VX-548 in the treatment of acute pain

Abstract

Acute pain management requires balancing analgesia with adverse effects risk. The voltage-gated sodium channel NaV1.8 plays an important role in pain physiology, and its inhibition was shown to have analgesic effects. VX-548 is a new oral NaV1.8-specific inhibitor that received United States Food and Drug Administration Fast Track and Breakthrough Therapy designations. Its efficacy was demonstrated in two Phase II trials of patients who underwent abdominoplasty and bunionectomy. These showed that VX-548, when given as an oral loading dose of 100 mg followed by 50 mg 12-hly, significantly decreased pain scores compared with placebo. Similarly, two Phase III trials of patients who underwent abdominoplasty and bunionectomy comparing VX-548 with hydrocodone bitartrate-acetaminophen and placebo reported significantly reduced pain scores compared with placebo, but no improvement compared with hydrocodone bitartrate-acetaminophen. Evidence from Phase II and III trials suggest that VX-548 is well-tolerated, with headache, nausea, constipation and dizziness being the most common adverse effects. However, the safety of prolonged VX-548 administration is uncertain; a Phase II trial of patients with diabetic neuropathy who received high-dose VX-548 over 12 weeks reported decreased creatinine clearance. Data pertaining to VX-548 safety and efficacy within the context of multimodal analgesia and pregnancy are also needed.

Plain Language Summary

In the treatment of pain, we need to find a balance between providing sufficient pain relief and avoiding side effects. Recently, researchers have discovered that NaV1.8, a specific sodium channel in the body, plays a key role in how we feel pain. Medications that block NaV1.8, such as VX-548, can provide effective pain relief.

In clinical studies on patients who went for tummy tucks and bunion removal surgeries, those who took VX-548 after surgery had significantly less pain compared with those who took placebo (a sugar pill that does not have any medications). However, the degree of pain relief was almost the same as other painkillers like hydrocodone combined with acetaminophen.

Common side effects from VX-548 include headache, nausea, constipation and dizziness. While these are generally mild, we still do not know how safe VX-548 is if used over a longer period. Hence, more research is needed to determine how safe and effective VX-548 is, especially when combined with other pain treatments and when used in certain situations such as during pregnancy and breastfeeding.

Plain language summary

Article highlights.

• Voltage-gated sodium channels NaV1.8 play an important role in pain physiology, with NaV1.8-specific inhibitors having greater analgesic efficacy and lower risk of adverse effects compared with non-specific NaV inhibitors.

• VX-548 is an oral NaV1.8-selective inhibitor with over 31000-times greater selectivity for NaV1.8 than other NaV subtypes.

• Two Phase II trials of patients who underwent abdominoplasty and bunionectomy reported that high-dose VX-548 significantly decreased pain scores compared with placebo.

• Two Phase III trials also showed significant pain reduction with VX-548 versus placebo after abdominoplasty and bunionectomy, but no significant difference in pain scores compared with hydrocodone bitartrate-acetaminophen in the abdominoplasty trial and less reduction in the bunionectomy trial.

• Evidence from the Phase II and III clinical trials suggests that VX-548 is well-tolerated, with the most common adverse effects being nausea or vomiting, headache, constipation and dizziness.

• A single-arm safety and efficacy trial in patients with acute surgical and non-surgical pain concluded that treatment with VX-548 for up to 14 days was safe and well-tolerated, with headache being the most common adverse effect.

• Little evidence exists for prolonged VX-548 administration. A Phase II trial of patients with painful diabetic peripheral neuropathy who were administered VX-548 at varying doses over 12 weeks reported decreased creatinine clearance in the high-dose group.

• VX-548 has received Fast Track and Breakthrough Therapy designations from the US FDA for the treatment of moderate to severe acute pain.

• VX-548 has the potential to provide efficacious and well-tolerated analgesia for acute pain. However, this should be confirmed in larger clinical trials. Data pertaining to its safety and efficacy within the context of multimodal analgesia, pregnancy and breastfeeding women are also required.

