Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation

Mitochondrial disease incorporates a group of rare conditions with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This phase 2b program, aimed at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100 or 50 mg sonlicromanol or placebo twice daily (bid) for 28 days with a ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study, wherein they received 100 mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). Fifteen patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier phase 2a study. The RCT primary end point [change from placebo in the attentional domain of the cognition score (visual identification; Cogstate IDN)] did not reach statistical significance. Using a categorization of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (P = 0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, P = 0.0143), Cognitive Failure Questionnaire (P = 0.0113) and the depression subscale of the Hospital Anxiety and Depression Scale (P = 0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study [Test of Attentional Performance (TAP) with alarm, P = 0.0102; TAP without alarm, P = 0.0047; BDI somatic, P = 0.0261; BDI total, P = 0.0563; SF12 physical component score, P = 0.0008]. Seven of nine domains of RAND-Short Form-36-like SF-36 pain improved (P = 0.0105). Other promising results were observed in the Neuro-Quality of Life Short Form-Fatigue Scale (P = 0.0036), mini-Balance Evaluation Systems test (P = 0.0009), McGill Pain Questionnaire (P = 0.0105), EuroQol EQ-5D-5L-Visual Analog Scale (P = 0.0213) and EQ-5D-5L-Index (P = 0.0173). Most patients showed improvement in the Five Times Sit-To-Stand Test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to 1 year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.