First‐In‐Human, Single Ascending Dose and Food‐Effect Study in Healthy Volunteers of SUL‐238, a Novel Orally Administered Mitochondria‐Directed Drug Candidate

Background: There is compelling evidence that mitochondrial dysfunction may be crucial in the pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). SUL‐238 is a novel, investigational small molecule which improves mitochondrial function in animal models. Its oral administration (partially) restores AD‐associated changes in protein expression in an AD mouse model and results in a significant reduction in amyloid plaque size/accumulation, enhancement of synaptic transmission and improved memory performance. These findings indicate that modulating mitochondrial metabolism by SUL‐238 may provide a promising approach for treatment of AD. Method: This was a single, oral ascending dose (SAD) Phase 1, first‐in‐human, randomized, double‐blind, placebo‐controlled study conducted in healthy adults (ClinicalTrials.gov identifier, NCT06277492). Part 1 included 6 cohorts (50, 100, 250, 500, 1000 and 2000 mg orally, n=23). In part 2, pharmacokinetics (PK) of a single 1000 mg oral dose was investigated in 10 healthy adults. In Part 2B, food effect was assessed using a randomized, single oral 2000 mg dose, two‐treatment, two‐period, crossover design (n=20). The primary objectives were assessment of safety, tolerability, and PK. Cerebrospinal fluid (CSF)‐to‐plasma concentration percentage was determined in the SAD and food effect parts. Result: There were no adverse effects (AEs) that precluded dose escalation, AE rates were comparable between participants receiving SUL‐238 and placebo. All AEs were mild or moderate in severity. Mean t 1/2 ranged between 0.86‐3.80 hours and mean T max ranged between 0.50‐1.39 hours. Under fed condition there was a 50% reduction in C max and a 60% reduction in AUC 0‐inf as compared to fasting condition. The mean CSF‐to‐plasma percentages at 2‐ and 8‐hours post‐dose were 21.1% and 74.2%, respectively. Conclusion: In this Phase 1, first‐in‐human, healthy volunteer study, 50‐2000 mg single oral doses of SUL‐238 were safe and well‐tolerated, while demonstrating a favourable PK profile, and a high CSF penetration.