Goncalves, MB;
Mant, T;
Täubel, J;
Clarke, E;
Hassanin, H;
Bendel, D;
Fok, H;
Posner, J;
Holmes, J;
Mander, AP;
et al.
Goncalves, MB; Mant, T; Täubel, J; Clarke, E; Hassanin, H; Bendel, D; Fok, H; Posner, J; Holmes, J; Mander, AP; Corcoran, JPT
(2023)
Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286, a novel retinoic acid receptor-β agonist for treatment of spinal cord injury, in male healthy participants.
Br J Clin Pharmacol, 89 (12).
pp. 3573-3583.
ISSN 1365-2125
https://doi.org/10.1111/bcp.15854
SGUL Authors: Taubel, Jorg
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Abstract
AIMS: KCL-286 is an orally available agonist taht activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population. METHODS: The design was a double blind, randomized, placebo-controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. RESULTS: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration-time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. CONCLUSION: KCL-286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL-286 as a novel oral treatment for SCI.
Item Type: | Article | ||||||||
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Additional Information: | © 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | ||||||||
Keywords: | KCL-286, RARβ agonist, pharmacokinetics, safety, spinal cord injury, target engagement, 1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||
Journal or Publication Title: | Br J Clin Pharmacol | ||||||||
ISSN: | 1365-2125 | ||||||||
Language: | eng | ||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||
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PubMed ID: | 37452623 | ||||||||
Go to PubMed abstract | |||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/115615 | ||||||||
Publisher's version: | https://doi.org/10.1111/bcp.15854 |
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