1. Introduction

Management of acute pain requires a balance between providing adequate pain relief against the risk of analgesia-related adverse effects. Acute pain has been associated with impaired recovery, delayed hospital discharge and poor quality of life [1,2]. Furthermore, poorly treated acute pain increases the risk of developing chronic pain, with an estimated socioeconomic impact of $635 billion annually in medical expenses, loss of productivity and disability programs within the USA alone [3].

The current standard of pain management involves a multimodal approach that employs medications with different mechanisms of action such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, local anesthetics and N-methyl-D-aspartate (NMDA) receptor antagonists. Nonetheless, opioids remain the cornerstone of moderate to severe acute pain treatment, which is highly prevalent and affects approximately 75% of postoperative patients [4].

Analgesics such as opioids, gabapentinoids and NSAIDs can be associated with adverse effects including sedation, respiratory depression, nausea, vomiting, constipation and renal impairment [5]. Furthermore, the high abuse potential and dramatic rise in opioid utilization have contributed to the opioid epidemic, which was responsible for over 650,000 deaths from opioid overdoses since 1999 within the USA [6]. The concerns regarding analgesic-related adverse effects combined with limited available analgesic options have prompted the search for novel pharmacological treatments with improved efficacy and adverse effect profiles. The recent discovery of the important role played by voltage-gated sodium channel NaV1.8 in acute pain physiology has spurred research into developing NaV1.8-specific inhibitors. In this review, we will discuss the role of NaV1.8 in acute pain and summarize existing evidence pertaining to the novel NaV1.8-specific inhibitor VX-548 within the context of acute pain treatment.

2. Overview of the field

Pain is defined as an unpleasant sensory or emotional experience due to actual or potential tissue damage [7]. Fundamentally, the pain pathway can be divided into four distinct processes: transduction; transmission; modulation; and perception [2]. During transduction, noxious stimuli are detected by specialized nociceptors and converted into nerve impulses. These impulses are transmitted by Aδ- and C-type neurons to the dorsal root ganglion (DRG) and subsequently, to the thalamus through ventrolateral spinothalamic tracts within the spinal cord [2]. At various points during pain transmission, nociceptive stimuli can be altered by the process of modulation, thereby affecting the patient's overall pain experience [8]. Modulation can occur via several mechanisms, including the activation of opioid receptors by endogenous and exogenous opioids, autonomic nervous system responses and regulation of NMDA and gamma-aminobutyric acid (GABA) signaling [8]. Upon reaching the brain, perception of the nociceptive signals occurs via extremely complex processes involving multiple cortical and subcortical brain areas that process, relay and modulate the pain experience in a bi-directional manner [2].

Analgesics relieve pain through their actions at various points of the pain pathway. For instance, NSAIDs and acetaminophen reduce inflammation and nociceptive stimulation through inhibition of cyclooxygenase (COX) and peroxidase (POX) pathways, respectively [9,10]. Local anesthetics block transmission of nociceptive signals via non-specific sodium channel inhibition, gabapentinoids increase glutamate update and block calcium channels, while NMDA antagonists like ketamine and opioids act through modulation of pain signaling [8,11–13].

The discovery of the important role NaV tetrodotoxin-resistant voltage-gated sodium channels play in pain transmission has galvanized research into the potential analgesic use of NaV modulators. Of the nine known NaV subtypes (NaV1.1 to NaV1.9), NaV1.7, NaV1.8 and NaV1.9 are preferentially expressed in nociceptive neurons within the peripheral nervous system [14,15]. Initial research focused on developing NaV1.7 inhibitors, but despite promising in vitro results, NaV1.7 inhibitors fared poorly in clinical trials due to issues such as inadequate inhibition of spinal cord NaV1.7, short inhibition time, toxicity and limited bioavailability [16,17]. Conversely, development of NaV1.9 inhibitors was hampered by difficulties expressing the functional channel in vitro [15], hence placing the spotlight on NaV1.8.

