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# Suzetrigine
The Food and Drug Administration of the United States has approved a new non-opioid treatment for moderate to severe acute pain. The new drug, Journavx (suzetrigine), is a novel sodium channel blocker that is administered as an oral tablet. The approval was based on data from a phase 3 clinical trial that showed that Suzetrigine was effective in reducing pain intensity in patients with moderate to severe acute pain.
## The all-American problem of chronic pain management
### The opioid crisis
– opioid-related deaths in the US are public health emergency
– death rates from synthetic opioids are highest among those due to drug overdose
    – 727,000 deaths between 1999-2022
    – as of 2022, primarily driven by illegally distributed synthetic opioids (e.g. fentanyl) mixed with stimulants (e.g. ketamine)
– primary driver of opioid crisis is addiction to prescription opioids intended to manage chronic pain conditions
    – “factors such as homelessness, unemployment and isolation can make people more vulnerable to drugs and less likely to recover”
– 2023 Consolidated Appropriations Act, which includes:
    – NOPAIN Act
        – provides funding for research and development of non-opioid analgesics
        – mandates Medicare reimbursement for non-opioid analgesics with demonstrated ability of reducing intra- or post-operative pain that reduces opioid use
    – MAT Act
        – removes requirement for practitioners to get Notice of Intent before prescribing buprenorphine for opioid use disorder
        – does not cover naloxone, methadone, or other medications for opioid use disorder
– FDA Overdose Prevention Framework intends to address need for novel pain management strategies as a long-term solution to opioid crisis
    – aims to reduce opioid overdose deaths
    – includes strategies for reducing opioid prescribing, increasing access to medication-assisted treatment, and expanding access to naloxone

### The race for new paradigms

– Critical to consider pain as a symptom, not a disease
    – chronic pain is a complex condition that can be caused by a variety of factors (injury, infection, psychology, socioeconomic, neurodegenerative, autoimmune etc.)
    – treatment recommended to be multimodal, tailored to the individual patient
    – multimodal approach to pain management
– Nociceptive pain is specifically defined as pain caused by tissue damage or inflammation
    – nociception is any response to noxious stimuli. categorized by:
        – thermal
        – mechanical
        – chemical
    – classes include:
        – somatic
            – superficial somatic (e.g. skin, mucous membranes)
            – deep somatic (e.g. connective tissues)
        – radicular (i.e. irritated nerve roots, pinched nerve)
        – visceral (e.g. internal organs)
– This article considers nociceptive and neuropathic pain in PNS
    – specifically not addressing:
        – CNS neuropathies
        – psychogenic pain
        – nociplastic pain
– Many options exist for non-opioid analgesia
    – Canonical first-line
        – Oral NSAIDs, acetaminophen
        – topical agents
            – NSAID
            – non-opiate topical opioid receptor agonists (e.g. menthol, tramadol)
    – Canonical second-line
        – steroid
        – muscle relaxant
        – GABA receptor agonists (e.g. gabapentin, pregabalin)
        – capsaicin
        – serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and other antidepressants
    – Additional approaches
        – other IV infusions, including nonspecific sodium channel blockers
            – ketamine
            – dexmedetomidine
            – lidocaine
            – magnesium
        – Botox
        – nerve block injections
        – baclofen pump
        – cannabinoids
        – mental health hygiene-focused approaches (e.g. cognitive-behavioral therapy, mindfulness-based stress reduction)
        – physical therapy, bodywork (e.g. massage, acupuncture)
        – biofeedback-based medical devices (e.g. TENS units, EMG, spinal cord stimulators)
        – nutritional approaches
        – nerve ablation
– NaV1.7 sodium channel emerged as initially promising target for inhibition
    – gain of function led to pain hypersensitivity
    – loss of function led to congenital insensitivity to pain
    – null mutation did not lead to other physiological effects except for anosmia
    – multiple mid-process failures
    – 1.7-specific inhibitors were not selective enough; other sodium voltage-gated channels were affected
    – Degree of NaV1.7 inhibition required for analgesia unclear
    – Anatomical location of treatment delivery unclear (i.e. do NaV1.7 inhibitors need to be delivered at terminals of spinal cords, where they block BBB? This would require intrathecal delivery – which may be painfully invasive and/or susceptible to off-target effects via CNS-specific NaV)
    – synergistic effects with opioids?

