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

TMP-301，5 型代谢型谷氨酸受体 (mGluR5) 的负变构调节剂，用于治疗可卡因使用障碍

• 批准号: 10688133
• 负责人: Charles Daniel Meyers
• 金额: $ 325.04万
• 依托单位: TEMPERO BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688133
• 关键词: Abstinence; Addictive Behavior; Affect; Alcohol consumption; Alcohols; Attenuated; Behavior; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine use disorder; Cues; Data; Development; Disease; Dose; FDA approved; Formulation; GRM5 gene; Glutamates; Human Volunteers; Marketing; Mediating; Metabotropic Glutamate Receptors; Modafinil; Modeling; Naltrexone; National Institute of Drug Abuse; Oral Administration; Outpatients; Patients; Performance; Pharmaceutical Preparations; Phase; Placebos; Population; Positive Reinforcements; Prevalence; Procedures; Program Development; Public Health; Regimen; Regulation; Relapse; Reporting; Research; Research Personnel; Rodent; Rodent Model; Role; Screening procedure; Self Administration; Self Stimulation; Signal Transduction; Substance Use Disorder; Testing; Therapeutic; Time; Toxicology; United States; United States Food and Drug Administration; Wistar Rats; addiction; alcohol seeking behavior; alcohol use disorder; animal efficacy; antagonist; clinical efficacy; clinically significant; cocaine exposure; cocaine seeking; cocaine self-administration; cocaine use; craving; drug discrimination; drug induced behavior; effective therapy; efficacy outcomes; experience; glutamatergic signaling; healthy volunteer; improved; inhibitor; medication compliance; metabotropic glutamate receptor 5; neurotransmission; nonhuman primate; novel therapeutics; pharmacologic; phase 1 study; phase 1 testing; phase 2 study; placebo group; preclinical efficacy; preclinical study; programs; receptor; relapse prevention; volunteer

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.

项目摘要/摘要