Suzetrigine, a Non-opioid, Pain Signal Inhibitor With the Potential for Vomiting- or Nausea-free Acute Pain Relief

Todd Bertoch¹, Dominick D’Aunno², Jessica McCoun³, Daneshvari Solanki⁴, Louise Taber⁵, Joshua Urban⁶, Jessica Oswald⁷, Matthew W. Swisher⁸, Ina Jazić⁹, Simon Tian⁹, Wendy Kampman⁹, Darin J. Correll⁹, Scott G. Weiner¹⁰

¹CenExel JBR Clinical Research, Salt Lake City, UT; ²ERG Clinical, Houston, TX; ³CenExel ACMR Clinical Research, Atlanta, GA; ⁴HD Research, LLC, Bellaire, TX; ⁵Arizona Research Center, Phoenix, AZ; ⁶OrthoNebraska, Omaha, NE; ⁷Departments of Emergency Medicine and Anesthesia, UC San Diego Health, San Diego, CA; ⁸UC San Diego Health, San Diego, CA; ⁹Vertex Pharmaceuticals, Boston, MA; ¹⁰Brigham and Women’s Hospital, Boston, MA

INTRODUCTION

Opioids are effective for the management of moderate-to-severe acute pain but have safety, tolerability (including gastrointestinal tolerability issues such as vomiting and nausea), and addiction concerns¹

Voltage-gated sodium channel 1.8 (Na_V1.8) is a therapeutic target for pain based on its role in pain signaling and its selective expression in the peripheral nervous system²

Suzetrigine (SUZ) is a highly selective Na_V1.8 inhibitor with no addiction potential based on its mechanism of action²

In two Phase 3 trials evaluating SUZ, the primary endpoint of the time-weighted sum of the pain intensity difference as recorded on the numeric pain rating scale (NPRS) from 0 to 48 hours compared to placebo was met with SUZ treatment having a statistically significant greater reduction in pain compared to placebo³

SUZ is approved in the US to treat moderate-to-severe acute pain in adults

Here we report data including a post hoc analysis from the Phase 3 SUZ trials that evaluates a clinically relevant composite endpoint to assess the benefit/risk profile of SUZ relative to hydrocodone bitartrate/acetaminophen (HB/APAP)

OBJECTIVE

To evaluate a clinically relevant composite endpoint to assess the benefit/risk profile of suzetrigine relative to HB/APAP

MATERIAL AND METHODS

Two Phase 3 randomized, double-blind, placebo-controlled trials evaluated SUZ for 48 hours in participants with moderate-to-severe acute pain after abdominoplasty or bunionectomy (Figure 1)³

Participants were randomized 2:2:1 to SUZ, HB/APAP, or placebo

To evaluate a potential additional benefit of SUZ as a non-opioid analgesic, we compared the incidence of vomiting or nausea (common side effects of opioids) in participants receiving SUZ versus HB/APAP (secondary endpoint)

The proportions of participants receiving SUZ with ≥30%, ≥50%, and ≥70% reduction from baseline in NPRS (“responders”) at 48 hours compared to placebo were analyzed as other efficacy endpoints

In addition, a composite endpoint combining efficacy and safety (≥30%, ≥50%, and ≥70% “responders” at 48 hours who were vomiting- or nausea-free through 48 hours) was evaluated as a post hoc analysis

All P values are nominal

Study Design

Suzetrigine tablets: 100-mg then 50-mg every 12 hours administered orally

HB/APAP capsules: 5-mg/325-mg every 6 hours administered orally

Rescue medication: ibuprofen was permitted, if needed, for pain relief. Opioids and other pain medicines were not allowed during treatment

Key Eligibility Criteria

Age: 18 to 80 years

Reported pain: moderate or severe on the VRS and ≥4 on the NPRS within 4 hours after abdominoplasty or 9 hours after removal of the popliteal sciatic nerve block (with ropivacaine) after a bunionectomy

RESULTS

In Both Trials, There Were Fewer Adverse Events of Vomiting and/or Nausea in Participants Receiving Suzetrigine Than Those Receiving HB/APAP

Participants Receiving Suzetrigine Achieved ≥30%, ≥50%, and ≥70% Response Levels at Similar Proportions to Participants Receiving HB/APAP

In Both Trials, a Higher Proportion of Participants Receiving Suzetrigine Achieved the Composite Endpoint of Vomiting- or Nausea-free ≥30%, ≥50%, and ≥70% Reduction in NPRS at 48 Hours Compared to HB/APAP

Cumulative Response Pattern was Consistent: A Numerically Higher Proportion of Participants Receiving Suzetrigine Achieved a Vomiting- or Nausea-free Pain Response Compared to HB/APAP

DISCUSSION

Participants receiving SUZ had higher proportions compared to placebo and similar proportions to HB/APAP of ≥30%, ≥50%, and ≥70% responders

SUZ treatment demonstrated an improved benefit/risk profile relative to HB/APAP with respect to vomiting or nausea, with a higher proportion of participants who achieved ≥30%, ≥50%, and ≥70% response levels while not experiencing gastrointestinal side effects as measured by vomiting or nausea during the 48-hour treatment period