## Introducing the blockbuster drug

### Mechanism of action: how does suzetrigine work?

– NaV1.8 sodium channel blocker
    – NaV1.8 is expressed in peripheral sensory neurons, including in dorsal root ganglia
    – plays a key role in the transmission of pain signals
    – selective inhibition of NaV1.8 is expected to reduce pain sensation without affecting other physiological functions
    – NaV1.7 is upstream to it (regulates summation of local potentials), NaV1.9 is downstream
– oral administration
    – Median Tmax (time to reach max blood concentration): 3 hours (8-10hrs for M6-SUZ, its active metabolite) with fasting
    – Median Tmax delays to 5hrs and 24hrs with high- or moderate-fat meal. Cmax and area under curve of drug concentration profile not affected by meal changes

### Clinical trials: the evidence

– Phase 3
    – double-blind
    – placebo- and active-controlled
    – criteria: moderate-to-severe acute pain after abdominoplasty and bunionectomy, with supportive safety data from one single-arm, open-label study in 256 participants with moderate to severe acute pain in a range of acute pain conditions.
– Review designations
    – FDA fast track
    – breakthrough designation
    – priority review
– Drug expected to cost about $15.50 per pill wholesale

### What’s next for suzetrigine?

– Suzetrigine to be evaluated for other indications
    – Progression unclear for painful lumbosacral radiculpoathy (leg pain)
        – met primary endpoint with statistical significance in patient-reported pain (NPRS) between treatment, placebo groups
        – mean change in NPRS not meaningfully different (-1.98 placebo, -2.02 treatment)
        – post-hoc multiple comparisons to be performed later
        – variability in placebo response
        – fewer adverse events (25 of 109 treatment, 35 of 108 placebo)
            – one serious adverse event occurred in treatment group, but not linked to suzetrigine, did not lead to death or treatment discontinuation
        – Vertex still intends to pursue Phase 3, pending discussions with FDA
    –  Progression unclear for painful diabetic peripheral neuropathy
        – phase 2 concluded Dec. 2023
        – phase 2 review with FDA completed in Q1 2024
        – phase 3 ongoing with additional controls
    – phase 1 for delivery as spray-dried dispersion to begin March 2025
– Additional drug candidates being considered by Vertex
    – VX-993
        – oral formulation: phase 2 for “acute pain and peripheral neuropathic pain” expected to begin “later” in 2025
        – IV formulation: phase 1 expectex to begin “later” in 2025
    – VX-150
        – oral formulation: investigation as single-drug regimen for moderate-to-severe pain halted after phase 2 trials
        – current work ongoing for combination therapy with suzetrigine
– regulatory notes
    – NOPAIN act
        – being leveraged by Pacira CryoTech (Exparel, Iovera) for nerve block injections
– competitors also working on NaV1.8 inhibitors
    – SiteOne Therapeutics: STC-004
        – received $100M Series C funding in Dec. 2024
        – completed phase 1 trial
        – is collaborating with Vertex on NaV1.7 inhibitor
    – Latigo Biotherapeutics: LTG-001
        – targeting wisdom tooth extraction pain
        – faster uptake than suzetrigine
    – NaV1.7 inhibitors making a comeback?
– the future: NaV1.9 inhibitors?
    – AlphaNavi (Sumitomo) ANP-230

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Suzetrigine

Author Name: Kéita Yokoyama
Editor Name: Michaela Price

The Food and Drug Administration of the United States has approved a new non-opioid treatment for moderate to severe acute pain.1,2 The new drug, Journavx (suzetrigine), is a novel sodium channel blocker that is administered orally as a tablet.1,2 The approval was based on data from a phase 3 clinical trial that showed that Suzetrigine was effective in reducing pain intensity in patients with moderate to severe acute pain.1,3,4,5 

The all-American problem of chronic pain management

The opioid crisis

Opioid-related deaths in the United States have reached epidemic proportions, with over 727,000 deaths reported between 1999 and 2022.6,7,8 This public health emergency has been driven primarily by the illegal distribution of synthetic opioids, such as fentanyl, mixed with stimulants like ketamine.6,7,9  The opioid crisis is rooted in the misuse of prescription opioids that were initially intended to manage chronic pain conditions. According to science news outlet Nature News, socioeconomic factors, such as homelessness, unemployment, and social isolation, “can make individuals more vulnerable to drug addiction and less likely to recover.”6 

