JNJ-42165279 / J&J - LARVOL DELTA

Neurochemical in vivo microdialysis and postmortem tissue analysis of amygdala endocannabinoid levels after MAGL- and FAAH-inhibition in rodents. (PubMed, Neurochem Int) - "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. 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."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

The efficacy of elevating anandamide via inhibition of fatty acid amide hydrolase (FAAH) combined with internet-delivered cognitive behavioral therapy in the treatment of post-traumatic stress disorder: a randomized, placebo-controlled clinical trial. (PubMed, Neuropsychopharmacology) - P2 | "In this double-blind, placebo-controlled study, patients with PTSD (N = 100; 85 women) were randomized to the FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg b.i.d.) or placebo for 12 weeks...Thus, FAAH inhibition does not appear to be a suitable adjunct treatment for enhancing CBT in PTSD. This study was registered as Eudra-CT 2020-001965-36."

Clinical • Journal • CNS Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

A Safety and Efficacy Study of JNJ-42165279 in Participants With Social Anxiety Disorder (clinicaltrials.gov) - P2 | N=150 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Mood Disorders • Psychiatry • Social Anxiety Disorder

An Efficacy, Safety and Tolerability Study of JNJ-42165279 in Participants With Major Depressive Disorder With Anxious Distress (clinicaltrials.gov) - P2 | N=161 | Completed | Sponsor: Janssen Research & Development, LLC | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Efficacy and safety of JNJ-42165279, a fatty acid amide hydrolase inhibitor, in adolescents and adults with autism spectrum disorder: a randomized, phase 2, placebo-controlled study. (PubMed, Neuropsychopharmacology) - P2 | "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."

Clinical • Journal • P2 data • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders • Mental Retardation • Mood Disorders • Psychiatry

Effect of Pharmacological Elevation of Anandamide on Neural Functional Connectivity and Emotional Regulation in Patients with Post-Traumatic Stress Disorder (SOBP 2024) - " In a double-blind clinical trial (EudraCT 2020-001965-36), participants with PTSD (n = 101) were randomized to receive either 25 mg of FAAH inhibitor JNJ-42165279 or placebo twice daily... In the task, there was a significant (voxelwise p < 0.002, cluster alpha < 0.05) interaction between group and facial emotion in the fusiform gyrus, dorsal anterior cingulate, anterior insula, and the lingual gyrus. Within the treatment group, there was a significant 3-way interaction between blood drug level, facial emotion, and congruence of trial in the vmPFC and parahippocampal gyrus. There were no significant differences in vmPFC-amygdala functional connectivity between the treatment and placebo groups."

Clinical • Late-breaking abstract • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Efficacy and Safety of JNJ-42165279, a Fatty Acid Amide Hydrolase inhibitor, in Adolescents and Adults With Autism Spectrum Disorder: A Randomized, Phase 2, Placebo-Controlled Study (ACNP 2023) - "This is the first study to evaluate the efficacy, safety, and tolerability of JNJ-42165279, a modulator of the endocannabinoid system, in participants with ASD. Study enrollment completed in Q4 of 2022. This poster will present safety and efficacy results of this phase 2a study."

Clinical • P2 data • CNS Disorders • Mood Disorders • Pain • Psychiatry

Model Driven Patient Selection Using Eye-Tracking Features for Improved Efficacy in a Phase 2 Trial in Autism Spectrum Disorder With JNJ-42165279, a Fatty Acid Amide Hydrolase (FAAH) Inhibitor (ACNP 2023) - P=N/A, P2 | "These results indicate that the ADOS-2 + model driven patient selection approach employing ET features for enrichment achieved a better efficacy (~0.3 more in Cohen’s d) compared to ADOS-2 only patient selection. These findings highlight the advantage of using more objective measure-based patient selection in developing a precision medicine approach in ASD trials. As the model driven approach is based on ET features, it provides a unique opportunity for scalable deployment in future clinical trials to recruit the appropriate patient population for potential success."

