PF-05190457 / Pfizer - LARVOL DELTA

A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder. (PubMed, JCI Insight) - P2 | "PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963."

Clinical • Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Ghrelin and LEAP2 affect insulin and glucagon secretion in mouse but not in human islets, and their effects in mouse islets are mediated by somatostatin (EASD 2024) - "This study aims to explore the effects of ghrelin and LEAP2 on pancreatic hormone secretion in mice and humans, to test the efficacy of two other GHSR inverse agonists, LEAP2 (38-47) (a fragment of LEAP2 upregulated in Roux-en-Y gastric bypass) and PF-5190457 (PF), and to determine whether their effects are mediated directly or indirectly via SST... In mouse islets, ghrelin exhibits dose- and glucose-dependent inhibitory effects on GCG and INS secretion, while LEAP2 stimulates GCG secretion in G1 and INS secretion in G15. Notably, ghrelin stimulates SST secretion, whereas LEAP2 inhibits it. The effects of ghrelin and LEAP2 on INS and GCG secretion are indirect, mediated by SST, which is compatible with the high expression of GHS-R1a in δ-cells."

Preclinical • Metabolic Disorders • GCG

GHSR blockade, but not reduction of peripherally circulating ghrelin via β1-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice. (PubMed, Mol Psychiatry) - "Also, ICV administration of atenolol had no effect on peripheral endogenous ghrelin levels...The β1AR antagonism also did not prevent the effects of the GHSR blockers JMV2959 and PF-5190457 in decreasing binge-like alcohol drinking. These results suggest that the GHSR rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. Thus, GHSRs and β1ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems."

Journal • Preclinical • Addiction (Opioid and Alcohol)

In vitro pharmacological characterization of growth hormone secretagogue receptor ligands using the dynamic mass redistribution and calcium mobilization assays. (PubMed, Eur J Pharmacol) - "Among synthetic compounds, the agonists anamorelin and HM01, the antagonists HM04 and YIL-781, and the inverse agonist PF-05190457 have been tested, together with HM03, R011, and H1498 from patent literature. It demonstrated that the DMR assay can be successfully used particularly to discriminate between antagonists and inverse agonists. This study may be useful for the selection of the most appropriate compounds to be used in future studies."

Journal • Preclinical • Anorexia • Cachexia

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet. (PubMed, Commun Biol) - "Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity."

Journal • Preclinical • Genetic Disorders • Obesity

Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. (PubMed, Neuropharmacology) - "Systemic administration of the GHSR antagonists JMV2959, PF-5190457, PF-6870961, HM-04, and YIL-781 but not LEAP2 (likely peripherally restricted) reduced alcohol intake in both male and female mice...These findings suggest that central GHSR mediates binge-like alcohol intake. These data reveal novel pharmacological compounds with translational potential in the treatment of AUD and provide further evidence of the GHSR as a potential treatment target for AUD."

Journal • Preclinical • Addiction (Opioid and Alcohol)

The Growth Hormone Secretagogue Receptor Inverse Agonist/Antagonist PF5190457 Suppresses Fentanyl Intake and Seeking in Rats (CPDD 2023) - "Our preclinical data positions ‘457 as a medication of interest in opioid use disorder treatment to facilitate abstinence during recovery without abuse liability. 1"

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Mental Retardation • Psychiatry • Substance Abuse

Pre-Clinical Insights: Ghrelin Receptor Blockade Reduces Binge-Like Alcohol Drinking in Male and Female Mice (SOBP 2023) - "Our findings provide novel information that supports the ghrelin system as a potential target for AUD treatment. This work has translational relevance as PF-5190457 is the first GHS-R blocker that has moved to clinical studies"

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Mental Retardation • Psychiatry

Initial pharmacological characterization of a major hydroxy metabolite of PF-5190457: inverse agonist activity of PF-6870961 at the ghrelin receptor. (PubMed, J Pharmacol Exp Ther) - "We here expand understanding of the pharmacology of one such GHSR1a inverse agonist, PF-5190457, by studying the safety and pharmacodynamics of its major hydroxy metabolite, PF-6870961. Our data demonstrate biased inverse agonism of PF-6870961 at GHSR1a and provides new structure-activity relationship insight into GHSR1a inverse agonism."

Journal • Addiction (Opioid and Alcohol)

The Ghrelin System as a Potential Target for Treatment of Alcohol Use Disorder: Pharmacological Evidence (ACNP 2022) - "Ghrelin receptor blockade preferentially reduces alcohol intake, and there is little difference in intake between males and females in response to ghrelin receptor blockade. Additionally, circulating acyl-ghrelin has no effect on alcohol intake. Our findings provide novel information that supports the role of the ghrelin system in binge drinking and identifies that system as a potential target for pharmacological interventions against AUD."

