GET 73 / CT Pharmaceutical Laboratory - LARVOL DELTA

GET73 modulates lipopolysaccharide- and ethanol-induced increase in cytokine/chemokine levels in primary cultures of microglia of rat cerebral cortex. (PubMed, Pharmacol Rep) - "- The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Inflammation • CCL2 • IL1B • IL6 • TNFA

Clinical investigations of compounds targeting metabotropic glutamate receptors. (PubMed, Pharmacol Biochem Behav) - "PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059...Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression...The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Epilepsy • Fragile X Syndrome • Gastroenterology • Gastroesophageal Reflux Disease • Genetic Disorders • Mental Retardation • Mood Disorders • Movement Disorders • Pain • Parkinson's Disease • Psychiatry • Schizophrenia

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder. (PubMed, Drugs) - "Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD."

Journal • Review • Addiction (Opioid and Alcohol)

Novel mGluR5 Modulator Effects on Alcohol Drinking and MRI Outcomes (clinicaltrials.gov) - P1/2; N=90; Recruiting; Sponsor: Medical University of South Carolina; Not yet recruiting ➔ Recruiting; Initiation date: Jan 2022 ➔ Sep 2021

Enrollment open • Trial initiation date • Addiction (Opioid and Alcohol) • MRI

Alcohol-Drug Interaction Studies from Preclinical to Human Laboratory Studies: Evaluation of a Metabotropic Glutamate Receptor Subtype 5 as a Pharmacotherapy for Alcohol Use Disorder (ACNP 2021) - "The results from these translational studies confirm the safety and tolerability of GET 73 when co-administered with alcohol in rats, healthy volunteers and individuals with AD. Although, under this experimental condition, we did not detect an effect on alcohol craving and consumption in the laboratory, suggesting that additional studies should be conducted to administer GET 73 for an extended period in an outpatient setting."

Preclinical • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders

Alcohol-Drug Interaction Studies from Preclinical to Human Laboratory Studies: Evaluation of a Metabotropic Glutamate Receptor Subtype 5 as a Pharmacotherapy for Alcohol Use Disorder (ACNP 2021) - "The results from these translational studies confirm the safety and tolerability of GET 73 when co-administered with alcohol in rats, healthy volunteers and individuals with AD. Although, under this experimental condition, we did not detect an effect on alcohol craving and consumption in the laboratory, suggesting that additional studies should be conducted to administer GET 73 for an extended period in an outpatient setting."

Preclinical • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders

Novel mGluR5 Modulator Effects on Alcohol Drinking and MRI Outcomes (clinicaltrials.gov) - P1/2; N=90; Not yet recruiting; Sponsor: Medical University of South Carolina; Initiation date: Sep 2021 ➔ Jan 2022

Trial initiation date • Addiction (Opioid and Alcohol) • MRI

An inpatient human laboratory study assessing the safety and tolerability, pharmacokinetics, and biobehavioral effect of GET 73 when co-administered with alcohol in individuals with alcohol use disorder. (PubMed, Psychopharmacology (Berl)) - "The study confirms the safety and tolerability of GET 73 when co-administered with alcohol. Although, under this experimental condition, we did not detect an effect on alcohol craving and consumption in the laboratory, additional studies should be conducted administering GET 73 for an extended period in an outpatient setting."

Clinical • Journal • PK/PD data • Addiction (Opioid and Alcohol)

Novel mGluR5 Modulator Effects on Alcohol Drinking and MRI Outcomes (clinicaltrials.gov) - P1/2; N=90; Not yet recruiting; Sponsor: Medical University of South Carolina; Initiation date: Apr 2021 ➔ Sep 2021

Trial initiation date • Addiction (Opioid and Alcohol) • MRI

Novel mGluR5 Modulator Effects on Alcohol Drinking and MRI Outcomes (clinicaltrials.gov) - P1/2; N=90; Not yet recruiting; Sponsor: Medical University of South Carolina

New P1/2 trial • MRI

Effect of GET73 on MRS Measures of Central Glutamate and GABA in Individuals With Alcohol Use Disorder (clinicaltrials.gov) - P2; N=24; Completed; Sponsor: Laboratorio Farmaceutico Ct S.r.l.; Recruiting ➔ Completed; Trial completion date: Dec 2019 ➔ Mar 2020; Trial primary completion date: Dec 2019 ➔ Mar 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date

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Administration of the metabotropic glutamate receptor subtype 5 allosteric modulator GET7 3 with alcohol: A translational study in rats and humans. (PubMed, J Psychopharmacol) - "In humans, both single and thrice 300 mg GET 73 administration were well tolerated, in the presence and absence of alcohol, with no differences in adverse events. There were no significant differences in relative bioavailability between administering 300 mg GET 73 in the presence or absence of alcohol."

Journal • Preclinical

A Study of the mGluR5 Modulator Get 73 on Alcohol Pharmacokinetics and Pharmacodynamics in Non-Treatment Seeking Alcohol Dependent Individuals (ACNP 2019) - P1b/2a; "GET 73 showed an excellent safety profile in these non-treatment seeking, alcohol-dependent participants, with no effects on alcohol pharmacokinetics during co-administration. GET 73 increased the sedation subscale of the biphasic alcohol effects scale, but did not adversely affect cognitive/motor performance. Increased BAES sedation is observed in other medications that reduce alcohol consumption, including naltrexone, topiramate and baclofen."

Clinical • PK/PD data

SPAD: Safety and Pharmacodynamic Study of GET 73 in Alcohol Dependent (clinicaltrials.gov) - P1b/2a; N=25; Completed; Sponsor: Laboratorio Farmaceutico Ct S.r.l.; Trial completion date: Feb 2018 ➔ Nov 2018; Trial primary completion date: Feb 2018 ➔ Nov 2018

Clinical • Trial completion date • Trial primary completion date

MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis. (PubMed, Nat Cell Biol) - "...A comprehensive identification of Argonaute 2-associated microRNAs and mRNAs in endothelial cells identified a network of 122 microRNA families that target 73 mRNAs encoding cytoskeletal, contractile, adhesive and extracellular matrix (CAM) proteins...Inhibition of DROSHA or Argonaute 2, or disruption of microRNA recognition elements within individual target mRNAs, such as connective tissue growth factor, induced hyper-adhesive, hyper-contractile phenotypes in endothelial and fibroblast cells in vitro, and increased tissue stiffness, contractility and extracellular matrix deposition in the zebrafish fin fold in vivo. Thus, a network of microRNAs buffers CAM expression to mediate tissue mechanical homeostasis."

Journal

Effect of GET73 on MRS Measures of Central Glutamate and GABA in Individuals With Alcohol Use Disorder (clinicaltrials.gov) - P2; N=25; Recruiting; Sponsor: Laboratorio Farmaceutico Ct S.r.l.; Trial completion date: Jan 2019 ➔ Dec 2019; Trial primary completion date: Jan 2019 ➔ Dec 2019

Clinical • Trial completion date • Trial primary completion date