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

脊髓损伤（SCIs）没有有效的治疗方法。我们开发了一种新的口服维甲酸受体（RARb）激动剂KCL-286，可诱导成年大鼠臂丛撕脱伤（BPA）模型的轴突再生。在双酚a中，运动和感觉根与脊髓分离，后者永远不会再生，使这些患者的肢体永久性受损。KCL- 286调节损伤诱导的胶质瘢痕和内在神经元程序的抑制成分，促进中枢神经系统（CNS）的轴突再生并允许感觉恢复。本项目拟开展首次人体（FIM）研究，研究单次和多次口服KCL-286的药代动力学和耐受性，目的是根据动物模型的证据确定我们预测有效的剂量范围。靶标接触也将被评估为KCL-286活性的替代测量，使用在大鼠中鉴定的由RARb调节的生物标志物。此外，一个假定的再生标志物也已被确定，并将进行进一步的研究来验证其作为预后生物标志物的用途。如果成功，第一阶段的试验将在经历BPA的男性患者中进行一项小规模的2a期探索性研究，以评估其疗效。目前的申请并没有为这个概念验证（POC）研究寻求资金，但是已经成立了一个专门研究这种损伤的外科医生团队，为可能即将到来的试验做准备。BPA符合我们打算申请的孤儿药认定（ODD）。此外，KCL-286可能对其他中枢神经系统损伤有更广泛的适用性，如中风、挫伤和创伤性脑损伤（TBI），这可能会带来宝贵的医疗效益。

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.