Etavopivat Reduces Incidence of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: HIBISCUS Trial Phase 2 Results through 52 Weeks

Background: Etavopivat is a potent, selective, once-daily, orally bioavailable activator of the red blood cell (RBC) pyruvate kinase isozyme, decreasing 2,3 DPG levels and increasing ATP levels in RBCs. In a phase 1 study, treatment with etavopivat in patients with sickle cell disease (SCD) resulted in a rapid and sustained increase of hemoglobin (Hb) levels and decreased markers of hemolysis over 12 weeks (Saraf S et al. Blood Adv 2024). HIBISCUS (NCT04624659) is a multi-center, phase 2/3, randomized, double-blind, placebo (PBO)-controlled trial investigating the efficacy and safety of etavopivat in SCD. Here we report 52-week data from the phase 2 part of the trial.

Methods: Participants were aged 12-65 years, with any SCD genotype, Hb level ≥5.5 to ≤10.5 g/dL at screening, and 2-10 vaso-occlusive crises (VOC) requiring a medical setting visit in the previous 12 months. Participants were randomized 1:1:1 to blinded oral etavopivat 200 mg, etavopivat 400 mg, or PBO, once daily for 52 weeks. Permitted standard of care included stable dosing with hydroxyurea (HU; ≥90 days prior), crizanlizumab, or L-glutamine (≥12 months prior). Primary study endpoints were annualized, independently adjudicated VOC rate over 52 weeks and Hb response (>1 g/dL increase from baseline [BL]) at Week 24. The primary efficacy analysis is reported for the intent-to-treat (ITT) population. We also report the analysis for the per-protocol (PP) population, defined as ≥80% protocol compliance and completion of the double-blind period with no major protocol deviations. Hemolysis biomarkers (absolute reticulocyte count, indirect bilirubin and lactate dehydrogenase [LDH]), and patient-reported outcome measures (PROMIS Fatigue Scale) were assessed.

Results: Sixty participants (19 male [32%], 7 adolescents [12%], 54 HbSS genotype [90%]) were randomized to receive etavopivat 200 mg (n=21), etavopivat 400 mg (n=20), or PBO (n=19). Mean (SD) age was 33.5 (13.7) years and BL Hb level was 8.4 (1.16) g/dL. Mean (SD) number of VOCs in the previous 12 months was 3.3 (1.78). Concomitant HU was used by 16 (76%), 13 (65%) and 14 (74%) participants in the etavopivat 200 mg, 400 mg, and PBO groups, respectively. Six participants in each etavopivat group and 3 in the PBO group discontinued the study drug early (2 in the 200 mg group secondary to an adverse event [AE]).

In the ITT population, annualized VOC rates were 1.07 for the etavopivat 200 mg group, 1.06 for the 400 mg group and 1.97 for PBO. VOC rate ratios for etavopivat:PBO (95% CI; % reduction) were 0.55 (0.24, 1.26; 45.7%) for the 200 mg group and 0.54 (0.23, 1.26; 46.2%) for the 400 mg group. Median time to first VOC was 33.6 weeks for each etavopivat group and 16.9 weeks for PBO. Hb response at Week 24 was 38% (n=8/21) in the 200 mg group, 25% (n=5/20) in the 400 mg group and 11% (n=2/19) in the PBO group. Hb response with etavopivat was seen early by Week 2 and was maintained over 52 weeks.

In the PP population, annualized VOC rates were 0.66 (n=13) for the 200 mg group, 0.7 (n=12) for the 400 mg group and 1.77 (n=15) for PBO. VOC rate ratios (95% CI; % reduction) were 0.37 (0.16, 0.85; 62.7%) for the 200 mg group and 0.39 (0.17, 0.90; 60.5%) for the 400 mg group. Hb response at Week 24 was 46% (n=6/13) in the 200 mg group, 33% (n=4/12) in the 400 mg group and 13% (n=2/15) in the PBO group. Mean change from BL Hb levels at Week 24 were 1.11 g/dL (n=8) for the 200 mg group, 0.73 g/dL (n=10) for the 400 mg group and 0.15 g/dL (n=14) for PBO.

In the ITT population, all hemolysis biomarkers decreased from BL in both etavopivat groups at Week 24; with the LDH decrease sustained through Week 52. PROMIS Fatigue Scale showed improvements for participants receiving etavopivat. Most reported AEs in any group 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 Hb decrease possibly drug related) and 3 in the PBO group; 1 cerebrovascular accident unrelated to therapy occurred in the 200 mg group. Insomnia was reported by 3 participants in the 400 mg group.

Conclusions: Compared with PBO, etavopivat reduced annualized VOC rate through Week 52, increased Hb levels at Week 24, and improved hemolysis markers and patient-reported fatigue, consistent with potential clinical benefit. Etavopivat was well tolerated. Based on the totality of data, proof of concept was established for etavopivat in SCD.

Delicou:ELPEN: Honoraria; DEMO: Honoraria; ISIS: Research Funding; Vifor: Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Hippokrateio General Hospital: Current Employment. El Rassi:Afimmune: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding. Andemariam:Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hemanext: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fulcrum Therapeutics: Other: Data Safety Monitoring Board / Adjudication Committee; Vertex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Health Resources and Services Administration: Research Funding; Connecticut Department of Public Health: Research Funding; bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Society of Hematology: Research Funding; Editas: Other: Data Safety Monitoring Board / Adjudication Committee; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Afimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Accordant: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Abboud:Pfizer/GBT: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Vertex: Consultancy, Other: Data safety committee ; Novo Nordisk: Other: Travel support, Research Funding. Kanter:Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Optum United Health: Consultancy; Beam Tx: Consultancy, Research Funding; Novartis: Consultancy; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; NIH/NHLBI: Other: Federal Funding; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CDC: Other: Federal Funding; bluebird bio: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bausch: Consultancy; Fulcrum: Consultancy; Health Resources and Services Administration: Other: Federal Funding; Bristol Myers Squibb: Consultancy; Emerging Therapy Solutions: Honoraria; Bioline Rx: Consultancy; Sanofi: Consultancy; Affimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Guidepoint Global: Consultancy; EcoR1: Consultancy; GLG Pharma: Consultancy; Takeda: Research Funding; Watkins, Lourie, Roll & Chance: Consultancy. Telen:Novo Nordisk: Research Funding; GBT/Pfizer: Research Funding; CSL Behring: Research Funding. Githanga:Novo Nordisk: Consultancy, Honoraria. Inati:Novartis: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Agios: Research Funding; Bausch Health: Research Funding; Novo Nordisk: Consultancy, Research Funding; Roche: Consultancy, Research Funding; GBT/Pfizer: Consultancy, Research Funding; Pharmacosmos: Research Funding. Idris:Novo Nordisk: Consultancy, Research Funding; Agios: Consultancy. Navani:Pfizer: Ended employment in the past 24 months; Novo Nordisk Ltd: Current Employment; Novo Nordisk: Current equity holder in publicly-traded company. Wu:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company.

Etavopivat is under investigation for the treatment of sickle cell disease and other hematologic conditions, and is not currently licensed for these or other diseases.