Abstract
With ongoing global research efforts to tackle coronavirus disease 2019 (COVID-19), increasing attention is directed toward the long-term sequelae of COVID, entitled “long COVID” or post-acute sequelae of COVID-19. These long-COVID symptoms persist beyond 12 weeks in over 10%–40% of patients, with exertional fatigue predominant in at least 50%. Scientific evidence has linked long COVID fatigue with mitochondrial dysfunction and energetic dysregulation in multiple biological pathways. Single target-directed treatments could be insufficient to treat these heterogeneous disorders. A novel multi-targeted therapeutic strategy could better address long COVID fatigue by restoring mitochondrial function. Our systems biology platform identified mechanisms implicated in long COVID and prioritized the composition of endogenous metabolic modulators focused on amino acid combinations, related precursors, and metabolites with the potential to address mitochondrial dysfunction. AXA1125 is a novel composition of five amino acids (Leucine, Isoleucine, Valine, Arginine, and Glutamine) and an amino acid derivative (N-acetylcysteine) that could safely target multifactorial disease pathophysiology of fatigue-dominant long COVID. Our phase IIa, double-blind, randomized trial (NCT05152849) in exertional fatigue patients associated with long COVID interrogated this proposition and showed promising results. We hypothesize that AXA1125 holds the potential for improving functional clinical outcomes by targeting multiple disease pathways and improving mitochondrial function and energetics.