elcubragistat (Lu AG06466) / Lundbeck - LARVOL DELTA

Monoacylglycerol Lipase Inhibition Using ABX-1431 Attenuates Cerebral Ischaemia Early After Traumatic Brain Injury. (PubMed, Adv Exp Med Biol) - "Therefore, MAGL inhibition by ABX-1431 attenuates cerebral ischaemia early after TBI. The observed 2-AG-mediated cerebrovascular relaxation might involve both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium."

Journal • CNS Disorders • Hematological Disorders • Infectious Disease • Septic Shock • Thrombosis • Vascular Neurology

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder. (PubMed, Drugs) - "Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders."

Journal • Review • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Acute Effects of Monoacylglycerol Lipase Inhibitor ABX1431 on Neuronal Hyperexcitability, Nociception, Locomotion, and the Endocannabinoid System in HIV-1 Tat Male Mice. (PubMed, Cannabis Cannabinoid Res) - " Findings indicate that ABX1431 has potential neuroprotective effects in vitro partially mediated through CB1R. Acute treatment of ABX1431 in vivo shows antinociceptive effects, and seems to alter locomotor activity, with upregulating 2-AG levels in the striatum and spinal cord."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Supervised screening of Tecovirimat-like compounds as potential inhibitors for the monkeypox virus E8L protein. (PubMed, J Biomol Struct Dyn) - "As a result, we have shortlisted five drugs named ABX-1431, Alflutinib, Avacopan, Caspitant, and Darapalib that effectively engage the MPXV surface binding protein. Furthermore, the affinity of the proposed drugs is relatively higher than the Tecovirimat by having higher docking scores, establishing more hydrogen and hydrophobic bonds, engaging key residues in the target's structure, and exhibiting stable molecular dynamics.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease

The Monoacylglycerol Lipase Inhibitor ABX-1431 Does Not Improve Alcoholic Liver Disease. (PubMed, Cannabis Cannabinoid Res) - "Furthermore, survival rate declined with increasing doses of ABX-1431 when compared with mice administered vehicle only. These data suggest that MAGL inhibition does not improve ALD and is unlikely to be a good strategy for this condition."

Journal • Hepatology • Liver Failure • Non-alcoholic Fatty Liver Disease

Lu AG06466 in Participants With Post Traumatic Stress Disorder (PTSD) (clinicaltrials.gov) - P1 | N=35 | Completed | Sponsor: H. Lundbeck A/S | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Lu AG06466 in Participants With Post Traumatic Stress Disorder (PTSD) (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

A Study of Lu AG06466 for the Treatment of Spasticity in Participants With Multiple Sclerosis (clinicaltrials.gov) - P1b | N=37 | Terminated | Sponsor: H. Lundbeck A/S | N=78 ➔ 37 | Active, not recruiting ➔ Terminated; The study was terminated for strategic reasons

Enrollment change • Trial termination • CNS Disorders • Movement Disorders • Multiple Sclerosis

ABX-1431 inhibits the development of endometrial adenocarcinoma and reverses progesterone resistance by targeting MGLL. (PubMed, Cell Death Dis) - "In conclusion, the high expression of MGLL is involved in the occurrence and development of endometrial adenocarcinoma and progesterone resistance. Targeted inhibition of MGLL by inhibitors may be an effective method for the treatment of progesterone resistance in endometrial adenocarcinoma."

Journal • Endometrial Adenocarcinoma • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • AKR1C1 • MGLL

A Study of Lu AG06466 for the Treatment of Spasticity in Participants With Multiple Sclerosis (clinicaltrials.gov) - P1b | N=78 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Movement Disorders • Multiple Sclerosis

Chemical Probes to Control and Visualize Lipid Metabolism in the Brain. (PubMed, Acc Chem Res) - "Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling."

