Voxelotor induces robust improvements in anemia in patients with sickle cell disease

April 2020 EHA 2019 Vanessa Vernimmen
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In the phase III HOPE trial, the oral hemoglobin-oxygen affinity modulator voxelotor was found to be associated with rapid, robust and sustained improvements in the hemoglobin level and in the hemolysis of patients with sickle cell disease. Furthermore, voxelotor was generally well tolerated.


Sickle cell disease (SCD) is an inherited disorder caused by a single amino acid substitution in the β-chain of hemoglobin (Hb) resulting in the production of sickle hemoglobin (HbS). When deoxygenated, HbS polymerizes, leading to red blood cell (RBC) sickling and damage. Hb polymerization and RBC sickling leads to chronic anemia and hemolysis in patients, which in turn results in organ damage, an increased stroke risk and vaso-occlusion. These long-term complications contribute to the decreased quality of life and reduced life expectancy observed in patients with SCD. It is well established that lower Hb levels are associated with negative clinical outcomes. Moreover, improvements in Hb levels of at least 1.0 g/dL can potentially reduce the clinical complications and mortality in SCD. Voxelotor is a novel once-daily oral therapy that increases the Hb affinity for oxygen. In doing so, voxelotor inhibits Hb polymerization and red blood cell sickling. In the phase III HOPE trial, the efficacy and safety of voxelotor was evaluated in SCD patients aged 12-65 years.

Study design and results

The HOPE trial enrolled 274 patients with SCD (HbSS, HbSC, HbSβ0 thalassemia, or other variants) with a Hb level ≥5.5 and ≤10.5 g/dL, and between 1 and 10 vaso-occlusive crises (VOC) in the prior 12 months. Concurrent hydroxyurea was allowed if the dose had been stable for ≥90 days. Patients were randomly assigned to receive voxelotor 1,500 mg/day, 900 mg/day, or placebo for at least 24 weeks. The primary endpoint was the proportion of patients with a >1.0 g/dL increase in Hb from baseline at week 24. Secondary study objectives included the change from baseline to week 24 in measures of hemolysis (absolute reticulocyte count, reticulocyte count percentage, indirect bilirubin levels, and lactate dehydrogenase levels) and safety.

After 24 weeks of therapy, the percentage of patients who achieved at least 1.0 g/dL increase in Hb level was significantly higher in the voxelotor arm than in the placebo arm. With the 1,500 mg dose, this milestone was reached by 59.5% of patients, while the 900 mg dose induced this response in 38.0% of patients. In contrast, only 9.2% of placebo treated patients saw there Hb level increase with 1g/dL during the first 24 weeks (p<0.001 versus 1,500 mg and 900 mg cohort). In fact, over 80% of patients receiving voxelotor at a dose of 1,500 mg/day had an increase in their Hb level. With voxelotor an anemia improvement was seen irrespective of baseline anemia severity and previous hydroxyurea use. Consistent with improvement in Hb, voxelotor also resulted in concordant improvements in measures of hemolysis and fewer VOCs were observed. Overall, the treatment-emergent adverse events (TEAEs) were similar across all treatment arms except for diarrhea, which was higher with voxelotor (1,500 mg: 21%; 900 mg: 19%) compared with placebo (10%). The majority of TEAEs were grade 1 or 2 in severity.


Voxelotor demonstrated a dose-dependent increase in Hb, with the majority of patients on voxelotor 1,500 mg achieving a >1.0 g/dL improvement in Hb from baseline to week 24. In addition, there was a dose-dependent decrease in measures of hemolysis with voxelotor. Furthermore, voxelotor was generally well tolerated. These results suggest that voxelotor has the potential to be disease-modifying by improving anemia and reducing hemolysis and their associated morbidity and mortality.


Vichinsky E, Hoppe C, Ataga K, et al. Results from the randomized placebo-controlled phase 3 HOPE trial of voxelotor in adults and adolescents with sickle cell disease. Presented at EHA 2019; abstract S147.