NaV1.8 is a sodium channel that acts at C-type DRG neurons [18] and its role in the pain pathway has been validated in both genetic and pharmacologic studies. Renganathan et al. showed that mice expressing NaV1.8 produced all-or-none action potentials in C-type DRG neurons, in contrast to the small, graded responses observed in NaV1.8 knockout mice [18]. In another study using the rat model, inhibiting NaV1.8 gene expression using varying doses of antisense oligodeoxynucleotide following spinal cord injury demonstrated dose-dependent reduction in allodynic and hyperalgesic responses to neuropathic pain [19]. Conversely, human gain-of-function mutations in NaV1.8 were associated with increased neuronal excitability and may exacerbate pain arising from peripheral neuropathies [20]. In addition to its role in pain transmission, NaV1.8 neuronal cell bodies have been identified in several encephalic regions including the limbic system [21], indicating its involvement in pain perception. Put together, these findings suggest that NaV1.8 plays a critical role in pain sensation and perception, therefore representing a validated target for analgesia.

However, modulation of NaV channels should be approached cautiously given their expression in cardiomyocytes raising concerns of adverse cardiovascular effects. For instance, NaV1.8 mutations are associated with Brugada Syndrome and increased NaV1.8 expression has been associated with cardiac failure, myocardial hypertrophy and electrical remodeling [22–24]. Lidocaine, a non-specific inhibitor of NaV channels that is commonly used for management of postoperative and chronic pain, exhibits some analgesic effects at low doses but its effectiveness is limited by the risk of cardiovascular complications at higher doses [25,26], attributable to non-specific inhibition of other NaV subtypes that are predominantly expressed in cardiomyocytes such as NaV1.5 [27,28].

Hence, it was hypothesized that NaV1.8-specific inhibitors may improve analgesic efficacy while reducing the risk of adverse effects mediated by other NaV subtypes. Unfortunately, although compounds specifically targeting NaV.1.8 such as A-803467, VX-128 and VX-150 demonstrated promising efficacy in animal studies, they failed to achieve adequate analgesic efficacy or had significant adverse effects in human trials. For example, A-803467 demonstrated 1000-fold increased selectivity for NaV1.8 over other NaV subtypes, effectively blocking sensory neuron excitability both in vitro and in vivo, and significantly reduced nociceptive sensitivity after nerve injury and inflammation in animal experimental pain models [29]. In preclinical trials, however, A-803467 was abandoned due to poor oral bioavailability and limited effectiveness in reducing formalin-induced pain, acute thermal pain and postoperative pain [29]. In the case of VX-128, a Phase I dose-escalation study evaluating its safety, pharmacokinetics and pharmacodynamics was prematurely terminated due to skin rash in 19.2% of participants and one case of angioedema (3.8%) [27]. Of note, although pain assessments within this trial were exploratory, the authors showed that VX-128 exhibited dose-dependent increases in pressure pain and cold pressor pain thresholds, which suggest that VX-128 may possess analgesic efficacy [27]. Another compound, VX-150 was evaluated in a Phase I randomized, double-blind, placebo-controlled crossover study of 20 healthy male adults, which reported significant change in cold pressor and heat pain, though these effects were attributed to modulation of receptors other than NaV1.8 such as Transient Receptor Potential M8 (TRPM8) [30]. VX-150 was also evaluated in proof-of-concept clinical studies involving patients with acute pain from bunionectomy and small fiber neuropathy [31,32]. However, further development was curtailed by the high doses required to achieve moderate analgesic effectiveness and adverse effects such as headaches.

The reformative compound VX-548 was subsequently developed to address some of the issues encountered with prior NaV1.8-specific inhibitors.

3. Pharmacology

VX-548 (Suzetrigine, Vertex Pharmaceuticals Inc) is an oral NaV1.8-selective inhibitor that exhibited over 31000-times greater selectivity for NaV1.8 than other NaV subtypes, and high potency (50% of maximal inhibitory concentration, IC₅₀ = 0.68 ± 0.16 nM) in human DRG neurons [33]. Pharmacokinetic studies on associated drug–drug and food–drug interactions [34–38], as well as the use of VX-548 in patients with various organ system impairments [39,40] are currently under way.

