Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency

Abstract

Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).

Graphical abstract

Figure 1.

Pathophysiology of iron overload in PK deficiency. 1, Adapted from Grootendorst et al; 2, adapted from Zaninoni et al; 3, adapted from van Vuren et al; 4, adapted from Finkenstedt et al; 5, adapted from Gupta et al; 6, adapted from Coffey and Ganz. EPO, erythropoietin.

Figure 2.

ACTIVATE/LTE study design. Key eligibility criteria: (1) age of ≥18 years; (2) documented 2 mutant alleles in PKLR with 1 missense mutation (excluding patients homozygous for R479H mutation or who have 2 nonmissense mutations, without another missense mutation); (3) ACTIVATE: not regularly transfused (≤4 transfusion episodes in the previous year); baseline hemoglobin of ≤10 g/dL; (4) LTE study: completed the fixed-dose period of ACTIVATE and demonstrated clinical benefit from mitapivat treatment, or were assigned to the placebo arm in ACTIVATE and elected to continue to the LTE study. ∗Stratified by average of screening hemoglobin values (<8.5 g/dL vs ≥8.5 g/dL) and PKLR gene mutation category (missense/missense vs missense/nonmissense). BID, twice daily; R, randomized.

Figure 3.

Changes from baseline in markers of iron homeostasis with treatment with mitapivat in the ACTIVATE/LTE trial. (A) Hepcidin, (B) erythroferrone, (C) sTfR, (D) LIC by MRI, (E) erythropoietin, and (F) reticulocyte percentage. The baseline for LIC by MRI is defined as the last assessment before randomization for patients randomized and not dosed, or the last assessment before the start of study treatment for patients randomized and dosed. The baseline for the other parameters is defined as the average of all screening assessments within 45 (42 + 3) days before randomization for patients randomized and not dosed, or before the start of study treatment for patients randomized and dosed. Assessments collected within 61 days after a transfusion were excluded from the baseline derivation. n is the number of patients in the full analysis set within each treatment group who had an assessment at the visit or who (for the summaries of change from baseline) had a baseline assessment and ≥1 postbaseline assessment at the visit. 95% CI was calculated based on t-distribution. BL, baseline.

Figure 4.

Pooled change from baseline in LIC after treatment with mitapivat in patients with baseline iron overload. Patients were considered to have iron overload at baseline if they met at least 1 of 3 criteria: baseline ferritin of >1000 μg/L, baseline LIC of >3 mg Fe/g dw, and/or chelation therapy within the last year before start of treatment with mitapivat. The baseline for LIC by MRI is defined as the last assessment before randomization for patients randomized and not dosed, or the last assessment before the start of study treatment for patients randomized and dosed. BL, baseline.