DISCUSSION
nerve injuries, dry irritated, axonal regenerationThe TEAEs, SAD
MINOR
The treatment of nerve injuries including SCI is a major unmet clinical need as there are no therapies that can lead to axonal regeneration and functional recovery. RARβ2 activation is an attractive target to treat an SCI, as it is a neuronal located transcription factor that has multiple effects on pathways involved in axonal regenerationThe TEAEs observed are consistent with the known clinical safety of oral retinoids, such as bexarotene, acitretin, isotretinoin and alitretinoin, where it has been shown that they cause dry irritated and peeling skin, which once drug administration is stopped is fully reversible.The highest dose achieved in both the SAD and MAD cohorts was 100 mg, which surpasses the anticipated desired pharmacological exposures in the rat efficacy model.Concentrations of KCL‐286 were not measured in cerebrospinal fluid in this trial as concentrations in cerebrospinal fluid are a poor indicator of CNS penetranceRenal clearance of unchanged KCL‐286 is a minor elimination process. This may be due to a formation of other metabolites although in our preclinical studies of the potential for KCL‐286 (2 μM, 0.669 μg/mL) to be metabolized by a wide range of recombinant human cytochrome and UDP glucuronosyltransferases only CYP1A2 and UGT1A1 were found to metabolize KCL‐286 to an appreciable extent. Nevertheless, as KCL‐286 development advances in the clinic the identification of KCL 286 metabolites will be determined to confirm these findings.Given that healthy volunteers were assessed in this study, CNS tissue could not be obtained to assess RARβ2 expression, so WBCs were used instead. The increase in RARβ2 expression does show that the drug engages its receptor. How much activation is required to elicit an effect in the injured nerve tissue is not known, but exposure has been achieved in the human healthy participants, which exceeds exposure in the injured rat to give a pharmacological response, suggesting that a clinical effect can be achieved in nerve injured patients. In addition, since a ceiling of RARβ2 expression was not achieved, it is possible that higher exposure may give a better therapeutic outcome.The accumulation of the retinoid within the cell