Vatiquinone (EPI-743) is an investigational, oral, first-in-class 15-lipoxygenase inhibitor being developed for the treatment of patients with Friedreich’s ataxia (FA). Here, we report long-term results of vatiquinone treatment in patients with FA from the MOVE-FA extension study (36 months) and Study EPI-2010-006 (24 months), compared with matched natural history cohorts from FACOMS (Friedreich Ataxia Clinical Outcome Measures). MOVE-FA (NCT04577352) was a global phase 3 study of vatiquinone in patients with FA aged ≥ 7 years (N = 143; mean age: 18.7 years); participants who completed MOVE-FA were eligible to rollover into the long-term extension (NCT05515536). EPI-2010-006 (NCT01728064) was a phase 2 study of vatiquinone in adult patients with FA ≥ 18 years (N = 63; mean age: 28.9 years). The pre-specified primary endpoint for these analyses was the modified Friedreich’s Ataxia Rating Scale (mFARS). After 36 months in the MOVE-FA long-term extension study, participants in the vatiquinone treatment group demonstrated a 3.75-point increase in mFARS. The matched FACOMS cohort progressed by 7.48 points over the same period. Vatiquinone treatment resulted in a 3.7-point benefit (p < 0.0001, n = 70) in mFARS relative to FACOMS, representing a clinically meaningful 50% slowing of disease progression over 3 years. Following 24-months of treatment with vatiquinone in EPI-2010-006, participants demonstrated a 0.92-point decrease in mFARS while participants in the matched FACOMS cohort progressed by 3.89 points. This resulted in a 4.8-point treatment benefit (p < 0.0001, n = 41), consistent with a 2-year delay in progression. The results of the extension studies provide further evidence of the potential benefit of vatiquinone for the treatment of FA. The pre-specified endpoints for two different long-term extension studies were met, with highly statistically significant evidence of durable treatment benefit in slowing disease progression in paediatric and adult patients.