The US Food and Drug Administration (FDA) is expected to issue a decision on the NDA for suzetrigine on January 30. An oral voltage-gated sodium channel (NaV) inhibitor selective for NaV1.8, suzetrigine was developed to treat moderate-to-severe acute pain. The drug could be the first novel drug class approved to treat acute pain in more than two decades. The FDA previously granted suzetrigine, manufactured by Vertex Pharmaceuticals, Fast Track and Breakthrough Therapy designations for this indication.
Acute pain – that is, pain lasting less than 3 months – is the most common reason people seek emergency care, accounting for up to 70% of emergency department visits. More than 80 million people take prescription medication for acute pain annually in the US, and about half of these are opioids.
Prescribers increasingly seek non-opioid analgesic alternatives due to concerns about dependency, opioid use disorder (OUD), and adverse effects (AEs). Suzetrigine could be a viable alternative to bridge this gap.
Suzetrigine’s Novel Mechanism for Acute Pain
Research implicates NaVs, especially NaV1.7 and NaV1.8, in the transmission of pain signals. These channels are involved in generating and propagating action potentials in sensory neurons, which are key processes involved in pain perception. NaV1.7 and NaV1.8 are abundantly present in dorsal root ganglion neurons and contribute substantially to nociceptive, neuropathic, and inflammatory pain. NaV1.7 functions as a “threshold” channel that amplifies weak electrical signals, thereby facilitating the activation of neurons, while NaV1.8 carries most of the sodium current during action potentials, supporting repetitive nerve signal firing.
Suzetrigine could be the first drug developed and approved to selectively inhibit NaV1.8 to treat acute and neuropathic pain. This drug has the potential to provide adequate pain relief and reduce dependence on other available therapies, particularly opioids. Its mechanism of action also does not present the potential for misuse.
The Non-Opioids Prevent Addiction In the Nation (NOPAIN) Act became effective in the US on January 1 of this year, mandating Medicare to provide a separate add-on payment in outpatient or surgical center settings for FDA-approved non-opioid pain therapies. Vertex Pharmaceuticals anticipates that suzetrigine will be included on the list of qualifying treatments under the NOPAIN Act, improving its accessibility.
Clinical Trial Evidence for Approval
Data from two Phase 3 randomized, double-blind, placebo-controlled trials supported suzetrigine’s NDA. One evaluated suzetrigine for managing moderate to severe acute pain following abdominoplasty (n = 1,118) and the other following bunionectomy (n = 1,073). Researchers randomized participants aged 18 to 80 years with moderate or severe postoperative pain (≥4 on the Numeric Pain Rating Scale [NPRS]) 2:2:1 to receive suzetrigine (100 mg loading dose, then 50 mg every 12 hours), hydrocodone bitartrate/acetaminophen (HB/APAP; 5/325 mg every 6 hours), or placebo for 48 hours. The primary endpoint for efficacy assessment was SPID48, which represents the time-weighted sum of the pain intensity difference over 48 hours, with higher SPID48 values indicating better pain relief. Key secondary endpoints included comparing suzetrigine’s SPID48 with that of HB/APAP and assessing the time to at least a 2-point NPRS reduction from baseline.
Both trials achieved the primary endpoint, indicating significant differences in least squares mean SPID48 scores of 48.4 in the abdominoplasty trial and 29.3 in the bunionectomy trial. Suzetrigine provided faster pain relief than placebo, with median times to a ≥2-point NPRS reduction of 119 minutes (abdominoplasty) and 240 minutes (bunionectomy) versus 480 minutes for placebo. However, suzetrigine did not demonstrate superior pain relief to HB/APAP, with SPID48 differences of 6.6 and -20.2 in the abdominoplasty and bunionectomy trials, respectively.
Suzetrigine was generally well tolerated. AE rates after abdominoplasty were 50% for suzetrigine, 56.3% for placebo, and 60.7% for HB/APAP. After bunionectomy, the rates were 31%, 35.2%, and 41.8%, respectively. Participants reported no serious AEs related to suzetrigine.
The Phase 3 program also included a single arm safety and effectiveness study of 222 surgical and 34 non-surgical participants aged 18 to 80 with pain rated ≥4 on the NPRS or moderate/severe on the verbal categorical rating scale (VRS). Participants were experiencing moderate to severe acute pain from a broad range of surgical and non-surgical causes. Surgical cases were predominantly orthopedic (41.9%), plastic (37.4%), and otorhinolaryngologic (10.8%), while non-surgical cases included sprains and strains. Participants received suzetrigine (same dosing previously described) for up to 14 days or until their pain resolved.
At the end of treatment, 83.2% of participants rated suzetrigine as good, very good, or excellent for pain relief based on the patient global assessment. Suzetrigine was generally safe; most AEs were mild to moderate – most commonly headache, occurring in 7% of patients – and participants reported no serious AEs related to the drug.
Continued Research
A Phase 2 study of suzetrigine for painful lumbosacral radiculopathy (LSR) – one of the most common causes of peripheral neuropathic pain — also concluded recently. Vertex announced positive results in December 2024 demonstrating a statistically significant mean NPRS reduction of 2.02 within the suzetrigine group at week 12. The placebo group showed a similar reduction of 1.98, and the study was not powered to directly compare the two groups. Suzetrigine was generally well tolerated, with fewer AEs in the suzetrigine arm (22.9%) compared to placebo (32.4%); most AEs were mild or moderate.
A Phase 3 study of suzetrigine in painful LSR is underway.