Sickle cell disease (SCD) is a genetic condition whereby mutated hemoglobin has a tendency to form polymers after unloading oxygen. These polymers cause red blood cells to form a ‘sickle’ shape and increases their likelihood of sticking to the blood vessel wall, causing vaso-occlusive crises (VOCs), stroke, or other serious problems. VOCs are painful episodes due to ischemic obstruction of blood vessels that risk permanent organ damage. Trials for new medicines are required to measure VOCs by some metric (hospitalization time, opioid requirement, etc), to show that any improvement in hemoglobin actually leads to a better clinical outcome. Hydroxyurea is the current standard of care, and has been shown to increase hemoglobin and reduce VOCs. However, there is a major unmet medical need in this area, as hydroxyurea is limited in the magnitude of its effects and leaves patients with debilitating SCD symptoms.
Voxelotor is a once-daily, oral SCD treatment by Global Blood Therapeutics (GBT). Once in circulation, Voxelotor binds to hemoglobin and keeps it in a normal conformation, preventing red blood cell sickling. The company is in the middle of Phase 3 trials, recently releasing preliminary data from their HOPE trial. These data show a convincing effect on raising hemoglobin more than 1g/dl, enough to meet their primary endpoint. The company is so convinced of the results of Voxelotor that they recently asked the FDA for accelerated approval based on the clinically meaningful increase in hemoglobin and improvement in hemolysis.
Unfortunately for GBT, it was previously agreed upon that the company would also have to meet an objective related to VOCs before full approval. SCD symptom exacerbation was measured from patient-reported outcomes (PRO) using a hand-held instrument, which was designed by GBT to capture the full range of daily SCD symptoms. The latest data released from the HOPE study showed that Voxelotor led to numerically fewer VOC episodes but this difference was not statistically significant. The company had also planned on measuring hopitalizations and red blood cell transfusions, but this data has not yet been reported.
Given this, it seems unlikely that the FDA would accept accelerated approval of Voxelotor with the current results. GBT is set to release more data at the American Society of Hematology conference on December 3rd, 2018. Here, we may get more insight into the secondary endpoints, to see whether Voxelotor has an effect on VOCs. Without an effect on VOCs, I do not expect the company to get support from the FDA.
I do not have a position in the company, nor do I intend to initiate one. Follow me on twitter @matthewlepoire to see if that changes.
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