outlining an additional anti-inflammatory mode of action for its lead phase IIb-stage drug candidate sonlicromanol
NIJMEGEN, the Netherlands – 13 January 2021: Khondrion, a clinical-stage biopharmaceutical company discovering and developing therapies targeting mitochondrial disease, today announces the publication of the mode of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 by sonlicromanol’s in vivo active metabolite KH176m, in the leading peer reviewed Nature journal, Scientific Reports. Sonlicromanol – Khondrion’s wholly-owned investigational lead asset which is currently in phase IIb development as a potentially disease-modifying treatment for mitochondrial disease – has already been shown to act as a potent redox modulator and ROS (reactive oxygen species)-scavenger, which are two common cellular consequences of mitochondrial diseases.
The paper, authored by Khondrion alongside scientific colleagues from the Faculty of Science, Leiden Academic Centre for Drug Research, the Netherlands, further characterises the pathology in mitochondrial complex I deficient patient-derived cells and examines the effects of KH176m in these cells.
It reports the outcome of a novel metabolomics-based screening undertaken by the team, targeted at inflammatory, oxidative and nitrosative stress markers to explore the role of oxidative stress and signaling lipids. The scientists found that levels of five interlinked prostaglandins were significantly increased in primary human skin fibroblasts from patients with mitochondrial complex I deficiencies, compared to healthy control cells. KH176m was found to selectively decrease the level of the inflammatory lipid modulator prostaglandin E2 (PGE2) in these fibroblast cells as well as in a mouse macrophage-like cell line RAW264.7.
ROS produced by defective mitochondria has attracted increasing attention because it has recently been found that this may lead not only to activation of redox-sensitive transcription factors, but also to activation of pro-inflammatory cytokines and inflammasomes. Of particular interest are potent bioactive lipids of the prostanoid family, especially PGE2.
Levels of prostaglandins, which are important lipid mediators that sustain physiological and homeostatic functions, are commonly elevated in inflamed tissues and known to induce and propagate the inflammation response. This has led researchers to explore the potential of human microsomal prostaglandin E synthase-1 (mPGES-1) – a key enzyme involved in production of PGE2 – as a promising target for the next generation of anti-inflammatory drugs, without the side effects of those currently available COX-1/2 inhibitors, e.g., non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs.
In this paper the authors describe how KH176m was found to inhibit mPGES-1 enzyme activity and transcription, reducing PGE2 production. This is of particular interest for the treatment of patients with mitochondrial diseases but may also, the authors conclude, benefit patients with other diseases associated with inflammatory pain, inflammatory neurologic diseases including Alzheimer’s disease and Parkinson’s disease, and inflammatory cancers like glioma. Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion and co-author of the paper, said: "These findings are highly encouraging and build our confidence in the potential of sonlicromanol as a novel therapeutic option for mitochondrial disease patients. Moreover, the proven anti-inflammatory effect of sonlicromanol’s active metabolite further establishes sonlicromanol as a differentiated therapeutic
modality in the mitochondrial disease segment. In summary, sonlicromanol – via its scientifically-validated triple mode of action – uniquely combines multiple mechanisms to combat the harmful cellular consequences of hampered oxidative phosphorylation in mitochondrial disease. Given the recent studies showing that mPGES-1 upregulation is found in several inflammatory diseases, we also believe further investigations into the potential of sonlicromanol or KH176m to treat inflammatory brain diseases and specific cancers are warranted.”
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