Safety, tolerability and toxicokinetics of the novel mitochondrial drug SUL-138 administered orally to rat and minipig.

Noncommunicable Chronic Diseases (NCD) are a socioeconomic burden and considered one of the major health challenges for coming decades. Mitochondrial dysfunction has been implicated mechanistically in their pathophysiology. Therefore, targeting mitochondria holds great promise to improve clinical outcomes in NCDs. SUL-138, an orally bioavailable small molecule efficacious from 0.5 mg/kg, improves mitochondrial function during disease in several preclinical animal models. As preparation for a First-in-Human (FIH) trial, SUL-138 was investigated in 30-day GLP repeated dose toxicity studies in rat and minipig, selected based on their comparability with human metabolism, to determine toxicokinetics, potential toxicity and its reversibility. Rats were allocated to either vehicle, 27, 136 or 682 mg/kg SUL-138 dose groups and minipigs were allocated to either vehicle, 16, 82 or 409 mg/kg. Treatment occurred orally for 30 days followed by a recovery period of 14 days. During these studies clinical observations, toxicokinetic, clinical pathology, necropsy and histopathology evaluations were performed. There was significant systemic exposure to SUL-138 and toxicokinetics was characterized by a rapid absorption and elimination. In the rat, toxicokinetics was dose-proportional and AUC

© 2024 The Authors.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.H. Swart is Chief of Operations, M. de Haan is senior consulting toxicologist, S. Adel is research technician, A.C. van der Graaf is Chief Executive Officer, G. Krenning is Chief Scientific Officer at Sulfateq B.V. (Groningen, The Netherlands) a company that owns patents on SUL-138 and funded the presented study. R.H. Henning chairs the Scientific Advisory Board of Sulfateq B.V. N. Ulu is Vice President R&D and Clinical Operations at Gen İlaç ve Sağlık Ürünleri A.Ş. (Ankara, Turkey) a company which is license-holder for the use of SUL-138 as a therapeutic for neurodegenerative disease.