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

脊髓损伤(SCI)尚无有效的治疗方法。我们开发了一种新的口服维甲酸受体β(RARb)激动剂KCL-286，可以诱导成年大鼠臂丛撕脱(BPA)模型的轴突再生。在BPAS中，运动和感觉神经根从脊髓中被切断，后者永远不会再生，留下这些患者永久受损的肢体。KCL-286调节损伤诱导的胶质瘢痕和内源性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。建议的项目是进行第一次人(FIM)研究，调查KCL-286单次和多次口服的药代动力学和耐受性，目的是定义一个我们基于动物模型证据预测有效的剂量范围。靶点参与也将被评估为KCL-286活性的替代测量，使用在大鼠中识别的受RARb调节的生物标记物。此外，一个假定的再生标记也已被确定，并将进行进一步的研究，以验证其作为预后生物标记的使用。如果成功，在第一阶段试验之后，将在经历双酚A的男性患者中进行一项小型探索性2a阶段研究，以评估疗效。这项概念验证(POC)研究在目前的申请中没有寻求资金，但已经建立了一个专门处理这种损伤的外科医生团队，为可能的即将到来的试验做准备。BPA有资格获得我们打算申请的孤儿药物指定(ODD)。此外，KCL-286可能对其他中枢神经系统损伤具有相当广泛的适用性，如中风、挫伤和创伤性脑损伤(TBI)，这可能会带来宝贵的医疗好处。

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.