Vivozon’s oral CNS drug curbs smoking cravings without targeting opioid receptors in phase 1

Vivozon Pharmaceutical is staking its second act on VVZ-2471, a dual-target oral drug designed to disrupt the brain’s reward circuitry in pain and addiction. The candidate cleared its first-in-human trial with a clean safety profile -- and delivered an early bonus: reduced smoking urges in higher-dose cohorts, hinting at the broader potential in opioid use disorder (OUD) and beyond.

The drug blocks two key receptors involved in craving and relapse: mGluR5, a glutamate receptor tied to reward signaling, and 5-HT2A, a serotonin receptor linked to mood and impulsivity. Vivozon is pitching VVZ-2471 as a first-in-class oral treatment for central nervous system (CNS) disorders, with particular promise in substance use.

Crucially, the drug sidesteps traditional opioid receptors -- including mu1 (OPRM1), delta1 (OPRD1), and kappa1 (OPRK1) -- which are often implicated in dependence. That distinction could offer an edge in addiction treatment, a field where many existing therapies carry the very risks they aim to reduce.

The phase 1 trial, published last month in CNS Drugs, enrolled healthy male volunteers at Seoul National University Bundang Hospital. Single doses of up to 600 mg and multiple doses of 400 mg daily over a week were well tolerated. Most adverse events -- mild dizziness, nausea -- were transient, and no respiratory safety issues emerged.

Perhaps most notably, VVZ-2471 curbed smoking urges in a 29-person smoker subgroup, with participants receiving 200 mg or more reporting consistent drops in craving scores on the QSU-Brief -- a validated tobacco urge scale -- despite being barred from smoking during the trial, a condition that typically heightens withdrawal.

“Since all subjects were prohibited from smoking during the study, it was reasonably assumed that the urges for smoking would increase over time,” researchers wrote. Instead, craving scores dropped in a dose-dependent fashion, approaching the 10–25 point reduction seen with approved smoking cessation drugs like varenicline.

Those reductions coincided with systemic exposure levels that had triggered anti-craving effects in preclinical studies. In morphine-dependent rats, the same drug curbed naloxone-induced withdrawal and helped prevent relapse -- without activating opioid pathways or interacting with the nociception receptor OPRL1.

That’s what sets VVZ-2471 apart from Vivozon’s first approved drug, Unafra (opiranserin), which acts on GlyT2 and 5-HT2A to treat postoperative pain. “A preliminary safety and efficacy profile of VVZ-2471 as a dual antagonist against mGluR5 and 5-HT2AR in healthy adults and a subgroup of smokers, respectively, lends support to an empirical framework of the multi-target approach for tapping into the complex nature of drug addiction,” the researchers wrote.

The drug’s clean pharmacokinetics support a dose range of 200 to 400 mg for future studies. That window is already being tested in a phase 2 study for postherpetic neuralgia in Korea. A U.S. phase 2 trial in OUD is also in the works, the company said.

VVZ-2471 is the second clinical-stage candidate in Vivozon’s non-opioid portfolio. Unafra, approved by Korean regulators in December 2024 as the country’s 39th domestically developed new drug, entered a new phase 2 trial for lower back pain earlier this month.