Phase 3 Trial Evaluating Voxelotor for Sickle Cell Disease Boasts Positive Top-Line Data

Positive top-line data from Part A of Global Blood Therapeutics, Inc.’s phase 3 HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) trial evaluating voxelotor for the treatment of sickle cell disease (SCD) has been released.

A statistically significant increase in hemoglobin was demonstrated in those who received voxelotor in either 1500 mg or 900 mg doses after 12 weeks of treatment compared with placebo.

Voxelotor (previously known as GBT440) is a developmental, once-daily, oral therapy for SCD patients that works by increasing hemoglobin's affinity for oxygen. Since oxygenated sickle hemoglobin fails to polymerize, the company postulates that voxelotor blocks polymerization, and consequently, the sickling of red blood cells that often results from that process.

“Given the well-established association between chronic hemolytic anemia and SCD-related morbidity and mortality, we believe the clinically meaningful increase in hemoglobin and improvement in hemolysis together with the safety profile demonstrated in Part A are highly encouraging,” shared Ted W. Love, MD, president and chief executive officer of GBT, in a recent statement.

For Part A of the phase 3 HOPE trial, investigators sought to assess the safety and efficacy of 154 patients with the primary endpoint being a greater than 1 g/dL increase in hemoglobin versus baseline. They found that 58% of those receiving the 1,500 mg dose (p<0.0001) were able to achieve a greater than 1 g/dL increase in hemoglobin at 12 weeks; this was true for 38% of patients who received the 900 mg dose of the drug (p=0.0021). Only 9% of patients who received the placebo were able to achieve this.

These findings were found to compare favorably with the hemoglobin increase assumption that had been agreed to with the US Food and Drug Administration (FDA) in the HOPE Study protocol of a 35% response, according to the recent news release.

With both voxelotor doses, statistically significant and dose-dependent improvements in hemoglobin, reticulocytes, and bilirubin were noted, which further demonstrated an improvement in hemolytic anemia. Additionally, the improvements observed in these clinical measures of anemia and hemolysis compared similarly in patients with or without background use of hydroxyurea; about 64% of trial participants are reported to be on background use of hydroxyurea.

Fewer vaso-occlusive crisis (VOC) episodes were reported in both voxelotor groups compared with those that occurred in the placebo group. Due to limited patient follow-up, these events were not considered to be statistically significant.

Because of low baseline symptom scores and high inter-subject and intra-subject variability, patient reported outcomes (PROs) data proved difficult to interpret. Due to this, PROs most likely will not be included as a key secondary endpoint.

Overall, voxelotor was found to be generally safe and well-tolerated in trial participants, showing a similar safety profile between the 2 doses. Furthermore, no evidence of tissue hypoxia was reported at either dose.

These findings support what was reported in the Independent Data and Safety Monitoring Board (DSMB)’s most recent clinical safety review, which was performed in May 2018, and did not find safety concerns regarding voxelotor at either dose level. The patient population assessment included all patients dosed in the ongoing SCD clinical program, including adult patients in the phase 3 HOPE Study and adolescent patients in the HOPE-KIDS 1 (GBT440-007) Study. The initiation of dosing in children as young as age 4 were supported by the DSMB.

“Based upon voxelotor’s robust impact on hemolytic anemia, we believe it meets the standard for accelerated approval, and we look forward to providing further updates on our regulatory discussions as soon as possible, but no later than year-end,” Dr Love explained. “We are grateful to the patients and families who have participated in our clinical studies, allowing us to potentially deliver this transformative therapy to the SCD community.”

Looking forward, Global Blood Therapeutics will continue to dose Part A patients plus approximately 100 additional patients across all 3 treatment arms to gather more data. This action derives from the positive Part A results and ongoing regulatory discussions.

“The pathophysiology and morbidity associated with SCD result from two distinct pathways: hemolytic anemia and vaso-occlusion. New therapies that address each pathway are important and desperately needed,” added Elliot Vichinsky, MD, director, Comprehensive Center for Sickle Cell Disease, UCSF Benioff Children’s Hospital Oakland. “Increasing hemoglobin levels by reducing hemolysis in SCD patients is likely to decrease morbidity and mortality.”

Previously, voxelotor was granted Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations for the treatment of patients with SCD by the FDA. The European Medicines Agency (EMA) has also included voxelotor in its Priority Medicines (PRIME) program, and voxelotor has been designated as an orphan medicinal product for the treatment of patients with SCD by the European Commission (EC).

Results from the phase 2a of the HOPE-KIDS 1 Study were released earlier this June.

The anticipated completion date for the phase 3 HOPE Study is June 2019.