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PHILADELPHIA -- An oral, non-addictive sodium channel blocker safely relieved moderate-to-severe acute pain following surgery, according to phase III data that could support regulatory approval.

Between two double-blind trials, participants randomized to suzetrigine (VX-548) over placebo experienced a significantly better reduction in pain, evaluated as the time-weighted sum of pain intensity difference per the numeric pain rating scale (NPRS) at the 48-hour mark after abdominoplasty (least squares mean difference 48.4, P<0.0001) and after bunionectomy (29.3, P=0.0002).

This result, modeling suzetrigine monotherapy, was backed by analysis without rescue imputation to represent multimodal therapy akin to real-world practice for these two established models of acute pain (47.7 for abdominoplasty, P<0.0001; 28.8 for bunionectomy, P=0.0004), according to Todd Bertoch, MD, of CenExel JBR Clinical Research in Salt Lake City.

"The magnitude of the treatment effect over 48 hours demonstrates that suzetrigine is effective as a monotherapy and as part of a multimodal therapy," Bertoch concluded from his presentation at the American Society of Anesthesiologists (ASA) annual meeting.

The "remarkable" finding of the study, he said, was that adverse events with suzetrigine were even lower than with placebo.

Thus, Bertoch said he felt "confident" that suzetrigine has the promise to mark a first new class of pain drug in over two decades. He declined to speculate on when the drug might hit the market, however.

Suzetrigine is an oral, small molecule that selectively inhibits voltage-gated sodium channel 1.8 (NaV_1.8). Given that NaV_1.8 is selectively expressed on peripheral nociceptors and within dorsal root ganglia (DRG) -- not the brain -- it poses no addiction risk and therefore no misuse potential, Bertoch reasoned.

"The phase III study results for 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 armamentarium," study co-author Jessica Oswald, MD, MPH, of University of California San Diego, told 妖姬直播.

Previously, phase II data for suzetrigine showed significant pain relief at the higher dose (a 100-mg oral loading dose followed by a 50-mg maintenance dose every 12 hours).

This was the dose selected for the present phase III studies in which people with moderate to severe acute pain at rest after surgery were randomized 2:2:1 to suzetrigine, hydrocodone bitartrate/acetaminophen (HB/APAP dosed 5/325 mg every 6 hours), or placebo. They allowed ibuprofen as rescue medication for breakthrough pain.

Participants represented abdominoplasty (n=1,118; average 41.8 years old, 98.2% women) and bunionectomy cohorts (n=1,073; average 48.0 years old, 85.0% women). The abdominoplasty group left surgery with a NPRS score averaging 7.4 while the bunionectomy cohort had a mean pain score of 6.8.

Results indicated that suzetrigine, as either monotherapy or a component of multimodal therapy, was no better than HB/APAP for acute pain relief.

However, suzetrigine provided faster pain relief (≥2-point reduction in NPRS) than placebo in both trials (median 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 were observed in 50.0% of the suzetrigine group, compared with 56.3% for placebo and 60.7% for HB/APAP. Following bunionectomy, these rates were 31.0%, 35.2%, and 41.8%, respectively. There were no serious adverse events related to the NaV_1.8 inhibitor, according to Bertoch.

During the ASA session Q&A, he acknowledged the cardiac concerns surrounding sodium channel inhibition, but assured the audience that the targeted channels are only expressed in peripheral nociceptors and DRGs. There was intensive safety monitoring in the form of in-house monitoring for 48 hours for each participant in the studies, he said.

Suzetrigine has not been evaluated for preemptive analgesia, Bertoch noted.

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