Etavopivat, an investigational oral therapy developed by Novo Nordisk, has shown promising results in reducing vaso-occlusive crises (VOCs) and increasing hemoglobin levels in patients with sickle cell disease (SCD). The findings, from the phase 2 part of the phase 2/3 HIBISCUS trial, were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) in San Diego, California.
The multi-center, randomized, double-blind, placebo-controlled HIBISCUS trial enrolled 60 participants aged 12 to 65 years with SCD. Participants were randomized to receive either etavopivat 200 mg/day (n = 21), etavopivat 400 mg/day (n = 20), or placebo (n = 19) for 52 weeks. The primary endpoints were annualized VOC rate at week 52 and hemoglobin response (increase in hemoglobin by >1 g/dL from baseline) at week 24.
Reduction in Vaso-Occlusive Crises
In the intent-to-treat (ITT) population, both etavopivat arms showed a reduction in annualized VOC rate compared to placebo. The etavopivat 200 mg group had an average of 1.07 VOCs (95% CI, 0.49-2.37), the 400 mg group had 1.06 VOCs (95% CI, 0.46-2.46), while the placebo group had 1.97 VOCs (95% CI, 0.89-4.36). This represents non-significant 45% and 46% reductions in annualized VOC rate, respectively.
A per-protocol (PP) analysis, including participants with at least 80% protocol compliance, showed a significant difference in annualized VOC rate. The etavopivat 200 mg group had a rate of 0.66 (95% CI, 0.28-1.58; n = 13), the 400 mg group had 0.70 (95% CI, 0.29-1.66; n = 12), and the placebo group had 1.77 (95% CI, 0.90-3.50; n = 15). This represents 63% (P = .020) and 61% (P = .028) reductions in VOCs, respectively.
Improvement in Hemoglobin Levels
At week 24, 38.1% of the 200 mg group, 25.0% of the 400 mg group, and 10.5% of the placebo group achieved hemoglobin responses in the ITT population. In the PP population, these numbers increased to 46.2%, 33.3%, and 13.3%, respectively, although no rate differences were found to reach statistical significance. The etavopivat arms also had a lengthened time to first VOC of 34 weeks compared to 17 weeks in the placebo group.
Safety and Tolerability
Etavopivat was generally well-tolerated. Most reported adverse events (AEs) were mild to moderate and resolved without action. Serious AEs, all of which resolved, were reported by 5 participants in the etavopivat 200 mg group (1 hepatic enzyme increase possibly drug related), 4 in the 400 mg group (1 hemoglobin decrease possibly drug related), and 3 in the placebo group; 1 cerebrovascular accident unrelated to therapy occurred in the 200 mg group. Insomnia was reported by 3 participants in the 400 mg group.
Clinical Implications
"The results are very encouraging," said Julie Kanter, MD, director of the Adult Sickle Cell Clinic at the University of Alabama at Birmingham. "We see a reduction in VOCs, an improvement in overall hemoglobin, and a decrease in hemolysis, as well as some early improvements in important patient-reported outcomes like fatigue. This suggests the drug may be beneficial for people with SCD and warrants further investigation in the ongoing phase III trial as well as a planned multi-national phase III trial."
Etavopivat is an investigational, oral, small molecule activator of erythrocyte pyruvate kinase. Its novel mechanism of action could offer great benefit in the treatment landscape of SCD. The ongoing phase 3 HIBISCUS trial will further evaluate the efficacy and safety of etavopivat in a larger patient population.
