Pain Medicine

Suzetrigine, a Non-Opioid Na_V1.8 Inhibitor for Treatment of Moderate-to-Severe Acute Pain: Two Phase 3 Randomized Clinical Trials

Bertoch, Todd MD
D’Aunno, Dominick MD
McCoun, Jessica MD
Solanki, Daneshvari MD
Taber, Louise MD
Urban, Joshua MD
Oswald, Jessica MD, MPH
Swisher, Matthew W. MD
Tian, Simon MD
Miao, Xiaopeng PhD
Correll, Darin J. MD
Negulescu, Paul PhD
Bozic, Carmen MD
Weiner, Scott G. MD, MPH

CenExel JBR Clinical Research, Salt Lake City, UT, USA. [email protected]
ERG Clinical, Houston, TX, USA. [email protected]
CenExel ACMR Clinical Research, Atlanta, GA, USA. [email protected]
HD Research, LLC, Bellaire, TX, USA. [email protected]
Arizona Research Center, Phoenix, AZ, USA. [email protected]
OrthoNebraska, Omaha, NE, USA. [email protected]
Department of Emergency Medicine, UC San Diego Health, San Diego, CA, USA; Department of Anesthesiology, Center for Pain Medicine, UC San Diego Health, San Diego, CA, USA. [email protected]
Department of Anesthesiology, UC San Diego Health, San Diego, CA, USA. [email protected]
Vertex Pharmaceuticals, Boston, MA, USA. [email protected]
Vertex Pharmaceuticals, Boston, MA, USA. [email protected]
Vertex Pharmaceuticals, Boston, MA, USA. [email protected]
Vertex Pharmaceuticals, Boston, MA, USA. [email protected]
Vertex Pharmaceuticals, Boston, MA, USA. [email protected]
Brigham and Women’s Hospital, Boston, MA, USA. [email protected]

Submitted for publication October 18, 2024. Accepted for publication March 6, 2025.

Clinical Trial Numbers and Registry URLs

1. ClinicalTrials.gov: NCT05558410, principal investigator Dominick D’Aunno, registration date October 10, 2022, https://clinicaltrials.gov/study/NCT05558410

2. ClinicalTrials.gov: NCT05553366, principal investigator Todd Bertoch, registration date October 3, 2022, https://clinicaltrials.gov/study/NCT05553366

Prior Presentations: Data from these trials were presented at the American Society of Anesthesiologists Annual Meeting, October 18-22, 2024, Philadelphia, PA, USA.

Acknowledgements: We thank the trial participants, their families, and the site investigators. Medical writing support was provided by Concetta G. Marfella, Ph.D. (CGM) and Allison K. Lord, Ph.D. (AKL) and graphic design support was provided by Alexandra Battaglia (AB) under the guidance of the authors. CGM, AKL, and AB are employees of Vertex Pharmaceuticals and hold stock and/or options in the company.

Summary statement: Not applicable

Funding statement: These trials were supported by Vertex Pharmaceuticals

Conflicts of interest: Drs. Bertoch, McCoun, Solanki, Taber, Urban, Oswald, Swisher, and Weiner have reported personal fees from Vertex Pharmaceuticals as members of the Acute Pain Steering Committee. Dr. Urban has reported personal fees and honoraria from Pacira Biosciences. Dr. Swisher has reported fees/honoraria from Epimed International, SPR Therapeutics, InfuTronix, Avanos Medical, Masimo, and Varian Medical Systems. Dr. Weiner has reported fees/honoraria from Cessation Therapeutics, Inc. Drs. Tian, Miao, Correll, Negulescu, and Bozic are employees of Vertex Pharmaceuticals and own stock and/or options in the company. Dr. D’Aunno has nothing to disclose.

APC Statement: The article processing charge was funded by Vertex Pharmaceuticals.

Corresponding Author: Carmen Bozic, MD. Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, [email protected], 617-961-0666

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Anesthesiology Publish Ahead of Print, March 21, 2025. | DOI: 10.1097/ALN.0000000000005460

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_V1.8) 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