Comment from Ruth McCrea

Mitapivat (Pyrukynd) for Long COVID An approved oral activator of cellular energy metabolism | For FDA repurposing / advisory review The opportunity Post-exertional fatigue in Long COVID is tied to energetic stress and impaired ATP production, and mitapivat is an approved oral drug that directly raises ATP at the enzymatic level. The mechanism targets the energy deficit Mitapivat (Pyrukynd) is a first-in-class oral allosteric activator of pyruvate kinase that enhances glycolytic flux and increases ATP production [1] — acting on the same energy-metabolism failure seen in these patients. The target is documented Ultra-high-field (7T) MRS studies show energetic stress and mitochondrial dysfunction — elevated lactate — in ME/CFS and Long COVID [2], and red cells depend entirely on glycolysis for ATP, with pyruvate kinase as the rate-limiting step [1]. The precedent is solid Mitapivat is FDA-approved for pyruvate kinase deficiency (ACTIVATE Phase 3) with sustained benefit, and shows positive results across thalassemia and sickle cell disease [1,3] — a proven, well-tolerated oral metabolic drug. The ask A biomarker-gated trial in energy-impaired Long COVID. The molecule is approved and well-characterized; it has simply never been tested for this purpose. Sources 1. Mitapivat (Pyrukynd, AG-348): oral PKR activator increasing ATP; FDA-approved for pyruvate kinase deficiency (ACTIVATE, NEJM 2022). 2. Brain and muscle 7T MRS in ME/CFS and Long COVID: energetic stress and elevated lactate. 2025. 3. Mitapivat in sickle cell disease and thalassemia: long-term safety and efficacy (ASH/Blood; clinical trials).