In response to the opioid crisis, the United States Congress included the Non-Opioids Prevent Addiction in the Nation (NOPAIN) and Mainstreaming Addiction Treatment (MAT) Acts as part of its omnibus bill for the 2023 federal budget.10,11 The NOPAIN Act provides funding for the research and development of non-opioid analgesics (pain-relieving medicine). The new law also mandates Medicare reimbursement for non-opioid analgesics that have demonstrated the ability to reduce intra- or post-operative pain and opioid use. Furthermore, the MAT Act removes the requirement for practitioners to obtain a Notice of Intent, a special form of regulatory consent to prescribe controlled substances that practically discourages the prescription of addiction-treating drugs, before prescribing buprenorphine for opioid use disorder.11

The United States Department of Health and Human Services has taken steps to address the opioid crisis through its Overdose Prevention Framework.12,13 The framework aims, among other things, to reduce opioid overdose deaths by implementing strategies to reduce opioid prescriptions and by expanding access and improving options for evidence-based treatments. The FDA is taking part in this framework by working to develop new mechanisms for controlling opioid access, working to prosecute their illegal distribution, expanding access to overdose withdrawal medications, and – crucially for suzetrigine – supporting the development of alternative, non-addictive technologies for pain management.

The race for new paradigms

In light of the latest wave of the opioid crisis, as well as the growing recognition of interdisciplinary approaches to chronic disease management following the COVID-19 pandemic, the medical community has been exploring new paradigms for pain management. A core reckoning has been the recognition that pain is a symptom, not a disease, and that chronic pain is a complex condition that can be caused by a variety of factors.14 Given that pain may be caused by injury, infection, psychology, socioeconomic status, neurodegenerative diseases, autoimmune conditions, or a complex constellation of any of these factors, the treatment of pain is recommended to be multimodal and tailored to the individual patient.14,15,16

Pain can be categorized in a variety of manners. First, pain may be considered to be nociceptive (i.e. caused by noxious stimulus such as thermal, mechanical, or chemical damage to tissues), neuropathic (i.e. caused by damage or dysfunction to the nervous system), psychogenic (i.e. pain due to a psychotic disorder), or nociplastic (i.e. chronic pain from changes in neural signal processing despite a lack of tissue damage).16 Notably, nociceptive pain can be further categorized by the source of the pain, such as somatic (e.g. skin, mucous membranes, muscles, or other connective tissues), visceral (e.g. internal organs), or radicular pain (i.e. based on pinched or irritated nerves). Furthermore, pain may be considered acute (≤ 3 months) or chronic (>3 months), and the source of the pain may implicate different parts of the sensory nervous system (i.e. peripheral or central). By understanding how to identify and categorize pain, clinicians can better tailor treatment to the individual patient.14,16

Opioids impact the central nervous system and are relatively nonspecific in their effects. To avoid over-prescribing them for pain management as a blanket solution, clinicians are encouraged to consider other options for pain management. Excluding opioids, the first-line option for pain management is typically considered to be over-the-counter oral medications, such as ibuprofen or acetaminophen, and topical agents such as menthol.14,16 Clinicians who do not see their patients improving after being treated with those drugs may consider other classes of medications, such as steroids, muscle relaxants, GABA receptor agonists (e.g. gabapentin or pregabalin), capsaicin, and even antidepressants.14,16 In certain cases, more specialized approaches to pain management may also be used, such as nerve block injections, nerve ablation, pain-relieving injection pumps, and biofeedback-based medical devices (e.g. TENS units or implanted electrodes). Finally, nontraditional or otherwise alternative approaches, such as mental health hygiene-focused approaches, nutritional supplements, cannabinoid-based therapies, physical therapy, and bodywork (e.g. massage or acupuncture) may also be considered.14,16,17 However, every one of these approaches are either focused on masking pain systemically, only provide intermittent pain relief, or are expensive and invasive. Therefore, there is a critical need for a pain management technique that is noninvasive, cost-effective, repeatable, and specific to the source of the pain.

