TMP-301, A Negative Allosteric Modulator of type 5 metabotropic glutamate receptors (mGluR5), for Treatment of Cocaine Use Disorder

项目摘要/摘要 CUD与谷氨酸神经传递失调有关。临床前研究表明， 通过拮抗mGlu5受体调节谷氨酸信号可以减弱可卡因 中介的药物诱导行为，如寻求药物、自我给药和恢复(复发) 可卡因寻找行为(34-36)，支持mGlu5受体在调节 可卡因诱导成瘾行为和mGlu5受体拮抗剂可能对 CUD的治疗。 TMP-301，一种mGluR5负变构调节剂(NAM)，是本申请的主题，已经 在FIH的一项健康志愿者研究中证明了该药的安全性和耐受性。TMP-301显示临床前 疗效和显著减少可卡因自我给药和复发以及自愿饮酒 以及在动物功效模型中的正强化作用。 伴有AUD的CUD是更常见的疾病形式(14-16)。因此，TMP-301可能不仅有效 在CUD患者的人群中，也在更广泛的CUD与AUD患者的临床人群中。除了……之外 MGluR5 NAM Mavoglurant第二期临床研究的非临床支持原理和最新数据 在CUD患者中，可卡因使用天数和酒精使用的比例显著减少 接受Mavoglurant治疗的患者的天数与接受安慰剂的患者相比(NCT03242928，(27))。这些 结果提示，mGluR5的药理负变构调节是一种可行的治疗方法 调节可卡因寻觅行为和防止复发的方法。尽管有积极的结果，mavoglurant是 目前没有达到上瘾的程度。TMP-301有可能每天给药一次。这代表了 TMP-301与mavoglurant相比有一个重要的优势，mavoglurant每天必须给药两次。用药 成瘾患者的坚持通常是具有挑战性的；因此，每天一次的养生法可能会显著 提高服药依从性。 我们建议通过额外的第一阶段测试来推进FIH的TMP-301，包括多次提升 TMP-301和可卡因在可卡因中的新配方剂量研究和Ib相相互作用研究 经验丰富的志愿者。我们建议进行必要的毒理学研究，以便进行更长的持续时间 第二阶段和第三阶段的研究。因此，拟议的临床和临床前研究将允许TMP-301 至第二阶段研究。

Project Summary / Abstract CUD is associated with dysregulated glutamate neurotransmission. Preclinical studies indicate that the modulation of glutamate signaling through the antagonism of the mGlu5 receptor can attenuate cocaine mediated drug-induced behaviors such as drug-seeking, self-administration, and reinstatement (relapse) of cocaine-seeking behavior (34-36), supporting an important role for the mGlu5 receptor in the modulation of addictive behavior induced by cocaine and that antagonists of the mGlu5 receptor could be useful for the treatment of CUD. TMP-301, a mGluR5 negative allosteric modulator (NAM) that is the subject of this application, has been demonstrated to be safe and well-tolerated in a FIH study in healthy volunteers. TMP-301 showed preclinical efficacy and significantly reduced cocaine self-administration and relapse as well as voluntary alcohol drinking and positive reinforcement function in an animal efficacy model. CUD with AUD is the more prevalent form of the disorder (14-16). Thus, TMP-301 may not only be efficacious in a population of CUD patients but also in a broader clinical population of CUD with AUD patients. In addition to the nonclinical supporting rationale, recent data from a Phase 2 clinical study of the mGluR5 NAM mavoglurant in patients with CUD demonstrated a significant reduction in the proportion of cocaine use days and alcohol use days in patients receiving mavoglurant relative to patients receiving placebo (NCT03242928, (27)). These findings suggest that the pharmacological negative allosteric modulation of mGluR5 is a feasible therapeutic approach to modulate cocaine-seeking behavior and prevent relapse. Despite positive results, mavoglurant is not currently advanced for addiction. TMP-301 has the potential to be administered once daily. This represents an important advantage for TMP-301 over mavoglurant, which must be administered twice daily. Medication adherence among addiction patients is often challenging; therefore, a once-daily regimen could significantly improve medication adherence. We propose advancing TMP-301 from FIH through additional Phase I testing, including a Multiple Ascending Dose study with a new formulation and a Phase Ib Interaction study of TMP-301 and cocaine in cocaine- experienced volunteers. We propose performing the necessary toxicology studies to allow for longer duration studies in Phase II and Phase III. Thus, the clinical and preclinical studies proposed will allow TMP-301 to move to Phase II studies.