Phase 2b Trial of a Na_V1.8 Inhibitor for Acute Pain

Na_v1.8, a voltage-gated sodium channel expressed in the peripheral nervous system, has a critical role in pain signaling. Previous trials of Na_V1.8 inhibitors have shown effectiveness in reducing postoperative pain.

We conducted a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate LTG-001, a selective Na_v1.8 inhibitor, in patients with moderate-to-severe pain after abdominoplasty. Patients were randomly assigned in a 1:1:1:1 ratio to receive a 300-mg loading dose of LTG-001, followed by 150 mg every 12 hours (low-dose group); a 450-mg loading dose of LTG-001, followed by 300 mg every 12 hours (high-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen) every 6 hours; or placebo every 6 hours. All doses were administered orally over a 48-hour period. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour treatment period (SPID48), based on scores on the Numeric Pain Rating Scale (range, 0 to 10, with higher values indicating more severe pain; higher SPID48 values indicate greater pain reduction). Secondary end points included the amount of opioid rescue medication consumed in morphine milligram equivalents (MME) and no receipt of opioid rescue medication.

A total of 343 patients underwent randomization. The least-squares mean SPID48 was 161.05 (95% confidence interval [CI], 142.93 to 179.16) in the low-dose group, 185.30 (95% CI, 167.26 to 203.34) in the high-dose group, 164.08 (95% CI, 146.02 to 182.14) in the hydrocodone bitartrate-acetaminophen group, and 123.22 (95% CI, 105.23 to 141.21) in the placebo group. The least-squares mean difference in the SPID48 between LTG-001 and placebo was significant for each dose (low dose: 37.82 [P = 0.003]; high dose: 62.08 [P<0.001]), and that between hydrocodone bitartrate-acetaminophen and placebo was 40.86. High-dose LTG-001, but not low-dose LTG-001, was associated with significantly lower opioid use than placebo (11.00 MME vs. 18.35 MME, P = 0.01), as well as a significantly higher percentage of patients who received no opioid rescue medication (52% vs. 22%, P<0.001). High-dose LTG-001 was associated with a higher incidence of pyrexia than placebo (7% vs. 2%) and a higher incidence of presyncope (6% vs. 1%).

LTG-001 led to significantly greater reductions in pain scores than placebo over the course of 48 hours after abdominoplasty. (Funded by Latigo Biotherapeutics; LTG-001-010 ClinicalTrials.gov number, NCT07102459.).