Background
Phase 3, randomized, double-blind, placebo-controlled trial (ACTIVATE). 80 patients with pyruvate kinase (PK) deficiency who were not regularly transfused (transfusion-independent adults). PK deficiency is the most common inherited erythrocyte enzyme disorder, caused by mutations in PKLR. Deficient erythrocyte PK activity leads to reduced ATP production, hemolytic anemia, and secondary complications (iron overload, gallstones, splenomegaly). Mitapivat (AG-348/Pyrukynd) is a small-molecule allosteric activator of pyruvate kinase R (PKR) isoform that increases enzyme activity and ATP production in red blood cells, correcting the metabolic defect independent of the specific PKLR mutation.
Interventions and follow up
Arm A: Mitapivat 5 mg twice daily, escalating to 20 mg twice daily if tolerated, for 24 week
Arm B: Placebo twice daily for 24 week
Primary endpoint: Hemoglobin response (≥1.5 g/dL increase from baseline sustained over ≥2 of the last 3 assessments during weeks 16–24)
mFollow up: 24 weeks (primary); 40 weeks (safety extension)
Arm B: Placebo twice daily for 24 week
Primary endpoint: Hemoglobin response (≥1.5 g/dL increase from baseline sustained over ≥2 of the last 3 assessments during weeks 16–24)
mFollow up: 24 weeks (primary); 40 weeks (safety extension)
Results
Hemoglobin response rate: 40% (mitapivat) vs 0% (placebo); P<.001
Mean Hgb change from baseline: +1.3 g/dL (mitapivat) vs −0.1 g/dL (placebo)
Patients with ≥1 g/dL Hgb increase: 57.5% vs 10.0%
Hemolytic markers (LDH, bilirubin): Significantly decreased with mitapivat
Mean Hgb change from baseline: +1.3 g/dL (mitapivat) vs −0.1 g/dL (placebo)
Patients with ≥1 g/dL Hgb increase: 57.5% vs 10.0%
Hemolytic markers (LDH, bilirubin): Significantly decreased with mitapivat
Adverse events
Main adverse events: Insomnia (40% vs 21% placebo) and nausea (33% vs 5%) were the most common mitapivat-associated AEs. Grade ≥3 AEs: 20% vs 18%. Hemolytic anemia exacerbation with abrupt discontinuation — taper required. Rebound hemolysis upon discontinuation is a key safety concern (mitapivat withdrawal must be gradual). No serious drug-related liver toxicity. Male hypogonadism (reduced testosterone) noted in some patients — mechanism under investigation.
Conclusions
Mitapivat significantly increased hemoglobin levels in transfusion-independent adult PK deficiency patients vs placebo (40% vs 0% response rate), establishing the first approved pharmacological treatment for PK deficiency.
Key Limitations
Key Limitations: Only transfusion-independent patients enrolled — ACTIVATE-T trial (regularly transfused PK deficiency) published separately (Rab 2022, NEJM) and also showed benefit. 24-week primary analysis is short for a chronic disease. Abrupt discontinuation causes rebound hemolysis — patients must be counseled to taper. The 40% response rate means the majority of patients did not achieve the primary endpoint. Patients with homozygous missense mutations (not null/splicing) had better response rates. Long-term durability and iron overload impact unclear.
Clinical Context
Mitapivat (Pyrukynd) was FDA approved for adults with PK deficiency in February 2022, becoming the first approved therapy for this rare inherited hemolytic anemia beyond supportive care (transfusions, splenectomy). ACTIVATE-T (regularly transfused PK deficiency) showed significant transfusion reduction. Mitapivat is also being studied in sickle cell disease and thalassemia (ENERGIZE trial in non-transfusion-dependent thalassemia). Genotype-based response prediction is an active area — null/null mutations respond less than missense/missense given the allosteric activation mechanism requires some residual protein to activate.
References