Journal Article

Selective Inhibition of Na V 1.8 with VX-548 for Acute Pain

Lechner, Sandra M., Pollak, Richard A., Negulescu, Paul, Bozic, Carmen, Beaton, Alina, Pizzi, Lois J., Miao, Xiaopeng, Habib, Ashraf S., Weiner, Scott G., Jones, Jim, Simard, Christopher, White, Paul F., Jazic, Ina, Shaw, David, Bertoch, Todd, Hare, Brian, Buvanendran, Asokumar, Osteen, Jeremiah D., Correll, Darin J.

2023

Overview

The Na 1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na 1.8, on control of acute pain is being studied. After establishing the selectivity of VX-548 for Na 1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).

• Subject: Acetaminophen - therapeutic use / Acute Pain - drug therapy / Analgesics - therapeutic use / Analgesics, Opioid - therapeutic use / Double-Blind Method / Humans / Hydrocodone - adverse effects / NAV1.8 Voltage-Gated Sodium Channel - drug effects / Pain, Postoperative - drug therapy / Voltage-Gated Sodium Channel Blockers - chemistry / Voltage-Gated Sodium Channel Blockers - pharmacology