U01DA057118

TMP-301, a Negative Allosteric Modulator of Type 5 Metabotropic Glutamate Receptors (mGluR5), for Treatment of Cocaine Use Disorder - Project Summary / Abstract

Cocaine Use Disorder (CUD) is associated with dysregulated glutamate neurotransmission. Preclinical studies have shown that modulating glutamate signaling through the antagonism of the mGluR5 receptor can attenuate cocaine-mediated drug-induced behaviors, such as drug-seeking, self-administration, and reinstatement of cocaine-seeking behavior. This supports the important role of the mGluR5 receptor in the modulation of addictive behavior induced by cocaine and suggests that antagonists of the mGluR5 receptor could be useful for the treatment of CUD.

TMP-301, a mGluR5 Negative Allosteric Modulator (NAM), has been demonstrated to be safe and well-tolerated in a First-in-Human (FIH) study in healthy volunteers. In preclinical studies, TMP-301 showed efficacy by significantly reducing cocaine self-administration and relapse, as well as voluntary alcohol drinking and positive reinforcement function in an animal efficacy model. CUD with Alcohol Use Disorder (AUD) is the more prevalent form of the disorder. Therefore, 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. These findings suggest that the pharmacological negative allosteric modulation of mGluR5 is a feasible therapeutic approach to modulate cocaine-seeking behavior and prevent relapse. However, despite these positive results, mavoglurant is not currently advanced for addiction treatment.

TMP-301 has the potential to be administered once daily, which represents an important advantage 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 also 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.

Tempero Bio

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Oakland, California 94607 United States

Single Zip Code

Grand Opportunity in Medications Development for Substance-Use Disorders (U01 Clinical Trial Optional) (PAR-19-327)

Amendment Since initial award the total obligations have increased 158% from $2,060,520 to $5,310,920.