4. Clinical efficacy

The efficacy and safety of VX-548 in the treatment of acute pain was demonstrated in two Phase II and two Phase III clinical trials. Table 1 summarizes the characteristics of each trial, while Table 2 highlights the key findings.

Table 1.

Summary of Phase II and III trial characteristics.

	Phase II [33]		Phase III [41]
	548-101	548-102	548-104	548-105	548-107
Study design	Randomized-controlled	Randomized-controlled	Randomized-controlled	Randomized-controlled	Single-arm safety and effectiveness study
Surgery	Bunionectomy	Abdominoplasty	Bunionectomy	Abdominoplasty	Patients with acute surgical and non-surgical pain
Number of patients receiving intervention	274	303	1073	1118	256
Type of anesthesia	Regional: popliteal-sciatic and Mayo block	General anesthesia	Regional: popliteal-sciatic and Mayo block	General anesthesia	Information unavailable
Pain inclusion criteria	NPRS ≥4 and moderate or severe pain within 9 h after removal of popliteal-sciatic block	NPRS ≥5 within 4 h after end of surgery	Information unavailable	Information unavailable	Information unavailable
Treatment duration	48 h	48 h	48 h	48 h	Up to 14 days
Follow-up period for adverse events, safety and tolerability	18 days	17 days	17 days	17 days	28 days
VX-548 high-dose regimen	100 mg loading, then 50 mg Q12H	100 mg loading, then 50 mg Q12H	100 mg loading, then 50 mg Q12H	100 mg loading, then 50 mg Q12H	100 mg loading, then 50 mg Q12H
VX-548 middle-dose regimen	60 mg loading, then 30 mg Q12H	60 mg loading, then 30 mg Q12H	–	–	–
VX-548 low-dose regimen	20 mg loading, then 10 mg Q12H	–	–	–	–
Hydrocodone bitartrate-acetaminophen regimen	5 mg/325 mg Q6H	5 mg/325 mg Q6H	5 mg/325 mg Q6H	5 mg/325 mg Q6H	–
Multimodal analgesia	- 0.2% ropivacaine via continuous popliteal-sciatic block infusion, up to 5 am on POD 1 - Acetaminophen 975–1000 mg Q6H PRN if NPRS 4–6 - Fentanyl 12.5–25 mg Q2H PRN if NPRS ≥7 - Ibuprofen 400 mg Q6H PRN for rescue analgesia	- Fentanyl, up to 250 mcg from induction to emergence - Fentanyl 12.5–25 mcg if severe pain within 30 minutes after surgery completion - Ibuprofen 400 mg Q6H PRN for rescue analgesia	Information unavailable	Information unavailable	Information unavailable
Efficacy outcome	Least-squares mean difference in the time-weighted sum of pain intensity difference 48 h after first dose of study drug				Safety and tolerability
Safety outcomes	- Incidence of treatment-emergent adverse effects - Clinical laboratory values - Standard 12-lead ECG outcomes - Vital signs		Number of participants with adverse events and serious adverse events, including nausea, headache, constipation, dizziness, hypotension (further details not available).

ECG: Electrocardiogram; NPRS: Numeric pain rating scale; POD: Post-operative day; PRN: As needed.

Table 2.

Summary of Phase II and III trial findings.

