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

Design

Two phase 3, randomized, double-blind, placebo- and active-controlled trials

NAVIGATE 2 (post abdominoplasty; N= 1,118)

NAVIGATE 1 (post bunionectomy; N= 1,073)

Objective

To evaluate the efficacy and safety of suzetrigine in participants with moderate-to-severe acute pain after abdominoplasty or bunionectomy

Study Groups

Abdominoplasty (N= 1,118)

Suzetrigine (n= 447)

Hydrocodone bitartrate/acetaminophen (HB/APAP) (n= 448)

Placebo (n= 223)

Bunionectomy (N= 1,073)

Suzetrigine (n= 426)

Hydrocodone bitartrate/acetaminophen (HB/APAP) (n= 431)

Placebo (n= 216)

Inclusion Criteria

Age 18 to 80 years old, requested study drug for pain relief following abdominoplasty procedure under general anesthesia or a primary unilateral bunionectomy under regional anesthesia, pain rated as moderate or severe on verbal categorical rating scale (VRS) and ≥ 4 on numeric pain rating scale (NPRS)

Exclusion Criteria

Sensory abnormality or physical condition deemed serious enough to interfere with assessing postoperative pain, long-term opioid or non-steroidal anti-inflammatory drug (NSAID) use

Methods

In both trials, patients were randomized 2:2:1 to receive either suzetrigine, HB/APAP, or placebo during a 48-hour treatment period. Suzetrigine was administered as oral tablets, with loading dose of 100 mg followed by 50 mg every 12 hours. HB/APAP (active control) was given orally as 5 mg/325 mg capsules every 6 hours.  

Duration

Trial: 2022 to 2023

Intervention: 48 hours

Outcome Measures

Primary: Sum of the pain intensity difference for suzetrigine compared to placebo per NPRS from 0 to 48 hours (SPID48) after the first dose of study drug

Secondary: SPID48 for suzetrigine compared to HB/APAP; time to ≥2-point reduction in NPRS from baseline for suzetrigine compared to placebo

Baseline Characteristics

Abdominoplasty (N= 1,118)

Bunionectomy (N= 1,073)

Age, years

Female

Race

White

Black

70%

27%

71%

24%

BMI, kg/m²

NPRS

< 8

≥ 8

7.4

51%

49%

6.8

64%

36%

VRS

Moderate

Severe

59%

41%

67%

33%

Results

Abdominoplasty

Suzetrigine (n= 447)

SPID48

70.1 ± 6.1 - Placebo

111.8 ± 4.3 - HB/APAP

48.4 (33.6 to 63.1); < 0.0001

6.6 (-5.4 to 18.7); 0.2781

Time to ≥ 2-point reduction in NPRS from baseline, min

480

--; < 0.0001

Bunionectomy 

SPID48

70.6 ± 6.3 - Placebo

120.1 ± 4.5 - HB/APA

29.3 (14.0 to 44.6); 0.0002

-20.2 (-32.7 to -7.7); 0.0016

Time to ≥ 2-point reduction in NPRS from baseline, min

Results above presented for pre-specified analysis with rescue imputation. 

Adverse Events

Common Adverse Events (≥ 4%): nausea, constipation, headache, dizziness, hypotension, vomiting

Any adverse event:

Abdominoplasty trial: 50.0% suzetrigine, 60.7% HB/APA, 56.3% placebo

Bunionectomy trial: 31.0% suzetrigine, 41.8% HB/APA, 35.2% placebo

Serious Adverse Events: 

Abdominoplasty trial: 2.5% suzetrigine, 1.6% HB/APA, 2.3% placebo (none considered related or possibly related to suzetrigine)

Bunionectomy trial: None reported

Percentage that Discontinued due to Adverse Events: (if not listed in study, use N/A or “Not disclosed”)

Abdominoplasty trial: 1.1% suzetrigine, 1.1% HB/APAP, 0.5% placebo

Bunionectomy trial: None reported

Study Author Conclusions

Suzetrigine reduced moderate-to-severe acute pain over 48 hours after abdominoplasty or bunionectomy, with pain reduction similar to HB/APAP. Adverse events were mild to moderate.

