GBT sickle cell trial hits endpoint ahead of NDA filing

red blood cells
Concerns about the inability of Global Blood Therapeutics' voxelotor to move the needle against a key endpoint remain. (Pixabay)

Global Blood Therapeutics has shared updated data on the sickle cell disease trial it hopes will secure FDA approval of voxelotor. The proportion of patients who had a greater than 1 g/dL increase in hemoglobin is down on GBT’s prior update but still superior to placebo, resulting in the trial hitting its primary endpoint.

California-based GBT shared data on the first 154 patients to complete 24 weeks of follow-up in its phase 3 shortly after FDA green lit it to file for accelerated approval late last year. The data showed 65% of patients on the higher dose of voxelotor achieved the desired rise in hemoglobin, compared to 10% of people in the placebo cohort. Those figures came from a per-protocol analysis.

GBT now has 24-week data on all 274 patients enrolled in the trial of voxelotor, a stabilizer of sickle cell hemoglobin. On a per-protocol basis, 60% of patients in the higher-dose arm had a greater than 1 g/dL increase in hemoglobin, compared to 9% in the placebo cohort. The figures slipped to 51% and 7% in the intention-to-treat (ITT) analysis. 

The lower, 900 mg dose of voxelotor performed worse than the other treatment arm but nonetheless statistically beat placebo, with respectively 33% and 38% of people in the ITT and per-protocol analyses clearing the hemoglobin bar.

Mean change in hemoglobin was down slightly on the prior data, too. The earlier update linked the higher-dose arm to a 1.4 g/dL mean increase. That figure slipped to 1.1 g/dL in the final analysis but even so comfortably outperformed placebo, which was associated with a decline of 0.1 g/dL.

GBT’s laser focus on hemoglobin is a relatively recent development. Going into the trial, GBT planned to break the study into two parts and rely on patient-reported outcomes (PROs) or vaso-occlusive crises (VOCs) as a key secondary endpoint and cornerstone of its regulatory strategy. That changed last year when GBT dropped the second part of the study and talked up the potential to win accelerated approval on the strength of hemoglobin data from the first stage of the trial.

The willingness of the FDA to accept the revised regulatory strategy was key for GBT. In the full analysis, voxelotor failed to drive statistically significant reductions in VOCs over placebo. And GBT has previously said the PROs generated uninterpretable results.

Those shortcomings leave scope to question the benefits of voxelotor. A New England Journal of Medicine editorial to accompany the release of the data identified both evidence that voxelotor delivers real benefits and concerns about its ability so far to move the needle against a key endpoint.

“The clinical significance of this response was the associated reduction in hemolysis, a consequence of sickle cell disease that is associated with chronic organ injury. A trend toward a cumulative reduction in the incidence of vaso-occlusive pain episodes with voxelotor as compared with placebo may be emerging in an extended follow-up analysis out to 72 weeks. Follow-up studies are needed to examine this very important, clinically relevant end point,” the author of the editorial wrote.