Addiction (Opioid and Alcohol) • Ataxia • CNS Disorders • Mental Retardation • Psychiatry

A Human Laboratory Study on the Effects of a Novel Ghrelin Receptor Inverse Agonist Competitive Antagonist on Alcohol And Food-Related Behaviors in Individuals With Alcohol Use Disorder (ACNP 2022) - "We found that the novel ghrelin receptor inverse agonist PF-5190457 had a significant effect on food choice behavior during a virtual lunch buffet and an effect on attention to alcohol cue during a cue reactivity paradigm in a bar-like laboratory. However, there was no effect of the drug on alcohol or food cue elicited craving in the bar-like laboratory. These preliminary findings suggest that ghrelin may play a role in the attention to reward related cues and stimuli but not craving in detoxified individuals with AUD."

Clinical • Addiction (Opioid and Alcohol)

The Endogenous Ghrelin Antagonist LEAP-2 is Modulated by Alcohol Exposure and Pharmacological Manipulations of the Ghrelin System: Findings From Human Laboratory Studies (ACNP 2022) - P1, P2 | "Ghrelin administration increases cue-induced alcohol craving and alcohol self-administration, while preliminary human work suggests that the ghrelin receptor (GHS-R1a) inverse agonist PF-5190457 reduces alcohol cue-elicited craving... In summary, we provide the first description that IV and acute oral alcohol administration results in a higher LEAP-2:acyl-ghrelin ratio, suggesting an inhibition of GHS-R1a. This is congruent with earlier results showing lower acyl-ghrelin levels after acute alcohol administration. IV ghrelin, co-administered with IV alcohol, increased LEAP-2 levels, while GHS-R1a inverse agonism reduced LEAP-2 and LEAP-2:acyl-ghrelin ratio, and inhibited alcohol’s effect on LEAP-2 levels."

Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review. (PubMed, Front Pharmacol) - "Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene...In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will..."

Journal • Review • Addiction (Opioid and Alcohol)

A Novel Compound for Alcoholism Treatment: A Translational Strategy - Part II (clinicaltrials.gov) - P2 | N=42 | Terminated | Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA) | Completed ➔ Terminated; Early termination of the study due to the COVID-19 pandemic

Trial termination • Addiction (Opioid and Alcohol)

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)

Molecular mechanism of agonism and inverse agonism in ghrelin receptor. (PubMed, Nat Commun) - "Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin...Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors."

Journal

Synthesis of PF-6870961, a major hydroxy metabolite of the novel ghrelin receptor inverse agonist PF-5190457. (PubMed, Bioorg Med Chem) - "The metabolite was synthesized and fully characterized through a design that enabled it to be prepared in useful quantities. The synthesis provided direct access to the recently discovered PF-6870961 and is allowing researchers to conduct additional and deeper evaluation of its in vitro and in vivo properties."

Journal • Addiction (Opioid and Alcohol)

The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. (PubMed, Mol Psychiatry) - "This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder."

Journal • P1 data • Anesthesia

A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers. (PubMed, Clin Pharmacokinet) - P1 | "This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence."

Clinical • Journal • PK/PD data

A Novel Compound for Alcoholism Treatment: A Translational Strategy (clinicaltrials.gov) - P2; N=42; Completed; Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA); Recruiting ➔ Completed; Trial completion date: Dec 2020 ➔ Sep 2020; Trial primary completion date: Dec 2020 ➔ Feb 2020

Trial completion • Trial completion date • Trial primary completion date • Addiction (Opioid and Alcohol)

Pharmacological manipulation of the ghrelin system and alcohol hangover symptoms in heavy drinking individuals: Is there a link? (PubMed, Pharmacol Biochem Behav) - "...The second study tested the effects of an oral ghrelin receptor inverse agonist (PF-5190457) and included a fixed-dose oral alcohol administration experiment...This is the first study showing that exogenous ghrelin administration, but not ghrelin receptor inverse agonism, affects hangover symptoms. Future research should investigate the potential mechanism(s) underlying this effect."

Clinical • Journal • Biosimilar

A study of three PF-05190457 formulations in healthy volunteers (clinicaltrials.gov) - P1; N=16; Completed; New P1 trial

New trial • Diabetes

Pfizer pipeline (Pfizer) - P1 development for PF-05190457 in type 2 diabetes discontinued since May 10, 2012

Discontinued • Diabetes

Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder. (PubMed, Physiol Behav) - "PF-5190457, a GHS-R1a blocker, has been shown to be safe and tolerable when co-administered with alcohol...Collectively, the existing literature supports further examination of the ghrelin system as a therapeutic target for AUD. More research is also needed to understand the biobehavioral and molecular mechanisms underlying ghrelin's functions and to examine different interventional approaches to target the ghrelin system for AUD treatment."

Journal • Review

Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies. (PubMed, Brain Res) - "In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge...On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes."

Clinical • Combination therapy • Journal • Review • Addiction (Opioid and Alcohol) • CNS Disorders • Immune Modulation • Immunology • Inflammation • Psychiatry • CRP • IL10 • IL18 • IL6 • TNFA