Opiranserin

VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain.

Sixty patients undergoing laparoscopic and robotic-laparoscopic gastrectomy were randomly assigned to receive a 10-hour intravenous infusion of VVZ-149 Injections or placebo, initiated approximately 1 hour before completion of surgical suturing. Major outcomes included pain intensity and opioid consumption via patient-controlled analgesia and rescue analgesia provided “as needed.” The treatment efficacy of VVZ-149 was further examined in a subpopulation requiring early rescue medication, previously associated with the presence of high levels of preoperative negative affect in a prior Phase 2 study (NCT02489526).

Pain intensity was lower in the VVZ-149 (n = 30) than the placebo group (n = 29), reaching statistical significance at 4 hours post-emergence (P < .05), with a 29.5% reduction in opioid consumption for 24 hours and fewer demands for patient-controlled analgesia. In the rescued subgroup, VVZ-149 further reduced pain intensity (P < .05) with 32.6% less opioid consumption for 24 hours compared to placebo patients.

VVZ-149 demonstrated effective analgesia with reduced postoperative pain and opioid requirements. Consistent with the results from the previous Phase 2 study, patients with early rescue requirement had greater benefit from VVZ-149, supporting the hypothesis that VVZ-149 may alleviate the affective component of pain and mitigate excessive use of opioids postoperatively.

VVZ‐149, a dual antagonist of GlyT2 and 5HT2A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early‐stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ‐149 injections in healthy male volunteers were explored in a randomized, double‐blind, single‐ and multiple‐ascending‐dose (SAD and MAD, respectively), placebo‐controlled clinical study. Subjects randomly received a 4‐hour intravenous infusion of 0.25‐8 mg/kg VVZ‐149 or placebo in the SAD study (n = 46) or a 4‐hour intravenous infusion of 4–7 mg/kg VVZ‐149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ‐149 and its active metabolite (VVZ‐368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ‐149 and VVZ‐368 showed a dose‐proportional increase. VVZ‐149 did not accumulate in the plasma, whereas the plasma concentration of VVZ‐368 increased by 1.23‐ to 2.49‐fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single‐ or multiple‐dose administration of VVZ‐149 was generally well tolerated. These results showed that 0.5–8 mg/kg VVZ‐149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies.