ANS-6637 / Amygdala Neurosci, Gilead - LARVOL DELTA

Preliminary effects of oral ANS-6637, an ALDH2 inhibitor, on cue-induced craving, safety and alcohol consumption among adults with alcohol use disorder: a proof-of-concept, randomized, human laboratory trial. (PubMed, Alcohol Alcohol) - "Findings of liver toxicity with ANS-6637 led to early termination and reduced power to test hypotheses. Effect size estimates are consistent with the hypothesis that selective ALDH2 inhibition may reduce craving and drinking, however these estimates may be unreliable due to the small sample size. Additional research with non-hepatotoxic selective and reversible ALDH2 inhibitors is needed to evaluate this approach to AUD pharmacotherapy."

Clinical • Journal • Addiction (Opioid and Alcohol) • Hepatology • ALDH2

Phase 2 Study of ANS-6637, a Specific Inhibitor of ALDH2, in Treatment Seeking Individuals With Alcohol Use Disorder: A Combined Human Laboratory and Outpatient Clinical Trial (ACNP 2021) - "Disulfiram, the first drug approved to treat AUD, non-selectively inhibits both ALDH1 and ALDH2. This study, which embedded a human laboratory study within the context of a 5-week clinical trial, yielded critical safety data about unexpected liver toxicity that led to early termination of the study. In addition, while the effects on alcohol craving measured in response to an alcohol cue-exposure paradigm after 1-week of dosing were small, data from the participants treated for 5 weeks provide preliminary evidence suggesting that selective ALDH2 inhibition may reduce drinking, alcohol consequences and craving. However, these results must be interpreted with caution as the effect sizes could be unreliable due to the small sample size."

Clinical • P2 data • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • ALDH1A1 • ALDH2

Phase 2 Study of ANS-6637, a Specific Inhibitor of ALDH2, in Treatment Seeking Individuals With Alcohol Use Disorder: A Combined Human Laboratory and Outpatient Clinical Trial (ACNP 2021) - "Disulfiram, the first drug approved to treat AUD, non-selectively inhibits both ALDH1 and ALDH2. This study, which embedded a human laboratory study within the context of a 5-week clinical trial, yielded critical safety data about unexpected liver toxicity that led to early termination of the study. In addition, while the effects on alcohol craving measured in response to an alcohol cue-exposure paradigm after 1-week of dosing were small, data from the participants treated for 5 weeks provide preliminary evidence suggesting that selective ALDH2 inhibition may reduce drinking, alcohol consequences and craving. However, these results must be interpreted with caution as the effect sizes could be unreliable due to the small sample size."

Clinical • P2 data • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • ALDH1A1 • ALDH2

Development of a Selective ALDH2 Inhibitor to Treat AUD (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: University of California, Los Angeles; N=75 ➔ 0; Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Addiction (Opioid and Alcohol)

Safety and Preliminary Efficacy of ANS-6637 to Reduce Drug Craving and Harm in People With Opioid Use Disorder (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: University of Maryland, Baltimore; N=82 ➔ 0; Trial completion date: Dec 2021 ➔ Jan 2021; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Dec 2021 ➔ Jan 2021

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal

Safety and Preliminary Efficacy of ANS-6637 to Reduce Drug Craving and Harm in People With Opioid Use Disorder (clinicaltrials.gov) - P2; N=82; Not yet recruiting; Sponsor: University of Maryland, Baltimore; Trial completion date: May 2021 ➔ Dec 2021; Trial primary completion date: May 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=43; Terminated; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); N=81 ➔ 43; Trial completion date: Dec 2020 ➔ Jul 2020; Suspended ➔ Terminated; Trial primary completion date: Nov 2020 ➔ Jul 2020; Clinical Hold for Safety

Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Interaction of Ethanol and Oral ANS-6637, a Selective ALDH2 Inhibitor in Males: A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Cohort Study. (PubMed, Alcohol Clin Exp Res) - "A single oral dose of ANS-6637 with up to 5 standards drinks over 2.5 hrs was generally well tolerated in healthy males. The most common pharmacological response was flushing and an increase in HR, which are known effects of acetaldehyde accumulation and consistent with inhibition of ADLH2 with oral ANS-6637 in combination with alcohol. The results of this alcohol interaction study support further testing of ANS-6637 in individuals with substance use disorders who may consume alcohol."

