patients ages 4-11

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Children with sickle cell disease (SCD) as young as age 4 could be prescribed Oxbryta (voxelotor) if the U.S. Food and Drug Administration approves a supplemental new drug application (sNDA) submitted by the therapy’s developers.

Global Blood Therapeutics (GBT) is asking the FDA to expand the use of Oxbryta — the first approved therapy targeting the underlying cause of SCD — to children ages 4 and older who have the inherited blood disease.

The therapy’s current label, allowing an oral daily dose of 1,500 mg, covers SCD patients ages 12 and older.

GBT also submitted a separate new drug application, or NDA, asking for the approval of a pediatric weight-based formulation of Oxbryta, which was found to result in similar blood-related benefits as those seen with the approved dose in older patients.

“Starting at a very early age, sickle cell disease has a serious and life-altering impact on children, and current therapeutic options for children under 12 years of age are limited,” Ted W. Love, MD, GBT’s president and CEO, said in a press release.

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Both regulatory applications were proposed for priority review, which shortens the review process to six months from the standard 10 months. The FDA’s ruling on the completeness and acceptability of the applications, as well as on their potential for priority review, is expected within two months.

Love said GBT’s team “is committed to working closely with the FDA to potentially expand access to Oxbryta, thereby providing hope to families.”

“We believe there is significant potential to impact the longer-term outcomes [of SCD] by addressing the root cause of red blood cell sickling at a young age,” Love said.

Oxbryta targets SCD’s underlying cause by increasing hemoglobin’s affinity to oxygen. That prevents its polymerization, or clumping, and the resulting red blood cell sickling and destruction. Hemoglobin is the protein inside red blood cells that is responsible for transporting oxygen.

The therapy was conditionally approved in the U.S. in 2019 as the first disease-modifying therapy for SCD patients, ages 12 and older. It currently is under review in Europe for the same indication.

GBT’s recent regulatory filings are supported by data from the international Phase 2 HOPE-KIDS 1 trial (NCT02850406), which involves an estimated 155 children and adolescents, ages 9 months to 17 years, with SCD. The study is evaluating the therapy’s safety, pharmacokinetics — its movement into, through, and out of the body — and early effectiveness.

For children under 12, weight-based dosing criteria were developed to provide equivalent doses to the approved dose in proportion to the patients’ weights.

Previous six-month data from the first 45 treated children, ages 4–11, showed that Oxbryta’s weight-based doses were generally well-tolerated and resulted in rapid and sustained increases in hemoglobin levels. Reductions also were reported in the levels of several markers of red blood cell destruction.

Notably, these effects were comparable to those observed in older patients given Oxbryta’s approved dose in the Phase 3 HOPE trial (NCT03036813), completed in October 2019. The HOPE trial, which had supported the therapy’s current approval in the U.S, involved patients ages 12 to 65.

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HOPE-KIDS 1, which is still enrolling, also will test weight-based doses of Oxbryta in up to 30 infants and young children, ages 9 months to 3 years. More information on contacts and trial sites in the U.S., the U.K., and Lebanon can be found here.

Additionally, GBT announced that it is now recruiting SCD patients for two Phase 3 clinical trials — GBT2104-131 (NCT04935879) and GBT2104-132 (NCT04927247). Both are testing inclacumab, GBT’s experimental therapy for preventing vaso-oclusive crises (VOCs), in patients ages 12 and older.

A Phase 1 study evaluating GBT021601 (GBT601), a potential successor to Oxbryta, also is enrolling, the company said.

Apart from Oxbryta, the most advanced SCD therapy in the company’s pipeline is inclacumab, which is thought to lower the risk of blood vessel obstruction by blocking the activity of P-selectin, a protein that increases the stickiness of sickled red blood cells.

As such, the therapy, initially developed by Roche, is expected to reduce the rate of VOCs — painful crises caused by blood vessel blockage — and post-VOC hospital readmissions in people with SCD.

Notably, inclacumab was previously shown to lead to longer and more potent effects than once-a-month Adakveo (crizanlizumab), the first P-selectin inhibitor approved to lower VOCs frequency. Those results suggest that the experimental therapy may require less frequent dosing.

Both pivotal Phase 3 trials are evaluating inclacumab’s potential in SCD patients who have experienced between two and 10 VOCs in the prior year. The therapy will be given directly into the bloodstream (intravenously) at a dose of 30 mg/kg.

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The GBT2104-131 study is assessing whether inclacumab can prevent VOCs. The estimated 240 patients will be randomly assigned to receive an into-the-vein infusion of either inclacumab or a placebo, every three months, for nearly a year.

Its main goal is to measure VOCs frequency, while secondary goals include determining the time to first and second VOCs, the proportion of participants without VOCs, the rate of VOCs requiring admission to a healthcare facility, and hospitalization duration. More information on study contacts and sites can be found here.

The second trial, GBT2104-132, is evaluating the effect of a single dose of inclacumab given just prior to, during, or around the time of discharge. The therapy’s effects will be compared with that of a placebo on hospital readmission rates in up to 280 patients who were admitted to a healthcare facility due to a VOC.

The study’s primary goal is to assess how many patients are readmitted due to a VOC within 90 days. Other secondary goals include evaluating hospital readmissions occurring within 30 days, the time to first VOC-related hospital readmission, and the rate of VOCs leading to healthcare provider visits. Trial contact information is available here.

To date, GBT reports, the first patient has been enrolled in a Phase 1 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics — a medicine’s effects on the body — and preliminary effectiveness of single and multiple doses of GBT021601 in up to six adults, ages 18–60 years, with SCD.

Despite having the same mechanism of action as Oxbryta, GBT021601 may become its successor, as it showed greater efficacy at significantly lowering doses in a mouse model of SCD. The next-generation hemoglobin S polymerization inhibitor was previously tested in a study involving healthy volunteers, in which dosing already has been completed.

The developer plans to submit GBT021601’s preliminary proof-of-concept data for presentation at an upcoming medical meeting.

“Our goal is to transform sickle cell disease into a well-managed condition, and we are committed to advancing our pipeline of innovative therapies that address the multiple [underlying mechanisms] of this inherited disease in parallel with working to expand access to Oxbryta,” said Kim Smith-Whitley, MD, GBT’s executive vice president and head of research and development.

“We are excited to initiate enrollment in our two pivotal studies for inclacumab, in parallel with our Phase 1 study of GBT601 in people with sickle cell disease,” Smith-Whitley added.