Novel mechanism for the treatment of epilepsy: New Vitamin K analogs target energetics and have low toxicity due to excellent specificity and low dose requirements compared to current therapies

 描述（由申请人提供）：癫痫是第四常见的神经系统疾病，每26人中就有1人在一生中的某个时候发生癫痫（发生一次以上的无端癫痫发作）。不幸的是，30-40%的患者患有难治性（耐药性）癫痫。因此，需要靶向替代作用机制的新的抗癫痫药物（AED）。Neuroene Therapeutics的长期目标是开发一种新的无毒治疗剂，用于难治性癫痫发作患者，以及目前AED药物产生不可接受的不良反应的患者。本STTR的目的是通过优化其血清半衰期、生物利用度和抗惊厥活性来研究新型AED的可行性。使用斑马鱼癫痫模型进行的小型靶向筛选确定了一个命中，其中心部分基于维生素K（VK），一种天然化合物。合成另外的VK类似物。主要候选药物Alkyne-VK（1）在浓度比丙戊酸低200倍时减少斑马鱼的癫痫发作（一种常见的AED），（2）在多种小鼠癫痫模型中有效，（3）当急性测试或以100 mg/kg每天IP注射三周时无毒，（4）在15分钟内迅速穿透小鼠脑，和（5）具有固有的，由于其在维持能量稳态中的作用，具有高度有效的神经保护特性。目前还没有针对能量的AED，尽管这是癫痫的主要促成因素。与目前市场上的AED相比，治疗剂量低意味着这种新疗法可能具有更少的副作用。最大的障碍是 在人类中可行的治疗是其短的血清半衰期（~1小时）。该I期研究的假设是，通过协同化学修饰和快速的体外和体内表征，将实现一种先导性的炔-VK类似物，这将被定义为一种新的可行的AED。目标1.设计和合成30-50个炔-VK类似物，并在斑马鱼癫痫模型中证实体外神经保护和体内功效。目的2：确定在小鼠中具有优异的脑渗透和保留的活性VK候选物。在该研究结束时，具有可接受的血清半衰期（>6小时）并保留其抗癫痫活性的炔-VK类似物候选物将被认为是可行的作为新一代AED。在II期研究中，将在多种癫痫小鼠模型中评价主要候选药物的抗癫痫发作疗效，并进行完整的临床前PK/PD、ADME和完整的毒理学评价，从而进行IND前备案并与FDA会面。由于30-40%的患者无法很好地控制癫痫发作，这代表了美国400万人口，不包括与当前药物相关的不良反应患者。我们预计，如果该疗法被批准用于临床，其市场价值至少为7亿美元，这是基于对AED市场37亿美元（占市场份额的20%）的保守估计。在第二阶段之后，将确定一个IND前候选者，并与南卡罗来纳州医科大学的研究开发基金会合作，寻求与制药/生物技术公司的合作伙伴关系，将治疗剂纳入人体临床试验。

 DESCRIPTION (provided by applicant): Epilepsy is the 4th most common neurological disorder, with 1 in 26 people developing epilepsy (the occurrence of more than one unprovoked seizure) at some point in their lifetime. Unfortunately, 30-40% of all patients have intractable (medication-resistant) epilepsy. Thus, new anti-epileptic drugs (AEDs) that target alternative mechanisms of action are needed. The long-term goal of Neuroene Therapeutics is to develop a new non-toxic therapeutic agent for patients with intractable seizures, and for patients who currently have unacceptable adverse effects from their current AED medication. The goal of this STTR is to examine the feasibility of a new class of AEDs by optimizing its serum half-life, bioavailability, and anticonvulsant activity. A small targeted screen using a zebrafish model of epilepsy identified one hit, with a central moiety based on Vitamin K (VK), a natural compound. Additional VK analogs were synthesized. The lead candidate, Alkyne-VK, (1) reduced seizures in zebrafish at concentrations 200-fold less than valproic acid (a common AED), (2) was effective in multiple mouse models of epilepsy, (3) was non-toxic when tested acutely or injected IP daily for three weeks at 100 mg/kg, (4) penetrates mouse brain rapidly within 15 min and (5) has inherent, highly potent neuroprotective properties, due to its role in maintaining energy homeostasis. There are currently no AEDs that target energetics, despite this being a major contributing factor for epilepsy. Having a low therapeutic dose compared to current AEDs on the market means this novel therapy is likely to have fewer side effects. The greatest barrier for this to be a feasible treatment in humans is its short serum half-life (~1 hr). The hypothesis of this Phase I study is that a lead Alkyne-VK analog will be achieved through synergistic chemical modification and rapid in vitro and in vivo characterization, which will be defined as a new feasible AED. Aim 1. Design and synthesize 30-50 Alkyne-VK analogs and confirm neuroprotection in vitro and efficacy in vivo in a zebrafish model of epilepsy. Aim 2: Define the active VK candidate that has excellent brain penetration and retention in mice. At the end of this study, an Alkyne-VK analog candidate with acceptable serum half-life (>6 hr) retaining its anti-epileptic activity will be deemed feasible as a new generation AED. In Phase II studies the lead candidate will be evaluated for its anti-seizure efficacy in multiple mouse models of epilepsy, and undergo full pre-clinical PK/PD, ADME, and full toxicology evaluation leading to a pre-IND filing and meeting with the FDA. As 30-40% of patients do not have good control of their seizures, this represents a population of 4 million in the US, not including patients with adverse effects related to their current medication. We expect the market value to be at least $700 million if the therapy is approved for clinical use, based on a conservative estimation of the AED market at $3.7 billion (20% of the market share). After Phase II, a pre-IND candidate will be identified and partnerships with Pharma/Biotech will be sought in collabration with the Foundation of Research Development at the Medical University of South Carolina, to take the therapeutic agent into human clinical trials.