JNJ-42165279

This study is the first to investigate the target modulation of the MAGL inhibitor elcubragistat (ABX-1431; Lu-AG06466) and the FAAH inhibitor JNJ-42165279 in the amygdala, a brain region involved in stress-induced psychiatric disorders. We aimed to assess dynamic changes in the endocannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide (AEA) following pharmacological inhibition of MAGL and FAAH, enzymes regulating their metabolism. Freely moving rats received oral doses of elcubragistat or JNJ-42165279. Microdialysis probes in the basolateral amygdala and nucleus accumbens measured extracellular 2-AG and AEA levels over 240 min using LC-MS/MS. A supplementary mouse study analyzed postmortem endocannabinoid levels in the basolateral amygdala. MAGL inhibition by elcubragistat selectively increased extracellular and tissue 2-AG levels in the basolateral amygdala in a dose-related manner without affecting AEA. Conversely, FAAH inhibition by JNJ-42165279 selectively elevated AEA levels without altering 2-AG. Highest endocannabinoid concentration in basolateral amygdala tissue was between 2 and 4 h after MAGL or FAAH inhibition. In vivo microdialysis is a sensitive method to study target modulation of both MAGL and FAAH inhibitors in the amygdala of freely moving rats. The results of the microdialysis study are in general agreement with postmortem tissue analysis of both 2-AG and AEA and suitable to support the preclinical drug discovery process in concert with disease related animal models.

JNJ-42165279, a highly selective and orally bioavailable fatty acid amide (FAA) hydrolase inhibitor, was evaluated for efficacy and safety in adolescents and adults with autism spectrum disorder (ASD) in this phase 2, double-blind, placebo-controlled, multicenter study (NCT03664232). Participants aged 13-35 years, with a diagnosis of ASD (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; Autism Diagnostic Observation Schedule, 2nd edition) were randomized (1:1) to 12 weeks of treatment with JNJ-42165279 (25 mg, twice-daily) or placebo. Primary endpoints were the change in the Autism Behavior Inventory (ABI) Core Domain (ABI-CD), ABI-Social Communication (ABI-SC), and ABI-Repetitive/Restrictive Behavior (ABI-RB) scores from baseline to day 85. Of the 61 participants (16 female, 45 male) included in the efficacy analyses, 53 (87%) completed the double-blind treatment. At day 85, the JNJ-42165279 group did not show a statistically significant reduction in ASD symptoms versus placebo, as assessed with ABI-CD (p = 0.284), ABI-SC (p = 0.290), and ABI-RB (p = 0.231). However, the following secondary outcomes exhibited small to moderate changes directionally favoring JNJ-42165279: Social Responsiveness Scale 2 (SRS, p = 0.064), Repetitive Behavior Scale-Revised (RBS-R, p = 0.006), Zarit Burden Interview short version (ZBI, p = 0.063), Child Adolescent Symptom Inventory-Anxiety (CASI-Anx, p = 0.048), and Caregiver Global Impression of Severity (p = 0.075). Notably, versus placebo, JNJ-42165279-treated participants showed increased concentrations of FAAs throughout the treatment period, with those achieving elevated concentrations experiencing the greatest reduction in the SRS total score at day 85. JNJ-42165279 demonstrated an acceptable safety profile. Although primary endpoints were not met, JNJ-42165279 may have a therapeutic effect on certain aspects of core ASD symptoms.