One promising avenue for pain management is the development of sodium channel blockers that target specific voltage-gated sodium channels.18 These channels are expressed in the peripheral and central nervous systems and play a key role in the transmission of pain signals.18,19,20 By selectively inhibiting these channels, it is possible to reduce pain sensation with minimal impact on other physiological functions. The development of these drugs, particularly those that only select voltage-gated sodium channels in the peripheral nervous system, has been a focus of research in recent years. Researchers initially focused on the NaV1.7 sodium channel, which is expressed in peripheral sensory neurons and plays a key role in the transmission of pain signals.21 NaV1.7 was particularly promising due to its unusually straightforward mechanism. When the protein that forms the channel had a gain-of-function mutation, people with those mutations exhibited hypersensitivity to pain; patients with loss-of-function mutations, on the other hand, were insensitive to pain.22,23,24 Furthermore, people who exhibited null mutations (i.e. people without any NaV1.7 channels at all) did not have any other physiological effects aside from losing their sense of smell.23,24 Putting those three findings together, researchers initially believed that drugs that target NaV1.7 could modulate pain in the peripheral nervous system without significant off-target effects.21,24 However, the development of NaV1.7-specific inhibitors turned out to be mired with challenges, as drugs turned out to not be very selective to NaV1.7 versus other similar targets.5,18,21 As a result, researchers have shifted their focus to other voltage-gated sodium channels that work in concert with NaV1.7.

Introducing the blockbuster drug

Mechanism of action: how does suzetrigine work?

Sequential actions through NaV1.7 and NaV1.8 channels help to propagate electrical signals from peripheral sensory neurons, making NaV1.8 a viable target for managing pain.

In light of the difficulty of targeting NaV1.7, researchers began focusing on a similar, nearby protein involved in action potential propagation: NaV1.8.5,18 Like NaV1.7, NaV1.8 is expressed throughout the sensory peripheral nervous system, including in dorsal root ganglia, and is responsible for propagating pain signals from the periphery to the central nervous system.5,18,24 Thus, drugs that inhibit the function of NaV1.8 play a key role in stopping nociceptive signals from being transmitted into the central nervous system. Vertex Pharmaceuticals developed suzetrigine, a potent and selective inhibitor of NaV1.8, which obstructs pain signals from propagating through the peripheral nervous system.5,20,25 Suzetrigine is over 31,000 times more selective for NaV1.8 than for other voltage-gated sodium channels, allowing the drug to modulate pain signals without affecting other physiological functions.2,18,26,27

Suzetrigine is administered orally in 50 mg tablets, making it a convenient and accessible option for patients with moderate to severe acute pain.20,25,28 The drug is gradually absorbed into the bloodstream as it reaches maximum blood concentration in approximately 3 hours when taken on an empty stomach.2 The drug’s active metabolite, M6-SUZ, takes a longer time to reach maximum blood concentration (approximately 8-10 hours).2 The absorption of suzetrigine is only marginally affected by food, with high- or moderate-fat meals delaying the time to reach maximum blood concentration by only 2 hours.2 The drug’s maximum blood concentration and area under the curve (AUC) of the drug concentration profile are not affected by changes in meal composition.2 Thanks to the pharmacodynamic consistency imparted by M6-SUZ, suzetrigine can be taken once a day regardless of whether patients take it on an empty stomach. This is a dramatic change from current practice; unlike opioids, which must be taken several times a day, suzetrigine does not require patients to regularly ingest pills multiple times throughout the day. While it remains to be shown empirically, one could imagine that this change in dosing regimens may even facilitate behavioral changes that preclude drug-dependent behaviors and habit formation. 

Clinical trials: the evidence

Suzetrigine was evaluated in a phase 3 clinical trial with moderate to severe acute pain following abdominoplasty (“tummy-tucking”; 1,118 patients) or bunionectomy (removing a painful bone spur in the big toe; 1,073 patients).2,25,26 The trial was double-blind and placebo- and active-controlled, with participants randomized to receive suzetrigine, hydrocodone bitartrate-acetaminophen (active comparator), or a sugar pill (placebo).2,25,26 The trial was primarily evaluated based on how participants rated the intensity of their pain on a scale of 0 to 10. In this study, suzetrigine demonstrated a reduction in pain intensity that was statistically significant compared to placebo and comparable to the active comparator.2,25,26 The drug was well-tolerated, with the most common adverse events being nausea, dizziness, and headache.2,26 The safety profile of suzetrigine was consistent with that of other sodium channel blockers, with no new safety signals identified.2,26

Suzetrigine received a priority review designation from the FDA. This status speeds up the timeline for clinical trial review and staff feedback for drugs that offer significant improvements in the treatment of serious conditions.1,25,27 The drug was also granted a breakthrough therapy designation, which is intended to expedite the development and review of first-in-class drugs for serious conditions.1,25,27 The FDA approved suzetrigine for the treatment of moderate to severe acute pain in adults, making it the first non-opioid treatment for this indication in decades.1,25 While the drug is currently expected to cost about $15.50 per pill wholesale, this cost is expected to decrease as suzetrigine’s five-year new chemical exclusivity expires in 2030 and its patent ultimately expires in 2040.1,3,25,28

What’s next for pain management?

