Etavopivat in adolescents with sickle cell disease: Emerging safety and efficacy findings from the first cohort of the ongoing Phase 1/2 hibiscus kids study

Abstract Background: Etavopivat is a selective, orally bioavailable, small-molecule activator of the pyruvate kinase red blood cell (RBC) isozyme (PKR), under investigation for the treatment of individuals with sickle cell disease (SCD). Etavopivat's multimodal mechanism of action lowers RBC 2,3-diphosphoglycerate (2,3-DPG), enhancing hemoglobin (Hb)-oxygen affinity and elevating Hb levels, while increasing adenosine triphosphate (ATP) to promote RBC health. In the phase 2/3 HIBISCUS study in adults and adolescents with SCD, compared with placebo, the phase 2 part showed that etavopivat reduced annualized vaso-occlusive crises (VOCs) rate at Week (Wk) 52, increased Hb at Wk 24, lowered hemolysis markers and patient-reported fatigue scores, and was relatively well tolerated (Delicou S et al. Blood 2024;144[Suppl 1]:179). HIBISCUS Kids (NCT06198712) is an ongoing, phase 1/2, single-arm, four-cohort, open-label study investigating the pharmacokinetics (PK) and safety of etavopivat in children and adolescents with SCD (6 months–<18 years) with study sites in Canada, Kenya, Lebanon, Nigeria, and the UK. Here we report preliminary safety and efficacy findings from the first 15/25 planned participants in cohort 1 (aged 12–<18 years) who have completed the 24-wk primary treatment period. Methods: Participants received open-label study drug etavopivat 400 mg once-daily orally for 24 wks. Each age-based cohort will initiate etavopivat following a 12-wk safety and PK review of the preceding cohort. Participants had a documented SCD genotype, Hb level ≥5.5–<10.5 g/dL during screening, and severe SCD, defined by ≥1 of the following within 12 months of screening: 2–15 documented VOCs; hospitalization for SCD complication; urinary albumin:creatinine ratio (ACR); or normal or conditional transcranial Doppler (TCD) ultrasonography. Stable dose concurrent therapy with hydroxyurea, crizanlizumab and L-glutamine was permitted. Safety endpoints included serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), etavopivat discontinuations, dosing interruptions, and dose reductions. Laboratory safety markers were assessed. Efficacy endpoints were Hb response (>1 g/dL increase from baseline [BL]) at Wk 24 and change from BL to Wk 24 in Hb, VOC occurrence, hemolysis markers (absolute reticulocyte count [ARC], indirect bilirubin, and lactate dehydrogenase [LDH]), and Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue scores. Changes in ACR, cerebral blood flow (time-averaged mean of the maximum velocity [TAMMV] by TCD), and brain magnetic resonance imaging (MRI) were also assessed. Results: 15 adolescent participants (10 female, 10 Black/African American, 13 HbSS and 2 HbSβ0-thalassemia genotype) with a mean age of 14.5 years (range 12–17) received etavopivat 400 mg/day. Mean (standard deviation [SD]) BL Hb was 8.0 g/dL (1.13); all participants completed 24 wks of treatment. One participant required a dose interruption due to a drug-related SAE (cholestasis), which resolved. No deaths were reported. Most TEAEs (101/105 events) were mild or moderate in severity. The most common TEAEs were sickle cell anemia with crisis (9/15), malaria (4/15), headache (4/15), and tonsilitis (4/15). Changes in safety laboratory values over 24 wks were not clinically relevant. Ten participants had an Hb response, with a mean (SD) change in Hb from BL of 1.5 g/dL (0.69) at Wk 2 and 1.4 g/dL (0.99) at Wk 24. Mean (SD) number of VOCs over 24 wks was 1.8 (1.93). PROMIS Fatigue scores decreased: mean (SD) changes from BL to Wk 12 of –4.6 (9.37) and Wk 24 of –2.6 (12.10). Mean (SD) change from BL to Wk 24 in hemolysis markers: –84.5×109/L (64.5) for ARC, –28.3 µmol/L (26.3) for indirect bilirubin and –179 U/L (124.2) for LDH. At Wk 24, 4/15 participants showed an improvement in TAMMV as assessed by TCD measurement; one brain MRI scan revealed a non-clinically significant abnormality. Conclusions: In this preliminary analysis of the HIBISCUS Kids study, the first to investigate a PKR activator in a pediatric SCD population including children younger than 12 years, etavopivat was relatively well tolerated by adolescents. Cohort 1 enrollment and dosing are complete; weight-based dosing with a granule formulation has begun for cohort 2, children aged 6–<12 years. The study is expected to provide further insights into the safety, tolerability, and potential clinical benefits of etavopivat in younger children, including those as young as 6 months.