	Phase II [33]		Phase III [41]
	548-101 (bunionectomy)	548-102 (abdominoplasty)	548-104 (bunionectomy)	548-105 (abdominoplasty)
LSM SPID 48 compared with baseline, mean (standard error)
VX-548 high-dose regimen	137.8 (11.5)	110.5 (10.3)	99.9 (4.5)	118.4 (4.3)
VX-548 middle-dose regimen	86.9 (11.3)	95.1 (10.4)	–	–
VX-548 low-dose regimen	112.9 (15.5)	–	–	–
Hydrocodone bitartrate-acetaminophen regimen	115.6 (11.5)	85.2 (10.3)	120.1 (4.5)	111.8 (4.3)
Placebo	101.0 (11.6)	72.7 (10.2)	60.7 (6.3	70.1 (6.1)
LSM difference compared with placebo, mean (95% confidence interval)
VX-548 high-dose regimen	36.8 (4.6–69.0)	37.8 (9.2–66.4)	29.3 (14.0–44.6)	48.4 (33.6–63.1)
VX-548 middle-dose regimen	-14.1 (-46.1–17.9)	22.4 (-6.4–51.1)	–	–
VX-548 low-dose regimen	11.9 (-26.2–50.1)	–	–	–
Hydrocodone bitartrate-acetaminophen regimen	14.7 (-17.5–46.8)	12.5 (-16.1–41.1)	Data unavailable	Data unavailable
Adverse event rates, % (high-dose VX-548 group, hydrocodone bitartrate-acetaminophen group, placebo group)
Nausea	8,18, 8	18, 30, 36	8.2, 14.4, 10.6	19.0, 32.8, 25.2
Headache	8, 7, 12	14, 7, 6	4.9, 10.4, 9.3	4.2, 7.1, 5.0
Constipation	0, 2, 2	9, 12, 5	3.5, 5.1, 4.2	10.5, 8.7, 10.8
Dizziness	3, 2, 2	8, 11, 18	3.5, 5.3, 5.1	4.0, 5.4, 7.7
Vomiting	0, 5, 23	3, 11, 6	Data unavailable	Data unavailable
Hypotension	Data unavailable	Data unavailable	Data unavailable	2.5, 3.6, 6.8
Severe & life-threatening events	0, 0, 0	0, 1, 0	0, 0, 0	Low rate of serious adverse events, none related to VX-548

The results of the Phase III single-arm safety and effectiveness study [41] are not included in this table due to notable differences in study protocol compared with the other Phase II and III trials, such as treatment duration and conditions treated with VX-548. More information can be found in the text.

LSM: Least-squares mean; SPID: Sum of the pain intensity difference.

VX-548 was evaluated in two Phase II, randomized, double-blind, placebo-controlled trials [33] involving 577 patients aged 18 to 75, of whom 274 underwent bunionectomy and 303 underwent abdominoplasty. The primary outcome for both trials was least-squares mean difference in the time-weighted sum of the pain intensity difference (SPID), as measured by numeric pain rating scale (NPRS) scores over a period of 48 h between VX-548 and placebo. Secondary outcomes included the time-weighted SPID between VX-548 and placebo over a 24-h period, as well as the percentages of patients with a decrease in NPRS scores of at least 30%, 50% and 70% from baseline at 48 h after the first dose of the study drug. Safety outcomes like adverse events, derangement in clinical laboratory values, 12-lead electrocardiograms and vital signs were assessed by investigators who were not privy to trial group assignments.

In the bunionectomy trial (548–101) [33], 274 patients underwent bunionectomy under regional anesthesia (popliteal-sciatic and Mayo blocks), followed by a continuous infusion of 0.2% ropivacaine via popliteal-sciatic block up to 5 am on the first postoperative day. Patients were included if they reported NPRS of at least 4, or moderate or severe pain on the verbal categorical rating scale (VRS) within 9 h after removal of the popliteal-sciatic block. Participants were randomized to receive high, middle or low-dose VX-548 regimens, hydrocodone bitartrate-acetaminophen or placebo in a 2:2:1:2:2 ratio. Over 90% of patients completed the 48-h treatment period. A significant difference of 36.8 (95% CI -1.8 to 29.1) in the 48-h SPID least-squares mean difference between patients who received high-dose VX-548 compared with placebo was noted. However, no significant change was noted in the 48-h SPID least-squares mean difference between groups receiving middle and low-dose VX-548 regimens, hydrocodone bitartrate-acetaminophen or placebo. Similarly, no significant difference was noted in 24-h SPID least-squares mean difference between all intervention groups compared with placebo.

