Clinical Efficacy and Target Engagement of Glutamatergic Drugs: Placebo-Controlled RCTs of Pomaglumetad and TS-134 for Reversal of Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers

We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs: pomaglumetad (POMA) and TS-134 including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology. The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size differences. The TS-134 study was a single-blind, industry-sponsored, 6-day study of 20 or 60 mg/d TS-134 or placebo (5:5:2 ratio), designed to permit effect-size estimation for future studies. Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and Brief Psychiatric Rating Scale (BPRS). 95 healthy controls were randomized to POMA and 63 to TS-134. High-dose POMA had significant within and between-group reduction in ketamine-induced BPRS total symptoms (p<0.01, d=-0.41; p=0.04, d=-0.44, respectively) but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 had significant/trend level, moderate to large within and between group effects on BPRS positive symptoms (p=0.02, d=-0.36; p=0.008, d=-0.82, respectively) and dACC pharmacoBOLD (p=0.004, d=-0.56; p=0.079, d=-0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed. TS-134 20 mg showed evidence of symptom reduction and target engagement, indicating a curvilinear dose-response curve. These results warrant further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.