Mitapivat increases Hb levels in patients with pyruvate kinase deficiency

The use of mitapivat increased haemoglobin (Hb) levels in patients with pyruvate kinase deficiency (PKD) who did not receive any regular blood transfusions, according to the ACTIVATE* study.

This multicentre, double-blind, phase III trial involved 80 patients with PKD who had no history of any regular red-cell transfusions. The participants were randomly assigned to receive either oral mitapivat 5 mg twice/day, with a potential increase of up to 20 or 50 mg dosing (n=40; mean age 36 years, mean Hb level 8.6 g/dL), or placebo (n=40; mean age 37 years, mean Hb level 8.5 g/dL) for a 24-week treatment period (dose-escalation period [weeks 1–12] and fixed-dose period [weeks 13–24]). [N Engl J Med 2022;386:1432-1442]

Overall, 40.0 percent of the patients treated with mitapivat achieved an Hb response, which was defined as an increase of ≥1.5 g/dL in Hb level from baseline, compared with none of the patients treated with placebo (two-sided p<0.001).

At weeks 16, 20, and 24, patients in the mitapivat arm demonstrated a significantly greater response in terms of the average change in Hb level than those in the placebo arm (least-squares mean change from baseline, 1.7 vs -0.1 g/dL; p<0.001).

Mitapivat recipients also achieved improvements from baseline compared with placebo recipients with regard to clinical markers of haemolysis such as indirect bilirubin (-21.2 vs 5.1 µmol/L; p<0.001), lactate dehydrogenase (-92.0 vs -21.2 units/L; p=0.003), and haptoglobin levels (0.17 vs 0.01 g/L; p=0.008).

Patients who received mitapivat also had significantly greater improvements from baseline in PKDD** and PKDIA*** scores, indicating a reduced disease burden, compared with those who received placebo (-5.2 vs -2.1; p=0.02 and -4.7 vs -1.4; p=0.04, respectively).

Of note, all responses and improvements were both early and sustained with mitapivat treatment, the researchers said.

The most common adverse events (AEs) reported in the mitapivat vs the placebo arm were nausea (18.0 percent vs 23.0 percent) and headache (15.0 percent vs 33.0 percent).

Grade ≥3 AEs occurred at a higher rate in the mitapivat arm than in the placebo arm (25.0 percent vs 13.0 percent) but did not lead to death or treatment discontinuation. This result was consistent with that observed in a previous study with no new safety signals identified, noted the researchers.

“These results confirm that mitapivat … significantly increased Hb levels and improved haemolysis, haematopoiesis, and measures of health-related quality of life in a substantial minority of this patient population [with PKD] by specifically targeting the underlying enzymatic defect,” said the researchers.

“[Furthermore,] mitapivat appeared to be a disease-modifying pharmacotherapy for the management of PKD,” they added.

*ACTIVATE: A study to evaluate the efficacy and safety of AG-348 in not regularly transfused adult participants with pyruvate kinase deficiency

**PKDD: Pyruvate kinase deficiency diary