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

项目概要/摘要 CUD与谷氨酸神经传递失调有关。临床前研究表明， 通过mGlu 5受体的拮抗作用调节谷氨酸信号可以减弱可卡因 介导的药物诱导的行为，如药物寻求，自我管理，和恢复（复发） 可卡因寻求行为（34-36），支持mGlu 5受体在调节可卡因成瘾中的重要作用。 可卡因诱导的成瘾行为和mGlu 5受体拮抗剂可能是有用的， 治疗CUD。 TMP-301，一种作为本申请主题的mGluR 5负变构调节剂（NAM），已经被用于治疗糖尿病。 在健康志愿者的FIH研究中证明是安全和耐受性良好的。TMP-301显示临床前 有效性和显著减少可卡因自我给药和复发以及自愿饮酒 和正强化作用。 CUD与AUD是更普遍的形式的障碍（14-16）。因此，TMP-301可能不仅有效 在CUD患者人群中，也在更广泛的CUD伴AUD患者临床人群中。除了 非临床支持依据，mGluR 5 NAM mavoglurant II期临床研究的最新数据 在CUD患者中，可卡因使用天数和酒精使用比例显着降低， 接受mavoglurant治疗的患者相对于接受安慰剂治疗的患者的死亡天数（NCT 03242928，（27））。这些 研究结果表明，药理学负变构调节mGluR 5是一种可行的治疗方法， 调节可卡因寻求行为和预防复发的方法。尽管取得了积极的成果， 目前还没有成瘾。TMP-301有可能每天给药一次。这代表 这是TMP-301优于mavoglurant的重要优势，mavoglurant必须每天给药两次。药物 成瘾患者的依从性通常具有挑战性;因此，每天一次的方案可以显著提高 改善药物依从性。 我们建议通过额外的第一阶段测试，包括多次上升，从FIH推进TMP-301 TMP-301和可卡因在可卡因中的新制剂剂量研究和Ib期相互作用研究- 经验丰富的志愿者我们建议进行必要的毒理学研究，以允许更长的持续时间 II期和III期研究。因此，拟议的临床和临床前研究将允许TMP-301移动 II期研究。

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.