A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study of Mitapivat in Patients with Sickle Cell Disease: RISE UP Phase 2 Results

Background: Sickle cell disease (SCD) is characterized by the presence of hemoglobin S (HbS), a structural variant caused by a mutation in the HBB gene. Deoxygenated HbS molecules polymerize into “fibers”, causing red blood cells (RBCs) to sickle and hemolyze. Sickled RBCs have a shortened lifespan and impede blood flow to tissues, causing painful vaso-occlusive crises. Recurrent microvascular damage and chronic hemolytic anemia result in progressive multi-organ damage.

Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase, a key enzyme in RBC metabolism, with a dual mechanism of action under investigation in SCD: it increases adenosine triphosphate (ATP) in RBCs, improving survival, and decreases 2,3−diphosphoglycerate, increasing Hb oxygen affinity and thus diminishing HbS polymerization and RBC sickling. RISE UP is a global Phase (Ph) 2/3 double-blind, randomized, placebo (PBO)-controlled trial evaluating the efficacy and safety of mitapivat in patients (pts) with SCD (NCT05031780).

Methods: In the Ph 2 double-blind period (DBP), 2 dose levels of mitapivat were evaluated against PBO for 12 weeks (wks). Eligible pts were ≥16 years with ≥5.5 to ≤10.5 g/dL Hb and ≥2 to ≤10 sickle cell pain crises (SCPCs, including pain, priapism, acute chest syndrome, hepatic sequestration, and splenic sequestration) in year prior to entry. Pts were randomized 1:1:1 to mitapivat 50 mg twice daily (BID), mitapivat 100 mg BID, or matched PBO. Pts completing the DBP were eligible to receive mitapivat in a 216-wk open-label extension. Primary endpoints were Hb response (≥1.0 g/dL increase in average Hb concentrations from Wks 10 through 12 compared with baseline [BL], tested with Fisher’s exact test at 2-sided 0.05 significance level) and adverse events (AEs), including the type, severity, and relationship to study drug. Prespecified secondary endpoints included average change from BL from Wks 10 through 12 in Hb, markers of hemolysis, markers of erythropoiesis, and pt-reported fatigue score, as well as annualized rate of SCPCs.

Results: In the Ph 2 DBP, 79 pts were randomized and treated with mitapivat 50 mg BID (n=26), mitapivat 100 mg BID (n=26), or PBO (n=27). In the 50 mg BID, 100 mg BID, and PBO arms, mean (SD) age was: 29.9 (7.79), 30.2 (10.52), and 28.5 (10.30) years; female: 57.7%, 61.5%, and 74.1%; mean (SD) BL Hb: 8.76 (1.295), 8.82 (0.898), and 8.49 (1.141) g/dL; mean (SD) number of SCPCs during previous year: 3.1 (1.83), 3.2 (1.65), and 3.4 (1.91), respectively.

The primary endpoint was achieved; 46.2% (12/26) of pts in the 50 mg BID arm and 50.0% (13/26) in the 100 mg BID arm demonstrated a significant increase in Hb response compared with 3.7% (1/27) of pts in the PBO arm (2-sided p=0.0003 and p=0.0001, respectively). Mitapivat was generally well tolerated; observed safety profile was consistent with previously reported data of mitapivat in SCD and other hemolytic anemias. No serious treatment-emergent AEs were related to study drug; no AEs led to study drug discontinuation or death.

Least-squares mean (LSM [95% CI]) for average change from BL in Hb levels from Wks 10 through 12 was 1.11 (0.77, 1.45) g/dL, 1.13 (0.79, 1.47) g/dL, and 0.05 (−0.28, 0.39) g/dL for 50 mg BID, 100 mg BID, and PBO arms, respectively (Figure). Improvements were observed in markers of hemolysis and erythropoiesis. SCPCs annualized rates (95% CI) were 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59) for 50 mg BID and 100 mg BID arms, respectively, compared to 1.71 (0.95, 3.08) for PBO. LSM (95% CI) for average changes from BL in pt-reported fatigue score from Wks 10 through 12 was −3.80 (−7.16, −0.45), −0.10 (−3.27, 3.08), and −0.17 (−3.40, 3.07) for 50 mg BID, 100 mg BID, and PBO arms, respectively (Table).

Conclusion: During the Ph 2 DBP of RISE UP, treatment with mitapivat demonstrated statistically significant and clinically meaningful improvement in Hb response at both dose levels (50 mg BID and 100 mg BID) compared to PBO. Improvements in markers of hemolysis/erythropoiesis and annualized rate of SCPCs were observed for both doses as compared with PBO; the magnitude of improvement in markers of hemolysis and annualized rate of SCPCs was larger in the mitapivat 100 mg BID arm. Mitapivat was well tolerated with a safety profile consistent with previous studies. These data suggest that mitapivat, through its dual mechanism of action, may provide clinical benefit to pts with SCD and support continued development in the Ph 3 portion of the RISE UP trial.