Suzetrigine, a Non-Opioid NaV1.8 Inhibitor for Treatment of Moderate-to-Severe Acute Pain: Two Phase 3 Randomized Clinical Trials

Background: Opioids are effective for treating acute pain but have safety, tolerability, and addiction concerns while non-opioid analgesics have limited efficacy. Suzetrigine, an oral, non-opioid, small molecule, selectively inhibits the voltage-gated sodium channel 1.8 (Na V 1.8) and has potential to provide efficacious and safe relief for acute pain, without addiction concerns. Methods: To evaluate suzetrigine for treatment of acute pain, we conducted two phase 3, randomized, double-blind, placebo- and active-controlled trials in adults with moderate-to-severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale (NPRS) after abdominoplasty (N=1118) or bunionectomy (N=1073). After surgery, participants were randomized to suzetrigine (100mg then 50mg every 12hrs), hydrocodone bitartrate/acetaminophen (HB/APAP; 5/325mg every 6hrs), or placebo for 48 hours. The primary endpoint was time-weighted sum of the pain intensity difference in NPRS from 0-48hrs (SPID48) versus placebo. Key secondary endpoints were SPID48 versus HB/APAP and time to ≥2-point reduction in NPRS from baseline versus placebo. Results: The primary endpoint was achieved in both trials with suzetrigine demonstrating statistically significant and clinically meaningful reduction in pain versus placebo. The least squares mean difference in SPID48 between suzetrigine and placebo was 48.4 (95%CI:33.6,63.1; P <0.0001) after abdominoplasty and 29.3 (95%CI:14.0,44.6; P =0.0002) after bunionectomy. Neither trial achieved the first key secondary endpoint of superiority of suzetrigine versus HB/APAP on SPID48. For the second key secondary endpoint of time to ≥2-point reduction in NPRS, suzetrigine had a more rapid onset of clinically meaningful pain relief versus placebo after abdominoplasty (119min versus 480mins, nominal P<0.0001) and bunionectomy (240mins versus 480mins, nominal P=0.0016). Adverse events (AEs) were similar to those seen in post-surgical settings. Conclusions: As compared with placebo, suzetrigine reduced moderate-to-severe acute pain over 48 hours after abdominoplasty or bunionectomy. Pain reduction with suzetrigine was similar to that with HB/APAP. Suzetrigine was associated with adverse events that were mild to moderate in severity. Clinicaltrials.gov Registration: NCT05558410 and NCT05553366