InpharmD Researcher Critique

The study's strengths include its large sample size and rigorous design. Limitations include the predominantly female participant pool and the use of rescue medication, which may affect the interpretation of efficacy results. Further studies could explore suzetrigine's role in multimodal pain management strategies

Suzetrigine for Cancer-Related Bone Pain: A Three-Patient Case Series

Design

Case presentation 1

A male patient in his 70s with metastatic prostate cancer involving the spine and ilium presented with persistent, severe cancer-related bone pain despite prior treatment with nonsteroidal anti-inflammatory drugs and gabapentinoids. He was receiving hydrocodone at approximately 30 morphine milligram equivalents daily when suzetrigine was initiated as adjunctive therapy. After three weeks of treatment, he reported minimal to no improvement in pain, and therapy was discontinued because of lack of efficacy and the financial burden associated with lack of pharmacy coverage. No adverse effects were reported.

Case presentation 2

A male patient in his 60s with metastatic lung cancer involving the spine and brain presented with severe, refractory pain despite treatment with nonsteroidal anti-inflammatory drugs, gabapentinoids, and duloxetine. At the time suzetrigine was added as adjunctive therapy, he was receiving a fentanyl patch and hydrocodone totaling approximately 110 morphine milligram equivalents daily. Following a three-week trial, the patient reported no meaningful improvement in pain, and suzetrigine was discontinued without any reported adverse effects. His malignancy subsequently progressed, and he transitioned to hospice care.

Case presentation 3

A male patient in his 60s with metastatic prostate cancer involving the spine and ilium presented with chronic cancer-related bone pain refractory to nonsteroidal anti-inflammatory drugs and gabapentinoids. He was maintained on acetaminophen-codeine at approximately 45 morphine milligram equivalents daily when suzetrigine was initiated. After three weeks of therapy, he reported only minimal improvement in pain and elected to discontinue treatment because of lack of efficacy. No adverse effects were reported.

Study Author Conclusions

Suzetrigine did not demonstrate meaningful analgesic benefit in three patients with metastatic cancer-related bone pain, all of whom were receiving opioid therapy. While well tolerated, its efficacy in this population appears limited. Though we did not see any meaningful pain relief, we acknowledge that the dosing may be different for cancer-related pain, and welcome larger RCTs for cancer-related pain populations. Further research is needed to better define its role in cancer pain management and identify patient populations most likely to benefit.

Selective Inhibition of NaV1.8 with VX-548 for Acute Pain

Design

Two phase 2, randomized, double-blind, placebo-controlled clinical trials

N= 303 (abdominoplasty trial)

N= 274 (bunionectomy trial)

Objective

To evaluate the efficacy and safety of VX-548, a selective NaV1.8 inhibitor, in reducing acute pain after abdominoplasty or bunionectomy compared to placebo

Study Groups

Abdominoplasty trial

High-dose VX-548 (n= 76)

Middle-dose VX-548 (n= 74)

Hydrocodone bitartrate–acetaminophen (n= 76)

Placebo (n= 77)

Bunionectomy trial

High-dose VX-548 (n= 60)

Middle-dose VX-548 (n= 62)

Low-dose VX-548 (n= 33)

Hydrocodone bitartrate–acetaminophen (n= 60)

Placebo (n= 59)

Inclusion Criteria

Participants aged 18 to 75 years with acute pain after abdominoplasty or bunionectomy, rated at least 4 on the Numeric Pain Rating Scale (NPRS) and moderate or severe on the Verbal Categorical Rating Scale (VRS)

Exclusion Criteria

Participants with a history of sensory abnormalities or painful conditions that could confound pain assessment, and those with long-term use of opioids or NSAIDs

Methods

Participants were randomized according to trial site and baseline Numeric Pain Rating Scale score of <8 or ≥8. Both trials used a double-dummy design, with all participants receiving the same number of pills. High-dose VX-548 consisted of a 100-mg oral loading dose followed by 50 mg every 12 hours; middle-dose VX-548 consisted of a 60-mg loading dose followed by 30 mg every 12 hours; and the bunionectomy-only low-dose regimen consisted of a 20-mg loading dose followed by 10 mg every 12 hours. The active comparator was hydrocodone bitartrate 5 mg–acetaminophen 325 mg every 6 hours, and placebo was administered every 6 hours.

Pain intensity was recorded using the Numeric Pain Rating Scale at 19 prespecified time points from 0.5 through 48 hours after the first dose. Oral ibuprofen 400 mg every 6 hours was permitted as rescue medication; participants were encouraged to wait 90 minutes after the first study dose before requesting rescue therapy. Numeric Pain Rating Scale values recorded within 6 hours after rescue medication were replaced with the pre-rescue value using a windowed last-observation-carried-forward approach. The primary efficacy analysis used an analysis-of-covariance model adjusted for trial site and baseline pain score. No formal comparisons between VX-548 and hydrocodone–acetaminophen were prespecified or powered, and confidence intervals were not adjusted for multiple comparisons.

