Novel Biguanides to Treat Type 2 Diabetes

项目摘要 二甲双胍是治疗2型糖尿病(T2D)的最常用药物，但肾脏受损的患者 功能不能受益，因为危及生命的乳酸酸中毒的风险阻碍了它的使用。此外, 二甲双胍效力低，PK特性差，需要每天两次850 mg剂量才能达到预期效果， 重要的是，二甲双胍主要(~85%)在尿液中被消除(这对患有 肾功能受损，可能会经历药物水平的急剧上升)。一种新型还原双胍 乳酸中毒的风险对于肾脏疾病患者的T2D治疗具有巨大的潜力。 NovaTarg认识到双胍类药物的更大机会，已经合成了&gt；260新药 双胍优化二甲双胍用于肾脏疾病患者的治疗。 NovaTarg发现了一种对有机阳离子具有高亲和力的双胍(NT1195)底物 转运蛋白(特别是Oct3、OCT1和pmAt)，激活靶细胞中的AMPK。NT1195为~10倍 在小鼠口服葡萄糖耐量试验(OGTT)中比二甲双胍更有效。它有大量的 分布，表明目标组织(脂肪、骨骼肌和肝脏)的渗透率提高，并具有 -gt；在狗体内的半衰期为12小时(与人每天给药一次一致)。尿液中NT1195的消除被发现是 低(-lt；5%)，并显著低于使用二甲双胍；从而降低药物风险 肾脏疾病患者体内蓄积。 综上所述，本申请中概述的数据表明，新型双胍NT1195具有 在比二甲双胍剂量更低的情况下提高疗效的可能性，以及用更少的药物获得理想的PK曲线 从尿液中排出。NT1195的低肾脏清除率为患者提供了一定的安全水平 肾脏疾病在其他双胍类药物中没有见过。因此，NT1195具有适当的特性来提供一种治疗 约20%患有肾脏疾病的T2D患者的选择(这是目前服务较差的一组)。 本申请中描述的药物发现和开发计划突出了基于转运体的 使NovaTarg能够展示一种治疗T2D患者的药物的独特特性的方法 患有肾脏疾病。此外，早期开发活动没有暴露出药物概况中的障碍。 完成探索性IND赋能的计划正在进行中。 临床研究的启动将以NT1195的S治疗方案的详细评估为指导。 糖尿病和胰岛素抵抗的猴子。这将通过研究药物药理学和 通过与凯莉·卡瓦诺博士(维克森林)的合作获得耐受性。 对SBIR阶段2b的资助将使我们能够完成这些研究，提交探索性IND，并 执行第一阶段调查性临床研究，使我们能够展示所需的 新型双胍治疗肾功能受损患者的T2D。

Project Summary Metformin is the most prescribed drug for type 2 diabetes (T2D), but patients with impaired renal function cannot benefit because the risk of life-threatening lactic acidosis prevents its use. In addition, metformin has low potency and poor PK properties requiring 850mg doses twice daily for desired efficacy and, importantly, metformin is predominantly (~85%) eliminated in urine (creating a significant risk in patients with impaired renal function who can experience dramatically raised drug levels). A novel biguanide with reduced risk of lactic acidosis has tremendous potential for the treatment of T2D in patients with kidney disease. Recognizing greater opportunities of the biguanide drug class, NovaTarg has synthesized >260 novel biguanides to optimize metformin for use in T2D patients with kidney disease. NovaTarg has discovered a biguanide (NT1195) that is a high affinity substrate for organic cation transporters (particularly OCT3, OCT1 and PMAT) and which activates AMPK in target cells. NT1195 is ~10x more potent than metformin in mouse oral glucose tolerance tests (OGTT). It has a large volume of distribution, suggesting improved penetration of target tissues (adipose, skeletal muscle and liver) and has a half-life of >12h in dog (consistent with once daily dosing in man). NT1195 elimination in urine was found to be low (<5%) and significantly lower than that observed with metformin; thereby reducing the risk of drug accumulation in patients with kidney disease. Taken together, the data outlined in this application indicate that the novel biguanide, NT1195, has the potential for improved efficacy, at a lower dose than metformin, and a desirable PK profile with reduced drug elimination in urine. The low renal clearance of NT1195 provides a level of safety for use in patients with kidney disease not seen in other biguanides. Thus, NT1195 has the appropriate profile to provide a therapeutic option for ~20% of T2D patients with kidney disease (a group poorly served at present). The drug discovery and development plans described in this application highlight a transporter-based approach that has enabled NovaTarg to demonstrate the unique properties of a drug to treat T2D in patients with kidney disease. Further, the early development activities have not exposed impediments in the drug profile and the plan to complete an exploratory IND-enabling are on track. Initiation of clinical studies will be guided by a detailed assessment of NT1195’s therapeutic profile in diabetic and insulin resistant monkeys. This will be achieved through studies of drug pharmacology and tolerability through a collaboration with Dr Kylie Kavanaugh (Wake Forest). Funding of this SBIR Phase 2b will allow us to complete these studies, to file the exploratory IND and to perform Phase 1 investigative clinical studies that will allow us to demonstrate the desired product profile of a novel biguanide to treat T2D in patients with impaired renal function.