Positive trends for etavopivat in sickle cell disease

In a phase 2 study, etavopivat was associated with a reduction in the incidence of vaso-occlusive crises (VOCs) among patients with sickle cell disease in the per-protocol analysis. The authors also noted improvements in fatigue and haemoglobin levels, supporting further exploration of the agent in phase 3.

“Etavopivat is an investigational allosteric activator of erythrocyte pyruvate kinase-R (PKR) and was associated with swift and sustained improvements in haemoglobin levels and a reduction in haemolysis markers in patients with sickle cell disease in a phase 1 study,” explained Dr Sophia Delicou (Hippocrates General Hospital, Greece) [1]. The current phase 2 HIBISCUS study (NCT04624659) randomised 60 patients with sickle cell disease who had 2–10 VOCs in the previous year 1:1:1 to etavopivat 200 mg once daily, etavopivat 400 mg once daily, or to a placebo [2]. “At baseline, all participants were on standard-of-care treatments like hydroxyurea, crizanlizumab, or L-glutamine,” added Dr Delicou.

After 52 weeks, the annualised VOC rate was 1.97 in the placebo arm, 1.07 in the 200 mg arm, and 1.06 in the 400 mg arm (P=0.154). “Although there was a reduction of 45% in VOCs in the active arms compared with the placebo arm, this effect was not statistically significant in the intention-to-treat population,” clarified Dr Delicou. There was a significant reduction in annualised VOC rate in the per-protocol analysis of 63% and 61% in the 200 mg and 400 mg arm compared with placebo, respectively (P=0.020; P=0.028). The authors also reported that participants in the 200 mg arm and 400 mg arm were numerically more likely to have a haemoglobin increase >1 g/dL at week 24 than those in the placebo arm (38.1% vs 10.5%; P=0.19; 25.0% vs 10.5%; P=0.66). “Next to this, we saw trends in haemolytic markers and fatigue that favoured the etavopivat arms,” said Dr Delicou.

There were 2 possibly drug-related serious adverse events, being a case of increased hepatic enzymes in the 200 mg arm and a case of decreased haemoglobin level in the 400 mg arm. Further, etavopivat was well-tolerated, and no unexpected safety issues were reported.

“Based on the pharmacokinetics, pharmacodynamics, and efficacy responses, the 400 mg arm has been selected to be investigated in the phase 3 trial programme,” shared Dr Delicou. “Hopefully, the positive trends we observed in the current study will be confirmed in the larger phase 3 population.”

1. Saraf SL, et al. Blood Adv. 2024;8:4459-4475.
2. Delicou S, et al. Etavopivat reduces incidence of vaso-occlusive crises in patients with sickle cell disease: HIBISCUS trial phase 2 results through 52 weeks. Abstract 179, 66^th ASH Annual Meeting, 7–10 December 2024, San Diego, CA, USA.

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Posted on 29 January 2025