A phase 1 trial of a retinoic acid receptor beta agonist for the treatment of spinal cord injury

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There are no effective treatments for spinal cord injuries (SCIs). We have developed a novel orally available retinoic acid receptor beta (RARb) agonist, KCL-286, that induces axonal regeneration in an adult rat model of brachial plexus avulsion (BPA). In BPAs the motor and sensory roots are severed from the spinal cord and the latter never regenerate, leaving these patients with a permanently impaired limb. KCL- 286 modulates inhibitory components of the injury induced glial scar and intrinsic neuronal programs, promoting axonal regeneration in the central nervous system (CNS) and permitting sensory recovery. The proposed project is to carry out a first in man (FIM) study, to investigate the pharmacokinetics and tolerability of single and multiple oral doses of KCL-286 with the aim to define a dose range that we predict will be efficacious based on evidence from the animal model. Target engagement will also be assessed as a surrogate measurement of KCL-286 activity, using a biomarker identified in the rat that is regulated by RARb. Additionally, a putative regeneration marker has also been identified and further studies will be carried out to validate its use as a prognostic biomarker. If successful, the phase 1 trial is intended to be followed by a small exploratory phase 2a study in male patients who experience BPA, to assess efficacy. Funds for this proof of concept (POC) study are not sought in this current application but a team of surgeons specialised in this injury has been set up in preparation for the possible forthcoming trial.BPA qualifies for orphan drug designation (ODD) for which we intend to apply. Additionally, KCL-286 will potentially have a considerably wider applicability to other CNS injuries, such as stroke, contusions and traumatic brain injuries (TBI), which could lead to valuable healthcare benefits.