Etavopivat Well-Tolerated With Some Disease-Modifying Activity in SCD

Julie Kanter, MD

Credit: University of Alabama – Birmingham

Etavopivat was well-tolerated in people with sickle cell disease (SCD) and daily use resulted in improvements in vaso-occlusive crises (VOC), improvements in fatigue and hemolysis, and increases in hemoglobin levels compared to placebo.¹

These findings, from the phase 2 HIBISCUS trial, were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, by site principal investigator Julie Kanter, MD, director, Adult Sickle Cell Clinic and associate professor, Division of Hematology and Oncology, University of Alabama – Birmingham.

“The results are very encouraging,” Kanter said in a statement.² “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 being evaluated in the multi-center, phase 2/3, randomized, double-blind, placebo-controlled HIBISCUS trial. The trial enrolled 60 participants between the ages of 12 to 65 years (average, 33.5) with SCD who had had over 3 VOCs on average in the year before the study. Participants were randomized to etavopivat 200 mg/day (n = 21 in the intent-to-treat [ITT] population), etavopivat 400 mg/day (n = 20 ITT), or placebo (n = 15 ITT) for 52 weeks.¹

Kanter and colleagues found that in the ITT population, both etavopivat arms had an average of 1 VOC (200 mg, 1.07 [95% CI, 0.49-2.37]; 400 mg, 1.06 [95% CI, 0.46-2.46]) during the study period compared to just under 2 in the placebo group (1.97 [95% CI, 0.89-4.36]). These represent non-significant 45 and 46% reductions in annualized VOC rate, respectively. However, the investigators reported a significant difference in annualized VOC rate according to a per-protocol analysis including those with at least 80% protocol compliance and completion of the double-blind period with no major protocol deviations. In this analysis, annualized VOC rates were 0.66 in the 200 mg group (95% CI, 0.28-1.58; n = 13), 0.70 in the 400 mg group (95% CI, 0.29-1.66; n = 12), and 1.77 in the placebo group (95% CI, 0.90-3.50; n = 15), which represent 63% (P = .020) and 61% (P = .028) reductions in VOCs respectively.¹

Looking at hemoglobin responses, in the ITT population, 38.1% of the 200 mg group, 25.0% of the 400 mg group and 10.5% of the placebo group achieved hemoglobin responses (an increase in hemoglobin by over 1 g/dL from baseline) at week 24. In the per-protocol population, these numbers increased to 46.2%, 33.3%, and 13.3%, respectively, although no rate differences were found to reach statistical significance. Notably, the etavopivat arms also had a lengthened time to first VOC of 34 weeks compared to 17 weeks in the placebo group.¹

Etavopivat is an investigational, oral, small molecule activator of erythrocyte pyruvate kinase, and investigators noted that it could prove useful in the treatment landscape of SCD with its novel mechanism of action.

“This is a very exciting mechanism of action and could offer great benefit,” Kanter said.² “It’s not going to be for everyone, so we need to see who it’s going to be best for and how it can be used in combination with other therapies, but it’s absolutely a step in the right direction.”

REFERENCES

1. Delicou S, El Rassi F, Andemariam B, et al. Etavopivat Reduces Incidence of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: HIBISCUS Trial Phase 2 Results through 52 Weeks. Presented at: ASH Annual meeting; December 7-10; San Diego, California. Abstract 179.

2. Researchers Report New Opportunities to Improve Quality of Life for People with Non-Malignant Blood Disorders. Press release. ASH. December 7, 2024.