In the abdominoplasty trial (548–102) [33], 303 patients underwent abdominoplasty under general anesthesia. Up to 250 mcg of fentanyl was allowed from induction to emergence, followed by 12.5 to 25 mcg if patient was in severe pain within 30 minutes after surgery completion. Patients were included if they reported a pain score of at least 5 on the NPRS within 4 h after the end of surgery. Patients were randomized to receive high or middle-dose VX-548 regimens, hydrocodone bitartrate-acetaminophen or placebo in a 1:1:1:1 ratio, with 81.5% of patients completing the 48-h treatment period. The 48-h SPID least-squares mean difference was significantly different between the VX-548 high-dose group and placebo (37.8, 95% CI 4.6–69.0). This relationship was also observed in the 24-h SPID least-squares mean difference between the VX-548 high-dose group compared with placebo. No significant difference was noted in 24- and 48-h SPID least-squares mean difference between groups receiving lower-doses VX-548 regimen, hydrocodone-bitartrate, or placebo. NPRS scores in patients receiving high-dose VX-548 compared with those who received placebo in these two Phase II trials are illustrated in Figure 1.

Figure 1.

Mean NPRS scores over time in Phase II trials. Panel A shows the mean numeric pain rating scale (NPRS) scores over time for participants in the abdominoplasty trial who received VX-548 high-dose regimen vs placebo, throughout the entire treatment period and during the first 4 h of treatment (inset). Panel B shows the mean NPRS scores for participants in the bunionectomy trial who received VX-548 high-dose regimen vs placebo, throughout the entire treatment and during the first 4 h of treatment (inset). The I bars indicate the standard error (SE).

Data taken from [42] Copyright © 2023 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

To summarize, both Phase II trials reported that a high-dose regimen of VX-548 (100 mg loading dose, followed by 50 mg every 12 h) was associated with significantly decreased pain scores compared with placebo, while lower VX-548 doses showed no significant reduction in pain intensity compared with placebo or hydrocodone bitartrate-acetaminophen.

In January 2024, Vertex Pharmaceuticals Inc announced positive results from two Phase III randomized, double-blind, placebo-controlled clinical trials [41,43], involving 1118 patients undergoing abdominoplasty under general anesthesia and 1073 patients undergoing bunionectomy under popliteal-sciatic and Mayo block regional anesthesia that were treated with VX-548 (100 mg loading dose, followed by 50 mg every 12 h), hydrocodone bitartrate-acetaminophen or placebo, over 48 h post-operatively. These showed that treatment with VX-548 resulted in a statistically significant reduction in pain scores compared with placebo, along with rapid, sustained pain relief. However, when compared with hydrocodone bitartrate-acetaminophen, treatment with VX-548 resulted in a similar (abdominoplasty trial) or smaller (bunionectomy trial) degree of reduction in pain scores. The trend of NPRS scores over the 48-h treatment duration are summarized in Figure 2. It should also be highlighted that this data were provided in the company's press release, and that the Phase III studies and results have not been formally published in a peer-reviewed journal at time of writing this drug evaluation.

Figure 2.

Mean NRPS scores over time in Phase III trials. The top panel shows the mean numeric pain rating scales (NPRS) scores over time for participants in the abdominoplasty trial who received VX-548 vs hydrocodone bitartrate-acetaminophen vs placebo throughout the entire treatment period. The bottom panel shows the mean NPRS scores for participants in the bunionectomy trial who received VX-548 vs hydrocodone bitartrate-acetaminophen vs placebo throughout the entire treatment period. The I bars indicate the standard error (SE).

Data taken from [44] Copyright © 2024 Vertex Pharmaceuticals Incorporated. Reprinted with permission from Vertex Pharmaceuticals Incorporated.

The use of VX-548 in the treatment of neuropathic pain is also being explored. In late 2023, Vertex Pharmaceuticals Inc announced promising results of a Phase II study in patients with painful diabetic peripheral neuropathy [45] Further Phase II trials are under way for conditions such as lumbosacral radicular pain.