Duration

Include the duration of the trial as a whole, as well as the duration of the interventions.

Outcome Measures

Primary: Time-weighted sum of the pain-intensity difference over 48 hours, or SPID48, based on the Numeric Pain Rating Scale, comparing each VX-548 dose with placebo; higher SPID48 values indicated greater pain reduction

Secondary: SPID24 comparing VX-548 with placebo; percentage of participants achieving ≥30%, ≥50%, and ≥70% reductions from baseline in Numeric Pain Rating Scale score at 48 hour; safety based on adverse events, laboratory values, 12-lead electrocardiograms, and vital signs

Baseline Characteristics

High-Dose VX-548 (n= 76)

Middle-Dose VX-548 (n= 74)

Mean age, years

Female

Race

White

Black

57 (75%)

13 (17%)

57 (77%)

15 (20%)

53 (70%)

18 (24%)

57 (74%)

20 (26%)

Body Mass Index

Baseline NPRS score

Bunionectomy Trial

Mean age, years

Female

Race

White 

Black

42 (70%)

14 (23%)

44 (71%)

17 (27%)

22 (67%)

9 (27%)

44 (73%)

13 (22%)

Body Mass Index

Baseline NPRS score

Severe pain by VRS

Results

Abdominoplasty trial:

The least-squares mean SPID48 was 110.5 with high-dose VX-548, 95.1 with middle-dose VX-548, 85.2 with hydrocodone–acetaminophen, and 72.7 with placebo.

Compared with placebo, the least-squares mean difference in SPID48 was 37.8 (95% confidence interval [CI] 9.2 to 66.4) for high-dose VX-548 and 22.4 (95% CI −6.4 to 51.1) for middle-dose VX-548.

At 48 hours, ≥50% reductions in Numeric Pain Rating Scale score occurred in 45%, 43%, 42%, and 34% of participants receiving high-dose VX-548, middle-dose VX-548, hydrocodone–acetaminophen, and placebo, respectively.

Although high-dose VX-548 produced a numerically higher SPID48 than hydrocodone–acetaminophen, no formal direct comparison between these treatments was prespecified or performed.

Bunionectomy Trial:

The least-squares mean SPID48 was 137.8 with high-dose VX-548, 86.9 with middle-dose VX-548, 112.9 with low-dose VX-548, 115.6 with hydrocodone–acetaminophen, and 101.0 with placebo.

Compared with placebo, the least-squares mean difference in SPID48 was 36.8 (95% CI, 4.6 to 69.0) for high-dose VX-548, −14.1 (95% CI, −46.1 to 17.9) for middle-dose VX-548, and 11.9 (95% CI, −26.2 to 50.1) for low-dose VX-548.

At 48 hours, ≥50% reductions in Numeric Pain Rating Scale score occurred in 67%, 56%, 73%, 62%, and 61% of participants receiving high-dose, middle-dose, and low-dose VX-548, hydrocodone–acetaminophen, and placebo, respectively.

Although high-dose VX-548 produced a numerically higher SPID48 than hydrocodone–acetaminophen, no formal direct comparison between these treatments was prespecified or performed.

Adverse Events

Headache and constipation were common adverse events with VX-548. In the abdominoplasty trial, headache occurred in 14% of the high-dose VX-548 group compared to 6% in the placebo group, and constipation occurred in 9% of the high-dose VX-548 group compared to 5% in the placebo group.

Study Author Conclusions

VX-548 at the highest dose reduced acute pain over 48 hours after abdominoplasty or bunionectomy compared to placebo, with mild to moderate adverse events. Lower doses did not show significant pain reduction.

InpharmD Researcher Critique

The randomized, double-blind, active- and placebo-controlled design across two validated postoperative pain models supports the finding that high-dose VX-548 was effective compared with placebo. However, the study was neither designed nor statistically powered to test superiority or noninferiority versus hydrocodone–acetaminophen, and no formal direct comparison was performed; therefore, this study does not establish that Journavx is noninferior or superior to a standard-of-care analgesic despite numerically favorable results for the high-dose regimen.