Proof‐of‐Concept Study to Assess the Nociceptin Receptor Antagonist <scp>LY</scp>2940094 as a New Treatment for Alcohol Dependence

Post, Anke; Smart, Trevor S.; Jackson, Kimberley; Mann, Joanne; Mohs, Richard C.; Rorick-Kehn, Linda; Statnick, Michael A.; Anton, Raymond F.; O’Malley, Stephanie S.; Wong, Conrad J.

doi:10.1111/acer.13147

Cited by 37 publications

(22 citation statements)

References 43 publications

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“…At present, NIAAA is supporting studies of more than 30 promising targets, including the NOP receptor (Litten et al., ). Despite this attention, medications continue to show only limited effectiveness (similar to the Post et al., , NOP study) or no effect (Zindel and Kranzler, ). Identifying compounds with a modest or greater effect size is no trivial matter.…”

Section: Increasing the Effect Size Of Candidate Medicationsmentioning

confidence: 98%

“…Nonetheless, by working together, thinking creatively, setting rational and well‐conceived goals, and continuing our commitment to the effort, the alcohol research field will continue to move forward in developing effective and safe medications. Although progress may be measured in small but important steps, such as those demonstrated by the work of Rorick‐Kehn and colleagues () and Post and colleagues (), these can lead to large advances, providing clinicians and patients with new and varied options for treating this devastating disorder.…”

Section: Facilitating the Use Of Alcohol Treatment Medications In Reamentioning

confidence: 99%

“…One such compound is LY2940094, a selective nociceptin/orphanin FQ (NOP) receptor antagonist synthesized by Lilly Research Laboratories. In 2 recently published articles, LY2940094 reduced drinking in an animal model (Rorick‐Kehn et al., ) and demonstrated a positive signal in a proof‐of‐concept clinical trial (Post et al., ). In the preclinical study, LY2940094 reduced alcohol self‐administration in Indiana alcohol‐preferring (P) and Marchigian Sardinian alcohol‐preferring (msP) rats, without concomitant changes in food and water intake (Rorick‐Kehn et al., ).…”

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confidence: 99%

“…This initial animal study was followed by an 8‐week randomized placebo‐controlled, double‐blind, proof‐of‐concept clinical trial in 88 alcohol‐dependent patients (Post et al., ). LY2940094, compared with placebo, reduced the number of heavy drinking days and increased the number of days abstinent.…”

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confidence: 99%

“…The next trial, then, should examine the impact of the medication on these outcomes using different grace periods within the trial. It also would be interesting to test the moderators of treatment response initially implicated in the trial by Post and colleagues (). This includes the finding that women and people consuming less alcohol responded better to LY2940094.…”

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confidence: 99%

See 4 more Smart Citations

Nociceptin Receptor as a Target to Treat Alcohol Use Disorder: Challenges in Advancing Medications Development

Litten

2016

Alcoholism Clin & Exp Res

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Section: Increasing the Effect Size Of Candidate Medicationsmentioning

confidence: 98%

Section: Facilitating the Use Of Alcohol Treatment Medications In Reamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nociceptin Receptor as a Target to Treat Alcohol Use Disorder: Challenges in Advancing Medications Development

Litten

2016

Alcoholism Clin & Exp Res

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Advances in Pharmacotherapy Development: Human Clinical Studies

Litten

Falk

Ryan

et al. 2017

The Neuropharmacology of Alcohol

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For more than 25 years, researchers have made advances in developing medications to treat alcohol use disorder (AUD), highlighted by the US Food and Drug Administration's (FDA's) approval of disulfiram, naltrexone (oral and long-acting), and acamprosate. These medications are also approved in Europe, where the European Medicines Agency (EMA) recently added a fourth medication, nalmefene, for AUD. Despite these advances, today's medications have a small effect size, showing efficacy for only a limited number of individuals with AUD. However, a host of new medications, which act on variety of pharmacologic targets, are in the pipeline and have been evaluated in numerous human studies. This article reviews the efficacy and safety of medications currently being tested in human trials and looks at ongoing efforts to identify candidate compounds in human studies. As mentioned in the National Institute on Alcohol Abuse and Alcoholism's Strategic Plan 2017-2021 ( https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf ), medications development remains a high priority. By developing more effective and safe medications, and identifying those patients who will benefit the most from these treatments, we can provide clinicians with the tools they need to treat this devastating disorder, providing relief for patients and their families and markedly improving public health and safety.

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Advancing Pharmacotherapy Development from Preclinical Animal Studies

Egli

2018

The Neuropharmacology of Alcohol

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Animal models provide rapid, inexpensive assessments of an investigational drug's therapeutic potential. Ideally, they support the plausibility of therapeutic efficacy and provide a rationale for further investigation. Here, I discuss how the absence of clear effective-ineffective categories for alcohol use disorder (AUD) medications and biases in the clinical and preclinical literature affect the development of predictive preclinical alcohol dependence (AD) models. Invoking the analogical argument concept from the philosophy of science field, I discuss how models of excessive alcohol drinking support the plausibility of clinical pharmacotherapy effects. Even though these models are not likely be completely discriminative, they are sensitive to clinically effective medications and have revealed dozens of novel medication targets. In that context, I discuss recent preclinical work on GLP-1 receptor agonists, phosphodiesterase inhibitors, glucocorticoid receptor antagonists, nociception agonists and antagonists, and CRF1 antagonists. Clinically approved medications are available for each of these drug classes. I conclude by advocating a translational approach in which drugs are evaluated highly congruent preclinical models and human laboratory studies. Once translation is established, I suggest the burden is to develop hypothesis-based therapeutic interventions maximizing the impact of the confirmed pharmacotherapeutic effects in the context of additional variables falling outside the model.

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Proof‐of‐Concept Study to Assess the Nociceptin Receptor Antagonist LY2940094 as a New Treatment for Alcohol Dependence

Abstract: Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence.

Cited by 37 publications

References 43 publications

Nociceptin Receptor as a Target to Treat Alcohol Use Disorder: Challenges in Advancing Medications Development

Nociceptin Receptor as a Target to Treat Alcohol Use Disorder: Challenges in Advancing Medications Development

Advances in Pharmacotherapy Development: Human Clinical Studies

Advancing Pharmacotherapy Development from Preclinical Animal Studies

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