Clinical • P2 data • CNS Disorders

Envision: A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2 | N=78 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Autism Spectrum Disorder • Genetic Disorders

Envision: A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2 | N=78 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Autism Spectrum Disorder • Genetic Disorders

Envision: A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jul 2022 ➔ Oct 2022 | Trial primary completion date: Mar 2022 ➔ Oct 2022

Trial completion date • Trial primary completion date • Autism Spectrum Disorder • Genetic Disorders

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor. (PubMed, Toxicol Pathol) - "No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279."

Journal • Preclinical • Cataract • Ophthalmology

Envision: A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Nov 2022 ➔ Jun 2022

Clinical • Trial completion date • Autism Spectrum Disorder • Genetic Disorders

The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial. (PubMed, Neuropsychopharmacology) - "JNJ-42165279 did not affect fear conditioning or within-session extinction learning as evidenced by a lack of differences on a subjective and neural circuit level. Taken together, these results support the hypothesis that JNJ-42165279 at this dose shares some effects with existing anxiolytic agents in dampening response to emotional stimuli but not responses to conditioned fear."

Clinical • Journal • Mood Disorders • Psychiatry

A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: May 2022 ➔ Sep 2022

Clinical • Trial completion date • Autism Spectrum Disorder • Genetic Disorders

Jazz still FAAH from replacing Xyrem (Evaluate) - "JNJ-42165279: Study in autism ongoing, primary completion 2022...PF-04457845: $35m up-front payment from Jazz, development planned in PTSD (Yale running a trial in cannabis use disorder)..."

Financing • Trial completion • Autism Spectrum Disorder • CNS Disorders • Post-traumatic Stress Disorder

The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study. (PubMed, Neuropsychopharmacology) - P2a | "JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703."

Clinical • Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • Social Anxiety Disorder

A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Janssen Research & Development, LLC; N=60 ➔ 80; Trial primary completion date: Aug 2021 ➔ Mar 2022

Clinical • Enrollment change • Trial primary completion date • Autism Spectrum Disorder • Developmental Disorders • Genetic Disorders

A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Oct 2021 ➔ Mar 2022

Clinical • Trial completion date

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474. (PubMed, Br J Pharmacol) - "BIA 10-2474 potently inhibits FAAH in vivo, similarly to PF-04457845, but also interacts with a number of lipid processing enzymes, some previously identified in human cells as off-targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off-targets in the clinical trial accident remains unclear."

Journal • Preclinical

A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial primary completion date: Feb 2021 ➔ Aug 2021

Trial primary completion date

A Phase 2a Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy, Safety, and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor JNJ-42165279 in Subjects With Social Anxiety Disorder (ACNP 2019) - "Considering the totality of responses on the LSAS, CGI, and HAM-A, JNJ-42165279 appears to have a small to modest anxiolytic effect in patients with severe SAD. This was substantially less and later than the effect reported for SSRIs and venlafaxine. The strong relationship between plasma AEA levels and trough concentrations of JNJ-42165279 suggest that escape from full FAAH inhibition occurred in subjects with lower trough concentrations."

Clinical • P2a data

A Phase 2a Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Adjunct Treatment With the FAAH Inhibitor JNJ-42165279 in Subjects With Major Depressive Disorder With Anxious Distress (ACNP 2019) - "The trial design did appear to function as intended in identifying subjects who have an early response to placebo. These subjects may have had a strong expectation bias on the value of an experimental treatment, were responding to their standard treatments in the context of frequent clinic visits, or were recovering from their MDD episode. We did not identify significant therapeutic effects of 25 mg JNJ-42165279 per day for 6 weeks as an adjunct treatment for MDD with anxious distress."

Clinical • P2a data

A Study to Investigate the Efficacy, Safety, and Tolerability of JNJ-42165279 in Adolescent and Adult Participants With Autism Spectrum Disorder (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Mar 2021 ➔ Aug 2021

Clinical • Trial completion date

Fatty Acid Amide Hydrolase Inhibition by JNJ-42165279: A Multiple-Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers. (PubMed, Clin Transl Sci) - "Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ-42165279. No safety concerns were identified."

Clinical • Journal