Clinical • Journal

The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults. (PubMed, J Clin Pharmacol) - "A single grade 3 adverse event (alanine aminotransferase elevation) was identified and resolved following discontinuation of the study drug. Overall, multidose ANS-6637 was well tolerated and did not alter the PK of midazolam beyond a small increase in AUC that is unlikely to be clinically significant."

Clinical • Journal • PK/PD data

[VIRTUAL] Cardiovascular Safety of ANS-6637, a Reversible, Selective Aldehyde Dehydrogenase-2 Inhibitor to Treat Cocaine Use Disorder (CPDD 2020) - "Disulfiram, a nonselective ALDH and dopamine beta-hydroxylase inhibitor, decreased cocaine use in clinical trials, but it increased QT interval after ethanol (cocaine and alcohol are frequently used together). These studies suggest it may be safe to evaluate the effects of ANS-6637 in human clinical studies in combination with cocaine."

Clinical • Addiction (Opioid and Alcohol) • Cardiovascular • Hypertension

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=81; Suspended; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Active, not recruiting ➔ Suspended

Trial suspension

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=81; Active, not recruiting; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Recruiting ➔ Active, not recruiting

Enrollment closed

Safety and Preliminary Efficacy of ANS-6637 to Reduce Drug Craving and Harm in People With Opioid Use Disorder (clinicaltrials.gov) - P2; N=82; Not yet recruiting; Sponsor: University of Maryland, Baltimore; Initiation date: Jan 2020 ➔ Aug 2020

Clinical • Trial initiation date

Development of a Selective ALDH2 Inhibitor to Treat AUD (clinicaltrials.gov) - P2; N=75; Not yet recruiting; Sponsor: University of California, Los Angeles

New P2 trial

The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (clinicaltrials.gov) - P1; N=26; Completed; Sponsor: National Institutes of Health Clinical Center (CC); Active, not recruiting ➔ Completed; N=50 ➔ 26

Clinical • Enrollment change • Trial completion

SEARCH: Safety and Preliminary Efficacy of ANS-6637 to Reduce Drug Craving and Harm in People With Opioid Use Disorder (clinicaltrials.gov) - P2; N=82; Not yet recruiting; Sponsor: University of Maryland, Baltimore

Clinical • New P2 trial

Phase update (PRNewswire) - P1 ➔ P2, Addiction (Opioid and Alcohol)

Phase shift

Amygdala Neurosciences announces dosing of the first patient in the NIH funded phase 2 proof-of-concept study of ANS-6637 for the treatment of alcohol use disorder (PRNewswire) - "Amygdala Neurosciences...announced today the start of dosing in the National Institute on Alcohol Abuse and Alcoholism (NIAAA, an Institute of the National Institutes of Health (NIH)) sponsored Phase 2 proof-of-concept study of ANS-6637 in patients with alcohol use disorder....'In addition, we plan to initiate several other Phase 2 proof-of-concept studies early next year including an NIH HEAL Initiative funded Phase 2 study of ANS-6637 in patients with opioid use disorder and a Phase 2 study of ANS-6637 as an aide to smoking cessation.'"

New P2 trial • Trial status

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=81; Recruiting; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Not yet recruiting ➔ Recruiting; Trial completion date: Sep 2020 ➔ Dec 2020; Trial primary completion date: Aug 2020 ➔ Nov 2020

Enrollment open • Trial completion date • Trial primary completion date

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=81; Not yet recruiting; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Initiation date: Jul 2019 ➔ Oct 2019

Trial initiation date

The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (clinicaltrials.gov) - P1; N=50; Active, not recruiting; Sponsor: National Institutes of Health Clinical Center (CC); Trial completion date: Aug 2019 ➔ Jan 2020

Clinical • Trial completion date

HLAB-002 of ANS-6637 for Alcohol Use Disorder (clinicaltrials.gov) - P2; N=81; Not yet recruiting; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

New P2 trial

The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (clinicaltrials.gov) - P1; N=50; Active, not recruiting; Sponsor: National Institutes of Health Clinical Center (CC); Recruiting ➔ Active, not recruiting

Enrollment closed

The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: National Institutes of Health Clinical Center (CC)

Clinical • New P1 trial