5. Safety & tolerability

Available evidence suggests that VX-548 is well-tolerated with a favorable safety profile. The two Phase II trials reported that adverse events were largely of mild to moderate severity, the most common (occurring in at least 10% of trial participants in any group) being nausea, headache, constipation, dizziness and vomiting [33]. Apart from a higher incidence of headache and constipation in the VX-548 high-dose group as compared with placebo in the abdominoplasty trial, the incidence of most adverse events in the VX-548 groups were similar or lower as compared with placebo. Most episodes of headache and constipation were mild and resolved quickly with symptomatic treatment or no treatment, and discontinuation of trial drug was not necessary. Three participants in the abdominoplasty trial experienced serious events such as incision-site cellulitis (placebo group), sepsis, laryngeal stenosis (hydrocodone bitartrate-acetaminophen group) and pulmonary embolism (VX-548 middle-dose group) – but these events were deemed unrelated to any of the trial drugs. None of the participants experienced serious adverse events in the bunionectomy trial. In both trials (abdominoplasty/bunionectomy) study drug discontinuation was less in the high-dose VX.548 group (9.2%/3.3%) compared with the placebo (24.7%/13.6%) and the hydrocodone bitartrate-acetaminophen (17.6%11.7%) groups. Similar findings were found in the subsequent two Phase III trials, with the VX-548 group demonstrating lower incidence of adverse events compared with placebo and with no serious adverse events encountered in any trial group [41,43].

A single-arm safety and effectiveness trial on 256 patients with both acute surgical and non-surgical pain showed that treatment with VX-548 for up to 14 days was safe and well-tolerated [41,43]; with 36.7% of patients experiencing adverse events, of whom headache was the most common (>5%). Further details regarding other adverse events were not provided.

Less evidence is available regarding the safety of prolonged VX-548 administration. A Phase II clinical trial of 192 patients with painful diabetic peripheral neuropathy who were administered varying doses of VX-548 for 12 weeks reported decreased creatinine clearance in 10.9% of patients in the high-dose group (69 mg four-times a day) [45]. Further details on the magnitude and clinical implications of this reduction in creatinine clearance were not provided in the company's report.

6. Regulatory affairs

VX-548 (Suzetrigine, Vertex Pharmaceuticals Inc) has received prior Fast Track and Breakthrough Therapy designations from the United States Food and Drug Administration (FDA) for the treatment of moderate to severe acute pain. On 30 July 2024, Vertex Pharmaceuticals Inc announced that the New Drug Application (NDA) for VX-548 has been approved by the FDA, with a Prescription Drug User Fee Act (PDUFA) target action date of 30 January 2025 [46]. In addition, the FDA has granted VX-548 Breakthrough Therapy designation for the treatment of painful diabetic neuropathy [47].

7. Conclusion

Current evidence from Phase II and III clinical trials suggests that VX-548 holds significant promise as an efficacious and well-tolerated drug for the treatment of acute pain. There is also emerging evidence that VX-548 may potentially be efficacious in treating neuropathic pain. We eagerly await the publication of results from Phase III clinical trials and other pharmacokinetic studies, which may shed more light on the efficacy and safety profile of VX-548. Further research into VX-548 as part of a multimodal analgesia strategy to treat a variety of surgical and non-surgical pain is also needed. Research into the efficacy and safety of VX-548 in special patient populations like pregnant and breastfeeding women will also broaden its potential use.

Author contributions

A Kong: investigation, data curation, writing – original draft, writing – review & editing. HS Tan: investigation, data curation, writing – original draft, writing – review & editing. A Habib: conceptualization, writing – review & editing, supervision.

Financial disclosure

This manuscript was supported solely by departmental funds from the Department of Anesthesiology, Division of Women's Anesthesia, Duke University Medical Center.

Competing interests disclosure

AS Habib has received research funding from Pacira Biosciences and Haisco USA. He has also served on the Advisory Board of Merck & Co and Heron Pharmaceuticals, and is a consultant for Vertex Pharmaceuticals and Orion.