O-03: etavopivat treatment for up to 12 weeks in patients with sickle cell disease is well tolerated and improves red blood cell health

Purpose: Etavopivat, an investigational, once-daily (QD), selective activator of erythrocyte pyruvate kinase (PKR) increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers and patients with sickle cell disease (SCD).1,2 Here we report results of an open-label extension cohort from a Phase 1 study (NCT03815695) characterizing the safety and clinical activity of etavopivat at a maximal pharmacodynamic dose in patients with SCD. Materials and methods: Fifteen patients were to receive etavopivat 400mg QD for 12 wks followed by a 4-wk follow-up. Assessments included safety, pharmacokinetics, pharmacodynamics, RBC health parameters, and systemic markers of SCD pathophysiology. Results: Fifteen patients were enrolled (age 32.3 ±10.1 years; HbSS/SC, n=13/2); 14 completed 12-wks of treatment; 1 discontinued treatment after ~2 wks. Etavopivat 400mg QD was generally well tolerated. Adverse events (AEs) reported during treatment and follow-up were commonly low grade (Gr) and consistent with patients’ SCD. Gr1-2 AEs in >2 patients (n, %) were sickle cell pain events (9, 60%), headache (5, 33%) and upper respiratory tract infection (3, 20%). The Gr3-4 AE in >1 patient was sickle cell vaso-occlusion (VOC; 4, 27%). On-treatment serious adverse events (SAEs; n=1 each) were Gr3 VOC post Gr3 COVID (not treatment-related) and Gr3 left-femoral deep vein thrombosis (possibly related, resulting in treatment discontinuation as stated above). SAEs (n=1 each) during the 4-wk follow-up were Gr3 acute chest syndrome + Gr3 VOC, Gr3 non-cardiac chest pain and Gr3 syncope (all unrelated). Increases in ATP and decreases in 2,3-DPG were durable over 12 wks of etavopivat treatment. Etavopivat normalized HbS-oxygen affinity to that of HbA and improved measures of sickle RBC health, demonstrated by a reduction in RBC point of sickling and improved deformability (Figure 1) and hydration (Figure 2) (all P<0.01). Etavopivat treatment over 12 wks resulted in a sustained significant increase in Hb compared with baseline (P<0.0001), with mean maximal increase of 1.5 (range, 0.7-2.3) g/dL. On-treatment increase in Hb >1g/dL was achieved in 11 (73%) patients, for whom the mean maximal Hb increase was 1.8 (1.2-2.3) g/dL. Absolute reticulocytes, indirect bilirubin and lactate dehydrogenase significantly decreased from baseline over 12 wks (all P<0.05), indicating decreased hemolysis and increased RBC lifespan. Several markers of disease activity significantly decreased from BL, including the inflammatory marker tumor necrosis factor-α, which decreased by 35% (P<0.001). Based on preliminary exploratory analysis with an aggregate duration of etavopivat exposure of 3.32 patient-years, the trend for VOC hospitalizations decreased: annualized historical and on-treatment VOC hospitalization rates were 0.93 and 0.30, respectively; the 1 on-treatment VOC hospitalization was COVID-related. Conclusion: Etavopivat 400mg QD for up to 12 wks demonstrated a tolerable safety profile with improvements in various markers of RBC health in patients with SCD. Rapid and sustained increases in Hb were associated with decreases in reticulocytes and hemolysis markers, supporting increased sickle RBC lifespan and improved anemia. Together, these results support further evaluation of etavopivat in the Phase 2/3 Hibiscus Study (NCT04624659) currently enrolling patients. 1. Kalfa et al, Blood 2019. 2. Brown et al, Blood 2020.Etavopivat improved sickle RBC PoS and deformability (EImax) during 12-weeks of dosing.Etavopivat improved sickle RBC hydration (RBC Hb concentration [MCHC] and dense RBCs) during 12-weeks of dosing. I. OSUNKWO declares a conflict of interest: Consultancy, Expert: Site PI for Phase 1 study Other: now employed at Forma therapeutics F. KUYPERS declares a conflict of interest: Research support/Scientific studies: UCSF has received funds for the efforts of the RBC laboratory (department of pediatrics, hematology division) to generate data presented. J. GEIB declares a conflict of interest: Stock shareholder: Forma Therapeutics Other: Employee, Forma Therapeutics S. SARAF declares a conflict of interest: Consultancy, Expert: Global Blood Therapeutics, Novartis, Forma, Agios Research support/Scientific studies: Global Blood Therapeutics, Novartis, Forma