Sonlicromanol (KH176) is a clinical-stage oral drug compound developed by Khondrion as a potential treatment for primary and secondary mitochondrial diseases, such as Leigh's Disease, MELAS and LHON. Due to dysfunctional mitochondria, an increased level of cellular reactive oxygen species (ROS) is observed in these patients, causing a wide range of symptoms. The active metabolite of Sonlicromanol (KH176m, or KH183) has several mechanisms of action, acting both as antioxidant and as reactive oxygen species (ROS)-redox modulator. Through selective suppression of microsomal prostaglandin E synthase-1 (mPGES-1), Sonlicromanol even has potency as anti-cancer drug for mPGES-1 overexpressing cancer like prostate cancer. Sonlicromanol has been evaluated in phase II clinical trials in the KHENERGYZE, KHENEREXT and KHENERGYC studies as potent candidate in treatment for mitochondrial diseases and results have been published. Specifically, sonlicromanol showed meaningful improvements on key symptoms associated with mitochondrial diseases. A phase 3 trial in patients with the m.3243A>G variant has started recruitment (KHENERFIN). Also, a Long COVID proof-of-concept trial has started recruitment.
Medical use Sonlicromanol was principally developed as drug to release symptoms for patients with mitochondrial diseases like Leigh's disease, MELAS (Mitochondrial, Encephalomyopathy, Lactic acidosis, and Stroke-like episodes) spectrum disorders, and LHON (Leber's Hereditary Optic Neuropathy). Signs of these mitochondrial diseases include fatigue, loss of muscle strength and coordination, cognitive impairment, migraine, heart failure, diabetes, and stunted growth. These signs are the consequence of impairment in one of the five complexes forming the oxidative phosphorylation system, localized on the mitochondrial inner membrane. Disruption in the mitochondrial redox balance results in increased cellular oxidative stress due to increased levels of ROS. Especially superoxide and hydrogen peroxide levels are elevated with mitochondrial dysfunction, which triggers inflammation. In addition to mitochondrial diseases, Sonlicromanol was also found to be potentially useful as an anti-cancer drug. Only mPGES-1 overexpressing cancer like prostate cancer can possibly be treated with Sonlicromanol. Future research will have to prove whether Sonlicromanol is indeed applicable in this field.
History In vitro and in vivo animal studies showed promising pharmacokinetic and safety profiles for Sonlicromanol., allowing for randomized, placebo-controlled, double blind phase 1 clinical trials, performed in healthy male volunteers. This first human in vivo study was performed starting in 2015 and the results were published in 2017. The results of the exploratory phase IIA trial, the KHENERGY study, were published in 2019. This study included a single-center, double-blinded, randomized, placebo-controlled 2-way crossover trial, during which patients received 100 mg Sonlicromanol and placebo in random order, both for 28 days. Currently, three phase II trials are in progress. In the KHENERGYZE study, patients receive 50 mg Sonlicromanol, 100 mg Sonlicromanol and a placebo, all for 28 days in random order. Both dose-finding and efficacy assessment are aims of this study, which is planned to be completed in May 2022. KHENEREXT is the follow-up study, which is an open-label, multi-center trial, during which patients receive either 50 or 100 mg of Sonlicromanol twice a day for an entire year to explore the long-term safety and efficacy. Lastly, the KHENERGYC study is in progress, which aims to reveal the safety, efficacy and pharmacokinetics in children
Synthesis & Structure The water-soluble form of vitamin E (Trolox) and Trolox-derived antioxidants were found to be promising mitochondrial disease drug candidates. To further investigate these properties, Khondrion synthesized 226 compounds through modification of the side chain on the carboxyl moiety while conserving the chromanyl group, thereby conserving the antioxidant capacity. The ability to scavenge cellular ROS and to protect patient-derived cells from redox perturbation were tested on mitochondrial patient cells. The calculated IC50 values from the ROS assay and the EC50 values from the Redox Stress Survival assay for all screened compounds showed that KH176 (Sonlicromanol) had the best overall performance in terms of properties such as potency, stability, water solubility, oral bioavailability, blood-brain barrier permeability and metabolism. For all research, the (S,R) stereoisomer of Sonlicromanol is used.
Metabolism The most important metabolite of Sonlicromanol is formed via biotransformation catalysed by cytochrome P450 3A4, which leads to the active metabolite KH176m (KH183). A total of 20 metabolites of Sonlicromanol were found in humans and animals, most of which result from oxidation, hydration and glucuronidation. The extent of metabolism in vitro was rather low: only 2-15% of the parent compound was metabolized after 120 minutes. In vivo, however, on average 83% was converted to KH176m after 4 weeks of dosing.
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