FEBRUARY 14, 2025
PHILADELPHIA—A pair of phase 3 clinical trials have yielded promising results about the potential benefits of suzetrigine, a potent and highly selective inhibitor of the voltage-gated sodium channel 1.8 (NaV1.8), in the treatment of moderate to severe acute pain. The studies found that the novel agent was as effective as a hydrocodone-based opioid regimen in both abdominoplasty and bunionectomy models, with a very favorable safety profile.
“Suzetrigine is a potent, nonopioid small
PHILADELPHIA—A pair of phase 3 clinical trials have yielded promising results about the potential benefits of suzetrigine, a potent and highly selective inhibitor of the voltage-gated sodium channel 1.8 (NaV1.8), in the treatment of moderate to severe acute pain. The studies found that the novel agent was as effective as a hydrocodone-based opioid regimen in both abdominoplasty and bunionectomy models, with a very favorable safety profile.
“Suzetrigine is a potent, nonopioid small molecule that selectively inhibits peripheral NaV1.8 receptors,” said Todd Bertoch, MD, the chief medical officer at JBR Clinical Research, in Salt Lake City. “And because NaV1.8 channels are not expressed in the brain, suzetrigine, unlike opioids, does not possess addictive potential. Thus, suzetrigine has potential to be the first treatment for moderate to severe acute pain from a new pharmacologic class in over two decades.”
The two randomized, double-blind, placebo-controlled trials evaluated suzetrigine for 48 hours postoperatively in adult patients who had undergone either abdominoplasty (n=1,118 dosed) or bunionectomy (n=1,073 dosed). After surgery, participants with moderate to severe pain were randomized 2:2:1 to treatment with either suzetrigine (100 mg first dose; 50 mg every 12 hours thereafter), hydrocodone-acetaminophen (5 mg/325 mg every six hours) or placebo. Participants in both groups were permitted to receive 400 mg of ibuprofen every six hours, as needed, for breakthrough pain.
The primary end point in each trial was the time-weighted sum of the pain intensity difference in the first 48 hours after surgery (SPID48) compared with placebo, where higher SPID48 values indicated greater pain reductions from baseline. Key secondary outcomes included SPID48 for suzetrigine compared with hydrocodone-acetaminophen, as well as the time required to achieve a minimum 2-point reduction in pain scores from baseline for suzetrigine compared with placebo. The researchers also assessed safety as a secondary end point.
Presenting at the 2024 annual meeting of the American Society of Anesthesiologists (abstract A1187), Bertoch reported that the primary end point was met in both trials, as suzetrigine treatment resulted in statistically significant greater pain reductions relative to placebo. In abdominoplasty, the mean pain intensity difference for suzetrigine compared with placebo was –3.4 points, a 47% reduction from baseline (P<0.0001). In bunionectomy, the study drug also showed clinically significant pain reduction at 48 hours, with a mean pain intensity difference of –3.4 points, a 51% reduction from baseline (P=0.0002). Comparable results were found in both surgical models when suzetrigine was used as part of a multimodal analgesic regimen with ibuprofen.
By comparison, neither trial met the first key secondary end point of superiority of suzetrigine compared with hydrocodone-acetaminophen on the SPID48 after either abdominoplasty and/or bunionectomy.
With respect to the time needed to achieve a clinically meaningful reduction in pain scores (=2 points) from baseline, suzetrigine demonstrated a more rapid onset than placebo in both trials. Indeed, the median time to such reductions was 119 minutes in the abdominoplasty model and 240 minutes in the bunionectomy group for suzetrigine patients, compared with 480 minutes each for controls undergoing the procedures (P<0.0001 and P=0.0016, respectively).
Further analyses revealed that suzetrigine was generally safe and well tolerated in both trials; adverse events were consistent with those generally observed in the postoperative setting. Specifically, 50.5% of suzetrigine patients experienced adverse events after abdominoplasty, lower than observed in those receiving either hydrocodone-acetaminophen (60.7%) or, surprisingly, placebo (56.3%). In bunionectomy patients, these rates were 31.0%, 41.8% and 35.2%, respectively. No serious adverse events occurred in either trial that were related to the study drug.
“I’ve been the principal investigator for more than 150 clinical trials in my career, and this is the first one I’ve ever seen that shows a study drug having fewer adverse events than placebo,” Bertoch said. “I find that remarkable, particularly in a trial with such a large sample size.”
Given these findings, the researchers concluded that suzetrigine treatment provided both clinically meaningful and statistically significant pain relief in abdominoplasty and bunionectomy patients.
“Based on these data, we feel that suzetrigine has the potential to represent the first new pharmacologic class of treatment for moderate to severe acute pain in over two decades,” he said.
One of the audience members asked about the ibuprofen used as rescue medication in the trial, which he didn’t believe was strong enough for patients undergoing abdominoplasty or bunionectomy.
“We had dropout rates in both studies,” Bertoch replied. “But it was around 20% in the placebo arm and 10% in both active treatment arms.”
Session co-moderator Brian T. Bateman, MD, a professor of anesthesiology, perioperative and pain medicine at Stanford University, in California, congratulated the researchers on their work.
“In looking at the abdominoplasty model, the suzetrigine pain scores seem to be lower than hydrocodone-acetaminophen on average,” Bateman said. “That pattern is reversed in the bunionectomy model, and I’m wondering if you can reflect on that.”
“We postulate that circulating residual ropivacaine after discontinuation of the popliteal block is probably occupying sodium channels in a nonselective way,” Bertoch replied. “Even if the effect might be subclinical, it’s basically preventing us from seeing the activity of suzetrigine; the suzetrigine molecule can’t act on a channel that’s already blocked.
“Conversely, neither the opioid nor acetaminophen is affected by that,” he continued. “And we think the ropivacaine is continuing to act there, thereby making suzetrigine look less effective while adding to the apparent effectiveness of the comparator opioid group.”
—Michael Vlessides
Bateman reported no relevant financial disclosures. Bertoch reported a financial relationship with Vertex Pharmaceuticals, which manufactures suzetrigine. The abstract was voted as one of the meeting’s best.
