PHILADELPHIA — An oral, nonaddictive sodium channel blocker safely relieved moderate to severe acute pain after surgery, according to phase III data that could support regulatory approval.
Between two double-blind trials, participants randomized to suzetrigin (VX-548) versus placebo showed significantly better pain reduction, assessed as the time-weighted sum of the difference in pain intensity on the Numeric Pain Rating Scale (NPRS) at 48- time indication after abdominoplasty (least squares mean difference 48.4, R0.0001) and after pneumonectomy (29.3, P=0.0002).
This outcome, modeling suzetrigin monotherapy, was supported by unimputed salvage analysis to represent multimodal treatment similar to real-world practice for these two established models of acute pain (47.7 for abdominoplasty, P<0.0001; 28.8 for cholecectomy, P=0.0004), according to Todd Bertoch, MD, of CenExel JBR Clinical Research in Salt Lake City.
“The magnitude of the therapeutic effect at 48 hours indicates that suzetrigin is effective as monotherapy and as part of a multimodality therapy,” concluded Bertoch from his presentation at the American Society of Anesthesiologists (ASA) annual meeting.
The “remarkable” finding of the study, he said, was that side effects with suzetrigin were even lower than with placebo.
So Bertoch said she felt “confident” that suzetrigin has the promise to mark the first new class of painkiller in more than two decades. However, he declined to speculate on when the drug could be on the market.
Suzetrigin is an oral, small molecule, selective sodium 1,8 (NaV1.8). Since the NaV1.8 expressed selectively in peripheral nociceptors and within the dorsal root ganglia (DRG) — not in the brain — it carries no risk of addiction and therefore no potential for misuse, Bertoch reasoned.
“The results of the phase III study of VX-548 suggest potential for effective pain relief and a favorable safety profile, which may provide an additional pain management tool in a physician’s arsenal,” study co-author Jessica Oswald , MD, MPH, of the University of California San Diego, said MedPage Today.
Previously, phase II data for suzetrigin showed significant pain relief at the higher dose (oral loading dose of 100 mg followed by a maintenance dose of 50 mg every 12 hours).
This was the dose chosen for the present phase III studies in which subjects with moderate to severe acute pain at rest after surgery were randomized 2:2:1 to suzetrigin, hydrocodone dipartrate/acetaminophen (HB/APAP dose 5/325 mg each 6 hours ), or placebo. They allowed ibuprofen as a rescue medication for paroxysmal pain.
Participants represented abdominoplasty (n=1,118, mean age 41.8 years, 98.2% female) and pneumonectomy cohorts (n=1,073, mean age 48.0 years, 85.0% female). The abdominoplasty group left surgery with a mean NPRS score of 7.4 while the monionectomy cohort had a mean pain score of 6.8.
The results showed that suzetrigin, either as monotherapy or as a component of multimodality therapy, was not superior to HB/APAP for acute pain relief.
However, suzetrigin provided faster pain relief (≥2 points reduction in NPRS) than placebo in both trials (mean 119 minutes in the abdominoplasty trial and 240 minutes in the bunionectomy trial vs. 480 minutes for placebo in both trials . P<0.0001 and P=0.0016, respectively).
After abdominoplasty, adverse events occurred in 50.0% of the suzetrigin group, compared with 56.3% for placebo and 60.7% for HB/APAP. After pneumonectomy, these rates were 31.0%, 35.2%, and 41.8%, respectively. There were no serious adverse events related to NaV1.8 inhibitor, according to Bertoch.
During the ASA Q&A session, he acknowledged cardiac concerns about sodium channel inhibition, but reassured the audience that the targeted channels are only expressed in peripheral nociceptors and DRGs. There was intensive safety monitoring in the form of internal monitoring for 48 hours for every participant in the studies, he said.
Suzetrigin has not been evaluated for preventive analgesia, Bertoch noted.
Revelations
Bertoch disclosed consulting to Vertex Pharmaceuticals.
Oswald mentioned that he was on the steering committee for Vertex.
Primary source
American Society of Anesthesiologists
Source citation: Bertoch T, et al “Randomized, placebo-controlled, phase 3 trial of suzetrigin, a non-opioid, pain signal blocker for the treatment of acute pain after abdominoplasty or bunionectomy” ASA 2024.
