• Jim Jones, Darin J Correll, Sandra M Lechner, Ina Jazic, Xiaopeng Miao, David Shaw, Christopher Simard, Jeremiah D Osteen, Brian Hare, Alina Beaton, Todd Bertoch, Asokumar Buvanendran, Ashraf S Habib, Lois J Pizzi, Richard A Pollak, Scott G Weiner, Carmen Bozic, Paul Negulescu, Paul F White, and VX21-548-101 and VX21-548-102 Trial Groups.
• From Vertex Pharmaceuticals (J.J., D.J.C., S.M.L., I.J., X.M., D.S., C.S., J.D.O., B.H., C.B., P.N.) and Brigham and Women's Hospital (S.G.W.) - both in Boston; Lotus Clinical Research, Pasadena (A. Beaton), Cedars-Sinai Medical Center, Los Angeles (P.F.W.), and White Mountain Institute, Sea Ranch (P.F.W.) - all in California; JBR Clinical Research, Salt Lake City (T.B.); Rush University Medical Center, Chicago (A. Buvanendran); Duke University School of Medicine, Durham, NC (A.S.H.); the University of Pittsburgh Medical Center, Pittsburgh (L.J.P.); and Endeavor Clinical Trials, San Antonio, TX (R.A.P.).
• N. Engl. J. Med. 2023 Aug 3; 389 (5): 393405393-405.

BackgroundThe NaV1.8 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 NaV1.8, on control of acute pain is being studied.MethodsAfter establishing the selectivity of VX-548 for NaV1.8 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.ResultsA 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.ConclusionsAs 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.).Copyright © 2023 Massachusetts Medical Society.

14 keywords...

hide…