Substance Use Disorders are a public health crisis, and current treatments are not always effective, particularly when involves fentanyl addiction. Advantx‘s candidate ADV502 has been specifically designed to block Sigma-1 receptors, which are involved in various aspects of addiction, and partially activate the mu-opioid receptor as a substitution treatment
Substance Use Disorder
Opioid use disorder (OUD) and polysubstance use disorder (PSUD) involving recreational use of fentanyl alone or in combination with stimulants or sedatives represents a rapidly emerging public health threat characterized by significant toxicity and mortality. Opioid substitution treatment is a form of healthcare for opioid-dependent individuals using prescribed opioid agonists, but drugs such as methadone and buprenorphine were not designed to treat fentanyl use disorders, and both face challenges due to the 50-100 times greater potency of fentanyl. Overdose reversal treatments are also available, but drugs such as naloxone can precipitate intense withdrawal symptoms associated with fentanyl use, with greater sensitivity in women. Overall, both types of treatment have suboptimal safety, low efficacy and poor adherence to treatment, posing important limitations to their use.
A role for SIGMAR1 in stimulant addiction with cocaine, methamphetamine and fentanyl is well documented. Evidence involves activation of SIGMAR1 in the different aspects of abuse following acute, repeated, or overdose administration, and ultimately the therapeutic potential of SIGMAR1 antagonists in drug addiction. SIGMAR1 agonists were found to increase dopamine concentrations in the nucleus accumbens, a brain region important for the reinforcing effects of abused drug. The reinforcing effects of the SIGMAR1 agonists were blocked by SIGMAR1 antagonists.
A SIGMAR1 antagonist, and partial MOR agonist, activates the G-protein pathway that produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signaling pathways.
Potential market for Advantx candidate in Substance Use Disorder
OUD Prevalence>16m people in US
Treated Population>2.5m OUD patients
Market Growthest. 10.5% CAGR
Use disorders involving fentanyl have no effective treatment
OPIOID AGONIST THERAPY
The U.S. Food and Drug Administration (FDA) has approved three types of medications for treating Opioid Use Disorder (OUD). These include the full agonist methadone, the partial agonist buprenorphine, and the full antagonist naltrexone (in its extended-release form). Opioid agonist therapy, particularly with methadone or buprenorphine, is considered the standard of care for OUD. These agonists exert their therapeutic effects primarily through the µ-opioid receptor (MOR), however, their potency may be insufficient compared to fentanyl. Research suggests that opioid agonists induce reinforcing effects through the Sigma-1 receptor (SIGMAR1) in key reward-related brain regions, physically associating with several reward-related GPCRs, including opiate and dopamine receptors 1 and 2. This insight is crucial as SIGMAR1-related mechanisms may play a significant role in treatment-resistant stimulant abuse, and for developing effective medications for substance abuse.
Sigma-1 receptor antagonists offer a groundbreaking approach to OUD treatment, especially when combined with a MOR partial agonist in a bifunctional drug. These antagonists provide a well-tolerated therapy, reversing the reward effects of opioids, even fentanyl. not accompanied by potentiation of other opioid-induced effects, such as analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis, and enhancing safety and patient adherence. Additionally, Sigma-1 antagonists, as multidimensional drug targets, have also been recognized for seizure management, particularly in treating intoxication-induced seizures. Advantx’s innovative molecule acts as a potent Sigma-1 receptor antagonist, offering strong anti-addiction effects, while also serving as a mild opioid agonist, targeting neurons directly. This development in Sigma science is poised to offer a new oral therapy for treating Substance Use Disorders, showing promise beyond conventional treatments.
ADV502 PSUD is Advantx’s candidate for the treatment of PolySubstance Use Disorder.