Development of SBS-226, a MOR agonist / DOR antagonist, for OUD

Sparian Biosciences, Inc., New York City NY

Investigators

Abstract

ABSTRACT Opioid use disorder (OUD) is a chronic disorder characterized by the repeated, compulsive use of opioid drugs with a detrimental impact to one’s physical, social, and psychological wellbeing. The use of prescription opiates is often necessary to control moderate to severe levels of pain. However, about 10% of patients prescribed an opiate for a medical condition are at risk for developing OUD. Opiate Use Disorder is a global problem but is at crisis levels in the U.S with significant mortality. It is estimated in this country that about ~11M misuse opioids, ~5.6M people have OUD and close to 80K died from opioid related overdoses. Sadly, the COVID epidemic has worsened the epidemic by increasing risk factors for OUD and occurred at a time when fentanyl has flooded the supply. Current treatments are primarily buprenorphine and methadone. Despite treatment options, OUD is difficult to effectively treat long-term due to access, stigma, and efficacy of the compounds. Mitragyna speciosa, a plant commonly known as kratom, has anecdotally been used for treatment of opiate withdrawal and OUD. The naturally occurring active substance is believed to be mitragynine and the 7- OH mitragynine (7OH) metabolite which act through the mu opioid receptor. An active metabolite of mitragynine, 7OH mitragynine, demonstrates MOR agonist properties such as analgesia, tolerance, physical dependence, and reinforcing effects. In contrast, an analog of mitragynine named 9-methoxy corynantheidine pseudoindoxyl (9CP) has a very different receptor binding profile and in vivo properties. 9CP is an partial agonist at MOR and it is also a delta opioid receptor (DOR) antagonist. Unlike the natural products found in kratom, when studied in mice under acute dosing 9CP is non-addictive, and demonstrates far less respiratory depression, tolerance, and signs of physical dependence than morphine. Most importantly, in mice, 9CP can ameliorate naloxone-precipitated withdrawal in morphine-dependent mice. Sparian has created a series of 9CP analogs and screened them across CMC, ADME, and PK properties and identified a lead candidate – SBS-226. Therefore, as an innovative pharmacological approach, we propose the development of SBS-226 as a novel selective, potent and non-addictive chemical entity utilizing mixed MOR agonism/DOR antagonism for the treatment of OUD. In the present application, we propose a full IND-enabling development plan and Phase 1 clinical trial.