Ther Adv Rare Dis. 2026 Jan-Dec;7:7
26330040261473291
Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.
Keywords: clinical trial; drug development; mitochondrial disease; rare disease