Journal • CNS Disorders • Immunology • Inflammation • Metabolic Disorders • Mood Disorders • Multiple Sclerosis • Pain • Post-traumatic Stress Disorder • Psychiatry

A Study of Lu AG06466 for the Treatment of Spasticity in Participants With Multiple Sclerosis (clinicaltrials.gov) - P1b | N=78 | Recruiting | Sponsor: H. Lundbeck A/S | Phase classification: P1 ➔ P1b

Phase classification • CNS Disorders • Movement Disorders • Multiple Sclerosis

Binding and Effects of Lu AG06466 in the Brain of Healthy Men (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: H. Lundbeck A/S | Recruiting ➔ Completed | Trial completion date: May 2022 ➔ Aug 2022 | Trial primary completion date: May 2022 ➔ Aug 2022

Trial completion • Trial completion date • Trial primary completion date

A Study of Lu AG06466 in Participants With Treatment Resistant Focal Epilepsy (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: H. Lundbeck A/S | N=36 ➔ 1 | Trial completion date: Jun 2023 ➔ Apr 2022 | Recruiting ➔ Terminated | Trial primary completion date: Jun 2023 ➔ Apr 2022; The study was terminated due to enrolment challenges

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Epilepsy • Immunology • Inflammation

A Study of Lu AG06466 for the Treatment of Spasticity in Participants With Multiple Sclerosis (clinicaltrials.gov) - P1 | N=78 | Recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Oct 2022 ➔ Apr 2023 | Trial primary completion date: Oct 2022 ➔ Apr 2023

Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Multiple Sclerosis

Safety and Tolerability Study of Lu AG06466 in Healthy Young Japanese and Caucasian Participants (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: H. Lundbeck A/S | N=36 ➔ 24 | Recruiting ➔ Terminated; The study was terminated for strategic reasons.

Enrollment change • Trial termination

Lu AG06466 in Participants With Post Traumatic Stress Disorder (PTSD) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Nov 2022 ➔ Mar 2023 | Trial primary completion date: Nov 2022 ➔ Mar 2023

Trial completion date • Trial primary completion date • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

A Study of Lu AG06466 in Participants With Treatment Resistant Focal Epilepsy (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Nov 2022 ➔ Jun 2023 | Trial primary completion date: Aug 2022 ➔ Jun 2023

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Immunology • Inflammation

A Study Investigating Lu AG06466 in Healthy Men (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: H. Lundbeck A/S | Recruiting ➔ Completed

Trial completion

A Study to Evaluate Lu AG06466 in Participants With Fibromyalgia (clinicaltrials.gov) - P1 | N=3 | Terminated | Sponsor: H. Lundbeck A/S | N=30 ➔ 3 | Trial completion date: Sep 2022 ➔ Jan 2022 | Recruiting ➔ Terminated | Trial primary completion date: Sep 2022 ➔ Jan 2022; Study terminated due to enrolment challenges.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Fibromyalgia • Immunology • Inflammation • Musculoskeletal Pain • Pain • Rheumatology

Lu AG06466 in Participants With Post Traumatic Stress Disorder (PTSD) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Jan 2022 ➔ Nov 2022 | Trial primary completion date: Jan 2022 ➔ Nov 2022

Trial completion date • Trial primary completion date • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Binding and Effects of Lu AG06466 in the Brain of Healthy Men (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: H. Lundbeck A/S

New P1 trial

Inhibition of monoacylglycerol lipase for the treatment of neurological and neuropsychiatric disorders (ACS-Sp 2022) - "Dose- and time-dependent target engagement of MAGL was confirmed in PBMC using a substrate biomarker assay and in the brain using a novel, MAGL-specific PET probe. Currently Lu AG06466 is being explored in several Phase 1b studies in patients with psychiatric and neurological disorders."

CNS Disorders • Epilepsy • Mental Retardation • Mood Disorders • Pain • Psychiatry

Hexafluoroisopropyl carbamates as selective MAGL and dual MAGL/FAAH inhibitors: biochemical and physicochemical properties. (PubMed, ChemMedChem) - "The only small change in enzyme inhibitory activity with variation of the heteroaromatic system indicates that the reactive hexafluoro-isopropyl carbamate group is mainly responsible for the strength of the inhibitory effect of the compounds. Selected derivatives were also tested for hydrolytic stability in aqueous solution, liver homogenate and blood plasma as well as for aqueous solubility and for per-meability in a Caco-2 cell model. Some compounds showed a slightly higher MAGL inhibitory effect than the known selective MAGL inhibitor ABX-1431 and also partly surpassed this substance with regard to certain physicochemical and biochemical properties such as water solubility and cell permeability."

Journal

A Study to Evaluate a New Tablet Formulation of Lu AG06466 in Healthy Participants (clinicaltrials.gov) - P1; N=16; Completed; Sponsor: H. Lundbeck A/S; Recruiting ➔ Completed

Clinical • Trial completion