VVZ-149 is a dual antagonist of GlyT2 and 5HT2A. GlyT2 blockage increases inhibitory synaptic transmission by glycine in the spinal cord, resulting in reduced pain transmissions to the brain. VVZ-149 has been shown to have comparable efficacy to morphine in well-controlled animal studies. A phase 1 study performed in healthy subjects has shown no clinically significant adverse events at therapeutic doses of VVZ-149. In the current study, 60 patients undergoing laparoscopic colorectal surgery were randomized in a double-blind, parallel, placebo-controlled study to evaluate the efficacy and safety of VVZ-149 injections. Safety measurements included blood chemistry, CBC, thyroid, coagulation, and liver function tests preoperatively, 24 hours after initiation of the study drug, and at a follow up visit 14-30 days after surgery. Respiratory depression and adverse events were also assessed at all time points associated with the study. There was no significant difference in any of the laboratory values between subjects who received VVZ-149 versus placebo. Subjects in both groups had a significant increase from normal values at the 24-hour time point in glucose, WBC, and Prothrombin Time, and a decrease in hematocrit and phosphorus. These changes from baseline lab values can likely be attributed to the physiologic response to surgical stress. All tested values returned to normal range at the follow up visit. Postoperative nausea and vomiting (PONV) was the most common complaint in subjects, which is consistent with PONV being one of the most common adverse effects to general anesthesia. There was no difference between incidence of PONV between the study drug and placebo groups. Furthermore, there was no difference in the incidence of respiratory depression between the groups. This preliminary data supports the administration of VVZ-149 in colorectal surgery patients as a novel analgesic with an acceptable safety and tolerability profile. Supported by a grant from Vivozon Inc.

VVZ-149 is a dual antagonist of GlyT2 and 5HT2A. Blockade of GlyT2 inhibits synaptic transmission by glycine in the spinal cord, decreasing the transmission of painful stimuli to the brain. 5HT2A blockage decreases descending serotonergic facilitatory modulation on pain transmission by the brain and reduces nociceptor activation in peripheral nerves, which are primary sources of pain in post-surgical pain. VVZ-149 has been shown to have comparable efficacy to morphine in well-controlled animal studies. In the current clinical trial, 60 patients were randomized 2:1 to receive VVZ-149 or placebo, administered as an 8-hour infusion started after emergence from general anesthesia. Subjects were followed for 24 hours after initiation of the infusion; pain and adverse effects were monitored throughout the postoperative period, including at 1, 2, 4, 6, 8, 9, 12, 16, and 24 hours. Blood samples for pharmacokinetic analysis were collected at baseline, as well as hours 0.5, 1, 4, 8, while the infusion was administered. Additional samples were obtained at hours 9, 12, and 24 hours after the infusion was stopped. In patients who attained serum levels of >2000 ng/ml 4 hr after start of infusion, VVZ-149 resulted in a significant reduction of opioid consumption (56% - 67%) at 8, 9, and 12 hours. In patients who maintained serum levels of >2000 ng/ml 8 hr after start of infusion, a significant reduction in opioid consumption (58% - 71%) was seen at 8, 9, 12, and 16 hours in the VVZ-149 group. No significant differences were seen in opioid consumption between the VVZ-149 and placebo groups when subjects who received VVZ-149 attained serum levels of <2000 ng/ml. Results from this study support the efficacy of VVZ-149 as a novel analgesic in the treatment of postoperative pain in this study population. Supported by a grant from Vivozon Inc.

Treatment approaches must focus on patient-centered outcome measurements in order to improve quality of care. Among these measures, patient satisfaction will play a high role in reimbursements as new models of health delivery are developed. We report on the initial results on patient satisfaction of a randomized double-blinded placebo controlled trial of VVZ-149 infusions for the treatment of postoperative pain after laparoscopic colorectal surgery. In the current study, 60 subjects were randomized 2:1 following surgery to receive either the study drug or placebo along with IV patient-controlled analgesia. Preoperative assessments were made of anxiety, depression, and catastrophizing using the HADS and PCS instruments. Study drug infusions were started in the PACU and were continued until 8 hours after surgery. Satisfaction assessments were conducted at 8 and 24 hours postoperatively. At the 8 hr and 24 hr time point, patients were asked to complete a categorical patient satisfaction scale whereas 1 = extremely dissatisfied, 2 = dissatisfied, 3 = neutral, 4 = satisfied, and 5 = extremely satisfied with the pain management treatment. Levels of satisfaction were rated as "satisfied" or "extremely satisfied" in the VVZ-149 group in 97% and 90% of patients at the 8 hr and 24 hr time point compared to 92% and 78% in the placebo group. Average levels of patient satisfaction were higher in the VVZ-149 group overall (4.40) compared to the placebo group (4.13) on the 1-5 categorical ranking scale. There were no associations between preoperative levels of anxiety, depression, or catastrophizing on reports of patient satisfaction postoperatively. In summary, VVZ-149 infusions for the treatment of postoperative pain after colorectal surgery are associated with excellent levels of patient satisfaction 8 hours and 24 hours after surgery. Supported by a grant from Vivozon, Inc.