Sickle Cell Disease (SCD): Phase 3 HOPE Study

Michael R. DeBaun, MD, MPH: Voxelotor inhibits polymerization in the red blood cells of individuals with sickle cell disease. This is the sentinel event in sickle cell disease because it’s the polymerization of the hemoglobin that results in the downstream sequelae of the disease. The ability of voxelotor to inhibit polymerization essentially abates many of the clinical manifestations that you would anticipate associated with chronic hemolysis. The hemoglobin goes up, the reticulocyte count goes down, the LDH [lactate dehydrogenase] goes down, and total bilirubin goes down, all of which are direct and indirect indications of a decrease of chronic hemolysis.The HOPE study was an efficacy and safety trial, with 2 doses of voxelotor, a 1500-mg dose and 900-mg dose; both were given once a day. Patients in each of these groups were compared to individuals who received a placebo. Eligibility included individuals with a hemoglobin level between 5.5 and 10.5 g/dL.

The main outcomes of this phase 3 trial included the average hemoglobin level achieved while on voxelotor treatment when compared to placebo. In addition, there was an annualized incidence rate of vaso-occlusive pain episodes that were evaluated in the treatment group. The results indicated that the annual incidence rate of vaso-occlusive pain episodes, that is event per patient year, was 2.4 in the voxelotor 1500-mg group, 2.4 in the voxelotor 900 mg, and 2.8 in the placebo group, indicating there was really no clinical difference between the 2 doses of voxelotor and the placebo group, and no statistical difference either when either of the treatment doses was compared to the placebo group.What is important is that the 24-week analysis results showed an initial response in terms of increasing the hemoglobin level. The 72-week trial showed that this response was sustainable well over the window of time of the patients being followed. Similar to the 24-week analysis, there was no actual difference in the incidence of pain when comparing the treatment group with the placebo group.The implication is that if you can improve the hemoglobin level you will attenuate many of the chronic complications of the disease.

You will potentially decrease any part of pulmonary complications, you will potentially decrease any complications associated with the kidneys. You will improve the quality of life, decrease fatigue, which is associated with increased energy, potentially improved cognitive impairment, decreased CNS [central nervous system] manifestation. That’s the promise, however, the promise has not been revealed at this point. I’ll say it’s early days in evaluating the clinical benefit of voxelotor on abating or even attenuating the end organ disease, typically brain, heart, or kidney disease, in individuals with sickle cell disease.

What…demonstrated was that there was an increase in hemoglobin in a real-world setting, outside of a clinical trial, of about a gram and a little bit more, approximately 1.3 g/dL. This is what was identified in the formal controlled trial evaluation of voxelotor.We were tested during COVID-19, and we made a decision that an ounce of prevention is worth a pound of cure. We went early on in the pandemic, in March of 2020, to a telemedicine approach. We did this across our sickle cell disease center on both the adult side and the pediatric side. For our patients who required ongoing transfusions for primary and secondary stroke prevention, we elected to start them all on hydroxyurea at a low dose and keep them on hydroxyurea while we were transfusing them. In the event that transfusions were unavailable, as was the case in some of the harshest months of the pandemic in the spring and in the summer of 2020, for patients who were Jehovah’s Witnesses, for patients with alloimmunizations, where it was extremely difficult to transfuse, for patients with baseline low hemoglobin, hemoglobin less than originally 6 and then less than 7 [g/dL], we identified rosters of those individuals in our pediatric and adult population. We called them and we discussed with them options for prevention of any complications that may occur if they were infected with SARS-CoV-2 virus.

Transcript Edited for Clarity