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35th AM (2025) - Poster Session
Safety, Pharmacokinetics, and Receptor Occupancy o ...
Safety, Pharmacokinetics, and Receptor Occupancy of TMP-301, for the Treatment of SUDs
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This research evaluates TMP-301, a selective negative allosteric modulator (NAM) of the metabotropic glutamate receptor 5 (mGluR5), as a potential treatment for substance use disorders (SUDs). SUDs affect millions in the U.S., and current medications are limited in efficacy and have notable side effects. mGluR5 plays a key role in addiction-related brain circuitry by translating excessive dopamine release in the nucleus accumbens into dysphoria, anxiety, and cravings that drive relapse. Targeting mGluR5 offers a validated approach addressing substance use, craving, and associated mood symptoms.<br /><br />This Phase 1 clinical program included single ascending dose (SAD), multiple ascending dose (MAD), and PET receptor occupancy studies in healthy volunteers. TMP-301 was generally well tolerated at doses up to 270 mg. Common adverse events (AEs) were mild neuropsychiatric symptoms, consistent with central nervous system engagement. One serious adverse event involved a pre-existing psychosis case. Blood pressure increases were minor and transient.<br /><br />Pharmacokinetics (PK) showed rapid absorption (Tmax 2–5 hours), biphasic elimination (half-life up to 35 hours), and dose-proportional plasma concentration increases, with steady state reached by Day 14 in MAD studies. Food intake had minimal effect (~20% difference) on exposure.<br /><br />PET imaging demonstrated TMP-301’s good brain biodistribution and achieved mGluR5 receptor occupancy levels associated with therapeutic efficacy, comparable to levels from other mGluR5 modulators in prior proof-of-concept studies. The estimated plasma EC50 for receptor occupancy was 60 ng/mL. Dosing regimens of 25-50 mg once daily are predicted to maintain effective receptor engagement.<br /><br />In summary, TMP-301 shows a favorable safety profile, suitable pharmacokinetics, and target engagement consistent with its mechanism of action for treating SUDs. These data support further development of TMP-301 as a novel treatment addressing both addictive behaviors and related affective symptoms in SUD patients.
Keywords
TMP-301
metabotropic glutamate receptor 5
mGluR5
negative allosteric modulator
substance use disorders
clinical trial phase 1
pharmacokinetics
PET receptor occupancy
addiction treatment
neuropsychiatric adverse events
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