ADV502: Possible Role for Maintenance treatment of (Poly)Substance Use Disorder

Abstract Title: ADV502: Possible Role for Maintenance treatment of (Poly)Substance Use Disorder

Background:

None of the current common pharmacotherapeutic treatments for opioid use disorder (OUD) – methadone, buprenorphine, and naltrexone – were designed for the purpose (their use was, and continues to be, based primarily on serendipitous desirable features), and with the possible exception of buprenorphine, none have the pharmacologic (e.g., receptor binding) properties that would suggest efficacy for polysubstance use disorder (PSUD).  As a result, their negative attributes manifested during use for treatment of OUD are amplified by lower efficacy in PSUD.  A new orally active compound currently in development (ADV502) combines partial and biased MOR activity with sigma-1 receptor (SR-1) antagonist activity.  This might represent a more targeted strategic approach for maintenance treatment of OUD specifically, and PSUD more generally.

Purpose/Objectives:

The objective of this presentation is to summarize the results of preclinical studies that taken together appear to support the hypothesis that the dual mechanism of action of ADV502 (balanced partial MOR agonism and SR-1 antagonism) suggests a potential therapeutic utility for its use for maintenance treatment of PSUD, including OUD.  The intent was the creation of a short summary of current preclinical data that lead to the hypothesis of this putative role for ADV502.

Method:

In vitro studies involved receptor binding assays to measure ADV502 selective affinity for SR-1 and MOR over SR-2 and multi other receptors, enzymes, and ion channels; partial and biased activity at MOR (ß-FNA and ß-arrestin assays, respectively), and balanced (about equal) activity at SR-1 and MOR.  In vivo studies involved tests of oral efficacy in antinociceptive tests, and a wide variety of tests related to ADME (absorption, distribution, metabolism, and elimination), PK (pharmacokinetics), and toxicology, etc. 

Results:

In vitro, ADV502 displayed selective affinity for SR-1 (118 ± 6 nM) and MOR (64 ± 5 nM) over 180 other receptor, enzyme, and ion binding sites (500 >10,000 nM).  In vivo it displayed oral activity in a variety of acute and chronic pain models, and little or no development of tolerance (during daily dosing for 22 days in an OA model in rats), or naloxone-precipitated withdrawal (following daily dosing for 13 days in a PSNL model in rats).

Conclusions: Our hypothesis is that chronic excess drug use forces excursions away from normal homeostasis (including posttranslational modifications of proteins) that helps explain the neural network dysregulation. And that in response, the body develops compensatory physiological processes to protect itself against these negative effects of excess drug exposure. With time, this results in disruptive long-term changes, including maladaptive misfolding of proteins. OUD and PSUD is seen as involving two types of physiological adaptation: acute (classic-receptor changes) and
longer-term (dysregulation). Unlike methadone and buprenorphine, activation of chaperones (Sigma proteins) by selective ligands would be expected to restore and maintain homeostasis in a targeted fashion. If true, the positive effects of Sigma ligands should be independent of the abused substance or combinations of abused substances (opioid, or stimulant, or xylazine, or polysubstance, etc.). Treatment would require a two-pronged strategy: address the MOR requirement (perception, don’t precipitate withdrawal, recognize possible self-medication for a history of physical or psychological abuse), and address neural dysregulation. ADV502 attempts to accomplish this by combining in a single orally-active molecule, balanced partial and biased MOR agonist activity plus selective SR-1 antagonist chaperone activity.

References: 1. Pergolizzi et al. (2023) Cureus 15(3):e35756
2. Schmidt (2019) TiPS 40:636-54