The future of suzetrigine

Suzetrigine is expected to be evaluated for two other indications. The drug’s use in the first upcoming indication, painful lumbosacral radiculopathy (leg pain), showed mean changes in pain scores that were significantly, but not meaningfully, different between placebo (-1.98) and treatment groups (-2.02, p < 0.0001).21,29 Vertex appears to take the stance that the comparable decreases in pain levels for the placebo group are due to variability across study sites and that the presence of fewer adverse events in the treatment group justifies its ongoing phase 3 trial.29 The drug’s use in the second upcoming indication, painful diabetic peripheral neuropathy, concluded its phase 2 clinical trial in December 2023; Vertex completed its review of the trial results with the FDA in the first quarter of 2024.30 The phase 3 trial is ongoing, with additional controls in place to ensure the drug’s efficacy and safety. Furthermore, Vertex is planning to initiate a phase 1 trial for a spray-dried dispersion formulation of suzetrigine in March 2025.21

Other upcoming NaV1.8 inhibitors

Vertex Pharmaceuticals is also considering two additional drug candidates for the treatment of pain. VX-993, another NaV1.8 inhibitor, is being developed in both oral and intravenous formulations.27,29 The oral formulation is expected to enter phase 2 clinical trials for the treatment of acute pain and peripheral neuropathic pain later in 2025, while the intravenous formulation is expected to enter phase 1 clinical trials later in 2025. VX-150, a NaV1.7 inhibitor, was investigated as a single-drug regimen for moderate to severe pain but was halted after phase 2 trials.32 However, Vertex is now evaluating VX-150 as a part of a combination therapy alongside suzetrigine for the treatment of acute pain.32,33

It should be noted, though, that Vertex is not the only company working on NaV1.8 inhibitors. SiteOne Therapeutics is developing STC-004, a NaV1.8 inhibitor that has completed phase 1 clinical trials.34 SiteOne Therapeutics, which is ironically collaborating with Vertex for NaV1.7 inhibitors, has also received $100 million in Series C funding to support the development of STC-004.34,35 Latigo Biotherapeutics is developing LTG-001, a NaV1.8 inhibitor that is being evaluated for the treatment of pain following wisdom tooth extraction. LTG-001 has shown faster uptake than suzetrigine, suggesting that it may be a promising alternative to existing treatments.4 Additionally, NaV1.7 inhibitors are making a comeback, with researchers exploring new ways to target this channel for the treatment of pain.

A potential newcomer: NaV1.9 inhibitors

Finally, the future of pain management may lie in the development of NaV1.9 inhibitors.36,37 AlphaNavi, a subsidiary of Sumitomo, is developing ANP-230, a novel NaV1.9 inhibitor that has shown promise in preclinical studies.38 ANP-230 is being evaluated for the treatment of acute pain and is expected to enter phase 1 clinical trials later this year.

Regardless of its success in additional indications and combination therapies, suzetrigine represents a significant advancement in the field of pain management. By targeting specific voltage-gated sodium channels in the peripheral nervous system, suzetrigine offers a novel approach to pain management that is both effective and well-tolerated. As the first non-opioid treatment for moderate to severe acute pain in decades, suzetrigine has the potential to revolutionize the way pain is treated and managed. However, its true impact may be modulated by the success of other NaV1.8 inhibitors and the development of new drugs targeting other voltage-gated sodium channels.

References

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  28. Durant SJ et al., inventors; Vertex Pharmaceuticals Inc., assignee. Substituted tetrahydrofurans as modulators of sodium channels. US Patent 11,919,887. September 14, 2023.
  29. BusinessWire. Vertex Announces Results From Phase 2 Study of Suzetrigine for the Treatment of Painful Lumbosacral Radiculopathy. Published December 19, 2024. Accessed February 21, 2025. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-results-phase-2-study-suzetrigine-treatment
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