Phase II clinical evaluation of Omnitram in neuropathic pain

 描述(申请人提供)：神经性疼痛是由周围神经损伤引起的，如糖尿病神经病变。神经性疼痛很难治疗，许多患者的疼痛是现有治疗方法难以治愈的。奥美尼兰是Syntrix公司开发的一种新型混合机制止痛药，由O-去甲基曲马多的(-)和()对映体组成。()-对映体是一种有效的阿片受体激动剂，而(-)-对映体是一种与()-对映体协同的去甲肾上腺素再摄取抑制剂。Omnitram本质上是一种节省阿片类药物的阿片类药物-佐剂联合疗法，预计滥用潜力较低。O-脱甲基曲马多是曲马多的主要代谢物(M1)。奥美尼兰提供与曲马多相同的净药理作用，但与曲马多相反，它的活性不需要细胞色素P450 2D6(CYP2D6)的代谢(即它不依赖新陈代谢)。代谢不良者(PM)不能从曲马多获得止痛效果。在接受多种药物治疗的患者中，CYP2D6 PM状态的“真实世界”发生率高达三分之一。因此，Omnitram是开发一种“改进的曲马多”的机会，这种药物对所有患者都有效，无论他们的CYP2D6代谢状态如何。Omnitram成功地完成了1b期随机、双盲、安慰剂对照试验，证明在健康受试者的实验性疼痛模型中，Omnitram与安慰剂相比具有显著的止痛作用。这一快速通道应用旨在通过展示对患有糖尿病神经病变所致神经病理性疼痛的患者的止痛效果，进一步推动Omnitram计划的成功。Cochrane的一项系统评价得出结论，曲马多是一种有效的神经病理性疼痛治疗方法，其疗效与报道的抗抑郁和抗惊厥药物相似。奥美尼兰提供与曲马多相同的净药理，因此被预测在治疗神经病理性疼痛方面有效。

 DESCRIPTION (provided by applicant): Neuropathic pain is caused by damage to the peripheral nerves, as occurs in diabetic neuropathy. Neuropathic pain is difficult to treat, and many patients have pain that is refractory to existing treatments. Omnitram is a novel mixed-mechanism analgesic developed by Syntrix that consists of the (-) and (+) enantiomers of O-desmethyltramadol. The (+)-enantiomer is a potent µ-opioid receptor agonist, while the (-)- enantiomer is a norepinephrine reuptake inhibitor that synergizes with the (+)-enantiomer. Omnitram is inherently an opioid-sparing opioid-adjuvant combination therapy that is predicted to have low abuse potential. O-desmethyltramadol is the primary metabolite (M1) of tramadol. Omnitram provides the same net pharmacology as tramadol, but in contrast to tramadol, does not require metabolism by cytochrome P450 2D6 (CYP2D6) for its activity (i.e. it is metabolism-independent). Individuals who are CYP2D6 poor metabolizers (PMs) fail to obtain pain relief from tramadol. The "real world" incidence of CYP2D6 PM status in patients on polypharmacotherapy is as high as 1 in 3. Omnitram is therefore an opportunity to develop an "improved tramadol" that is effective in all patients irrespective of their CYP2D6 metabolic status. Omnitram successfully completed a Phase 1b randomized, double-blind, placebo-controlled trial that demonstrated Omnitram provided significant analgesia compared to placebo in an experimental pain model in healthy subjects. This Fast-Track application aims to further the success of the Omnitram program by demonstrating analgesic efficacy in patients suffering from neuropathic pain due to diabetic neuropathy. A Cochrane systematic review concluded that tramadol is an effective treatment for neuropathic pain with efficacy similar to that reported for antidepressants and anticonvulsants. Omnitram provides the same net pharmacology as tramadol and is therefore predicted to be efficacious in treating neuropathic pain.