S109: ACTIVATION OF PYRUVATE KINASE-R WITH ETAVOPIVAT (FT-4202) IS WELL TOLERATED, IMPROVES ANEMIA, AND DECREASES INTRAVASCULAR HEMOLYSIS IN PATIENTS WITH SICKLE CELL DISEASE TREATED FOR UP TO 12 WEEKS
Authors: M Telen, S Saraf, K Cruz, M Idowu, T Kalfa, I Osunkwo, R Hagar, J Geib, S Forsyth, P Schroeder, E Wu, P Kelly, R Brown
Journal: HemaSphere (2022)

Background: Etavopivat, an investigational, once daily (QD), selective, erythrocyte pyruvate kinase (PKR) activator, increases PKR activity, resulting in ↓2,3-DPG and ↑ATP in RBCs of healthy volunteers (HV) and patients (pts) with sickle cell disease (SCD) [1,2]. Aims: Multiple-dose studies in pts with SCD (NCT03815695): 2-wk multiple ascending dose (MD) cohorts to identify the etavopivat QD dose providing maximum PD activity with an acceptable safety profile and a 12-wk open-label (OL) study to characterize safety and clinical activity at the maximum pharmacodynamic (PD) dose. Methods: Completed MD cohorts: 20 pts with SCD were randomized 8:2 to etavopivat (300 mg, then 600 mg) or placebo (PBO) QD for 2 wks. Ongoing OL study: ≤20 pts will receive etavopivat 400 mg QD for 12 wks. Assessments: safety, PK, PD, and RBC health. All pts provided written informed consent. Results: MD cohorts (n=17 HbSS, n=2 HbSβ+thalassemia, n=1 HbSC) completed enrollment and data unblinded (300 and 600 mg etavopivat, n=8 each; PBO, n=4). OL cohort: As of July 13, 2021, 11 pts (HbSS/SC, n=10/1) were treated: median treatment (Trt) duration was 12 (range 1–12) wks; 6 pts completed 12 wks of Trt. In MD pts, etavopivat demonstrated dose-proportional PK with overlapping PD response (↓2,3-DPG; ↑ATP), confirming prior results in HVs that etavopivat 400 mg QD provides maximal PD activity. Etavopivat was well tolerated. AEs were reported in 1/4 (25%) MD PBO pts, most were grade (Gr) ≤3, with 1 Gr4 blood creatine phosphokinase (CPK) increase. AEs were reported in 13/16 (81%) etavopivat MD pts, most were Gr1/2 and commonly (n>2) included sickle cell pain (n=6[38%]), headache (n=5[31%]), and nausea (n=3[19%]). One pt had a serious AE (SAE) of Gr3 vaso-occlusive crisis (VOC, unrelated) after completing etavopivat. In the OL cohort, AEs were reported in 7/11 (64%) pts on etavopivat for ≥1 wk. AEs reported in >1 pt were headache and VOC (n=2[18%] each). Most AEs were Gr1/2; 1 pt had SAEs of Gr3 acute chest syndrome and VOC (unrelated), 1 pt had an SAE of Gr3 deep vein thrombosis (possibly related), and 1 pt had an AE of Gr4 transient blood CPK increase (unrelated). Hematologic and hemolytic parameters significantly improved at end of Trt (MD and OL cohorts); 11/15 (73%) evaluable MD pts had a hemoglobin (Hb) increase ≥1 g/dL over baseline (mean 1.1 g/dL, P<0.004) and markers of hemolysis decreased (Table). These initial findings were sustained in pts receiving ≤12 wks of etavopivat (Table, Fig.). Of 6 pts who completed 12 wks of etavopivat, 5 (83%) had >1 g/dL Hb increase over baseline (mean 1.39 g/dL). Markers of hemolysis decreased. Of 9 pts on etavopivat for ≥4 wks, 8 (89%) had an Hb increase >1 g/dL; highest mean Hb increase was 1.81 g/dL during Trt. Etavopivat-treated RBCs from MD pts (n=14) exhibited improved health, including point of sickling and deformability. Improved deformability persisted up to 1 wk after etavopivat in 36% of pts. Results in initial OL pts were similar. Data on additional pts will be presented. Summary: Etavopivat 400 mg QD for ≤12 wks was well tolerated, with a safety profile consistent with underlying SCD. Etavopivat increased sickle RBC lifespan and significantly improved severe anemia associated with SCD. These early Phase 1 data show longer-living sickle RBCs have improved health, which may further reduce the risk of VOCs and end-organ damage, and support further evaluation of etavopivat in the Hibiscus Study (NCT04624659).References 1. Kalfa et al, Blood 2019;134(suppl 1):616 2. Brown et al, Blood 2020;136(suppl 1):19