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

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.

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, with adaptive design to investigate the safety and pharmacokinetics (PK) of single and multiple oral doses of KCL-286. Target engagement will also be assessed as a surrogate measurement of KCL-286 activity. We have identified a putative pharmacodynamic (PD) marker: plasma tissue-type plasminogen activator (t-PA) which is known to be directly regulated by RARb activation. A regeneration marker has also been identified, S100B in plasma, that in preliminary studies, directly correlates with KCL-286 induced axonal regeneration measured at the end of treament in our animal model.
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.

Impact summary
There are currently more than 2.5 million individuals worldwide who are living with paralysis as the result of a spinal cord injury (SCI), making it a far more common ailment than many people realise. The majority of people who endure a life-changing spinal injury are young, and the effect on those afflicted can be devastating, affecting their personal prospects in a myriad of ways, from the obvious physical impairment to battles with mental health. The impact of such a condition can be far reaching, influencing the injured person's personal life and professional prospects, as well as the wider impact on family and friends.
We have developed a novel orally available RARb agonist (KCL-286) that induces axonal regeneration with functional recovery in a rodent model of spinal cord injury. This project's primary objective is to assess the safety, tolerability and pharmacokinetics of KCL-286 in heathy volunteers to enable the progression to Phase 2a study to test the human efficacy. The main deliverable will be the data on which to achieve the optimal design for the Phase 2a study and this will provide the most efficient path to proof of principal which is intended to be a small group of patients who suffered brachial plexus avulsion (BPA). A successful outcome will represent a significant breakthrough in the treatment of BPA in the shorter term and in a longer term, of other CNS injuries for which recovery is dependent on axonal regeneration and that are of high priority for global healthcare provision (other SCIs, traumatic brain injuries and stroke).
Therefore, another major impact goal of this project is the commercial exploitability of KCL-286 since its wide potential therapeutic value will be very attractive to pharmaceutical and commercial industries with specific interest in developing new drugs for the treatment of CNS regeneration.
This will have a substantial impact on clinical medicine and disease management, which will ultimately improve the economic competitiveness of healthcare in the UK as well as human health and quality of life on a global scale.