One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study

Abstract

Targeting the primary pathogenic event of sickle cell disease (SCD), the polymerization of sickle hemoglobin (HbS), may prevent downstream clinical events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. In the previously reported 8-week dose-finding period of this phase 2, investigator-initiated, open-label study, mitapivat was well tolerated and showed efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in which 9 of 10 included patients (90%) aged ≥16 years with SCD (HbSS, HbS/β0, or HbS/β+) continued with mitapivat. Mostly mild treatment-emergent adverse events (AEs) (most commonly, transaminase increase and headache) were still reported. Apart from the reported nontreatment-related serious AE (SAE) of a urinary tract infection in the dose-finding period, 1 nontreatment-related SAE occurred in the fixed-dose extension period in a patient who died of massive pulmonary embolism due to COVID-19. Importantly, sustained improvement in Hb level (mean increase, 1.1 ± 0.7 g/dL; P = .0014) was seen, which was accompanied by decreases in markers of hemolysis. In addition, the annualized rate of vaso-occlusive events reduced significantly from a historic baseline of 1.33 ± 1.32 to 0.64 ± 0.87 (P = .0489) when combining the dose-finding period and fixed-dose extension period. Cellularly, the ATP:2,3-DPG ratio and Hb-oxygen affinity significantly increased and RBC sickling (point of sickling) nonsignificantly reduced. Overall, this study demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780). This trial was registered at https://www.clinicaltrialsregister.eu/ as NL8517 and EudraCT 2019-003438-18.

Effects of mitapivat-mediated pyruvate kinase activation in sickle cell disease. Mitapivat (AG-348) is an oral allosteric activator of pyruvate kinase (PK), a key enzyme in RBC glycolysis. PK activation decreases 2,3-DPG levels and increases ATP levels in RBCs. This study showed that mitapivat decreased parameters of hemolysis, RBC sickling and vaso-occlusive events and increased hemoglobin (Hb) level and Hb-oxygen affinity.1,3-DPG, 1,3-Disphosphoglycerate; ADP, adenosine diphosphate; P, phosphate; 2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate; 3-PG, 3-Phosphoglycerate; PEP, phosphoenolpyruvate; RBC, red blood cell; Hb, hemoglobin.

Figure 1.

Study schema of the ESTIMATE study. Safety and efficacy analysis were planned after completion of the 1-year fixed-dose extension period. BID, twice daily; D, study visit day of the dose-finding period with D0 at the start; M, study visit month of the prolonged fixed-dose extension period with M0 at the start corresponding to W52 of the fixed-dose extension period; W, study visit week of the fixed-dose extension period with W0 at the start corresponding to D56 of the dose-finding period.

Figure 2.

Study flowchart for the reported fixed-dose extension period analysis. The study flowchart of this nonrandomized phase 2 trial is adapted from the format of the Consolidated Standards of Reporting Trials (CONSORT) flow diagram for randomized trials. Examples why patients did or could not participate included personal reasons such as a busy schedule, not willing to participate in experimental studies, or the COVID-19 pandemic and medical reasons such as Hb level >11.1 g/dL at baseline, no adequate organ function (ie, elevated transaminase levels), or a wish for children. n, number of patients.

Figure 3.

Improvements of efficacy parameters in the dose-finding period and the fixed-dose extension period of treatment with mitapivat treatment in patients with SCD (intention-to-treat analysis). (A) Hb level increases were sustained over time in patients with SCD compared with baseline (n = 9 BL-W24; n = 8 W32; n = 7 at W40 and W52). (B-D) The increase in Hb level is accompanied by decreases of laboratory markers of hemolysis: (B) ARC, (C) Total bilirubin, and (D) LDH toward the upper limit of normal. (E) Five of 9 patients (56%) with SCD showed a mean increase in Hb level ≥1 g/dL in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line). (F-G) Oxygen gradient ektacytometry showed in 4 of 8 patients (50%) with SCD a mean decrease in PoS of ≥10% in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line), which indicates that initiation of RBC sickling occurs at lower PO2 levels. Notably, fixed-dose extension period data are missing for 1 patient, a week 52 visit (n = 1 patient), and 4 visits from week 24 to week 52 (n = 2 patients). (H) Treatment with mitapivat increased Hb-oxygen affinity in patients with SCD, reflected by a decreases in P50 from baseline (red) to the end of the dose-finding period (darkest blue), week 24 of the fixed-dose extension period (middle blue), and week 52 of the fixed-dose extension period (lightest blue) toward P50 values of untreated healthy controls (Ctr; gray; n = 45). (I) The ATP:2,3-DPG ratio increased upon treatment with mitapivat, also compared with untreated healthy controls (Ctr; gray; n = 40). Means are presented. Error bars represent standard errors of the mean. Dashed, gray, horizontal reference lines represent LLN, ULN or 0% change from baseline as indicated. Dashed, gray, vertical reference lines separate untreated healthy controls (on the left) with different timepoints of the treated patients (on the right). ARC, absolute reticulocyte count; BL, baseline; D56/W0, day 56 of the dose-finding period corresponding with W0 of the fixed-dose extension period; F, female; LLN, lower limit of normal; ULN, upper limit of normal; W, study visit week of the fixed-dose extension period.

Figure 4.

Changes in annualized rates of VOEs and annualized SCD-related hospital admission days (intention-to-treat, per protocol set, and strict per protocol set analyses). (A) The annualized rate of VOEs reduced significantly from 1.33 ± 1.32 to 0.64 ± 0.87 (P = .0489) in the patients with SCD treated with mitapivat when combining the study drug treatment periods of the dose-finding period and the fixed-dose extension period in the intention-to-treat analysis. In the other efficacy analyses of the fixed-dose extension period including the (strict) per protocol set analyses, also with documented compliance ≥80% in the week before the event (on the right), this trend was also seen, although nonsignificantly. (B) The annualized SCD-related hospital admission days also reduced, although nonsignificantly, in all efficacy analyses. Means are presented. Error bars represent standard errors of the mean; ∗P < .05. DFP, 8-week dose-finding period; FDEP, 1-year fixed-dose extension period; ITT, intention-to-treat; PPS, per protocol set (all patients who were dosed and had Hb and oxygen gradient ektacytometry assessments at the start of the FDEP and week 52); SPPS, strict per protocol set (all patients of the PPS who were study drug compliant).