Hibiscus 2 (Trial-in-Progress): A global, Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of etavopivat in adolescents and adults with sickle cell disease

Abstract Background and Significance: Pyruvate kinase red blood cell (RBC) isozyme (PKR) is a key enzyme in glycolysis. In RBCs, the PKR isoform catalyzes the conversion of phosphoenolpyruvate to pyruvate, producing adenosine triphosphate (ATP), which is crucial for RBC membrane stability and function. In sickle cell disease (SCD), sickled RBCs display lower ATP levels and higher 2,3-diphosphoglycerate (2,3-DPG) levels. These changes lead to a decreased hemoglobin (Hb)-oxygen affinity, reduced membrane stability, and a shorter RBC lifespan. Pharmacologic activation of PKR improves glycolytic efficiency, resulting in increased ATP and decreased 2,3-diphosphoglycerate (2,3-DPG) to improve RBC health in SCD. Etavopivat is an investigational, once-daily (OD), orally bioavailable, selective PKR activator in development for treatment of people with SCD (PwSCD). In a phase 1 study (Saraf SL et al. Blood Adv 2024;8:4459–75), etavopivat was well tolerated at doses up to 600 mg. In the open-label extension (OLE) of the study, 12 weeks (wks) of etavopivat 400 mg OD treatment in PwSCD led to sustained increases in ATP and reductions in 2,3-DPG levels. HIBISCUS is a phase 2/3, 52-wk, randomized, placebo-controlled study of etavopivat 200 mg OD and 400 mg OD in adults and adolescents with SCD. In the phase 2 part of HIBISCUS, etavopivat reduced annualized vaso-occlusive crisis (VOC) rate over 52 wks, raised Hb levels from Wk 2, and lowered hemolysis markers and fatigue scores in PwSCD (Delicou S et al. Blood 2024;144[Suppl 1]:179). Exposure–response modeling showed OD dosing with 400 mg resulted in a stronger and more consistent Hb response than OD dosing with 200 mg of etavopivat. Based on the totality of available phase 1 and 2 data, the 400 mg/day dosage was selected for phase 3 studies. The phase 3 part of HIBISCUS aims to demonstrate superiority of etavopivat vs placebo for improving Hb levels and reducing the annualized VOC rate. HIBISCUS 2 will generate additional robust data on VOC reduction in adults and adolescents with SCD. Here, we describe the design of HIBISCUS 2. Study Design and Methods Study design: HIBISCUS 2 (NCT06612268) is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 study comprising a 4-wk screening period, a 52-wk double-blind treatment period, and a 52-wk OLE period. Study population: PwSCD of any genotype and aged ≥12 years are eligible if they have moderate-to-severe anemia, Hb ≥5.0–≤10.0 g/dL at screening, and 2–15 VOC episodes in the year before screening. Concomitant hydroxyurea and/or L-glutamine use is permitted if PwSCD have received stable dosing and are compliant with treatment before screening. Key exclusion criteria are chronic transfusion therapy, use of erythropoiesis-stimulating agents, voxelotor, or crizanlizumab before starting study intervention, and hepatic dysfunction. Study treatment and endpoints:Participants are randomized 2:1 to receive double-blind oral OD etavopivat 400 mg or placebo. The primary endpoint is the number of VOC events from baseline (BL) to Wk 52, as adjudicated by an independent committee of four SCD-experienced physicians. Confirmatory secondary endpoints include change in Hb >1 g/dL at Wk 24, time to onset of first adjudicated VOC, and change in standardized T-score on the PROMIS Fatigue 7a scale at Wk 52. Key supportive secondary endpoints include changes from BL to Wk 52 in Hb, lactate dehydrogenase, absolute reticulocyte count, indirect bilirubin, and distance walked in the 6-minute walking test. Safety endpoints include the number of reported adverse events from screening to Wk 52. Selected exploratory endpoints include changes in 2,3-DPG and ATP levels, and urinary albumin:creatinine ratio. Statistical considerations: 408 participants are expected to be randomized. Primary and confirmatory secondary endpoints will be tested using a fixed-sequence strategy to control the type I error at the 0.05 level, whereas supportive secondary endpoints will be descriptive. Study status HIBISCUS 2 is enrolling participants at sites in Australia, Belgium, Brazil, Canada, Colombia, France, Ghana, Greece, India, Italy, Kenya, Lebanon, the Netherlands, Nigeria, Oman, Saudi Arabia, Spain, Turkey, Uganda, the United Kingdom, and the United States. The results from this confirmatory study will provide additional evidence that etavopivat has the potential to delay or prevent VOCs, enhance Hb levels, and reduce fatigue in PwSCD.