VX-548 in the Treatment of Acute Pain

Overview

Journal Pain Manag

Specialty Psychiatry

Date 2024 Nov 18

PMID 39552600

Authors

Aaron Yik Hang Kong

Hon Sen Tan

Ashraf S Habib

Affiliations

Soon will be listed here.

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.

References

Hijma H, Siebenga P, de Kam M, Groeneveld G . A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a Highly Selective NaV1.8 Inhibitor, in Healthy Male Adults. Pain Med. 2021; 22(8):1814-1826. PMC: 8346919. DOI: 10.1093/pm/pnab032. View

Gan T . Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017; 10:2287-2298. PMC: 5626380. DOI: 10.2147/JPR.S144066. View

Tenza-Ferrer H, Collodetti M, Nicolau E, Birbrair A, Magno L, Romano-Silva M . Transiently Nav1.8-expressing neurons are capable of sensing noxious stimuli in the brain. Front Cell Neurosci. 2022; 16:933874. PMC: 9464809. DOI: 10.3389/fncel.2022.933874. View

Wick E, Grant M, Wu C . Postoperative Multimodal Analgesia Pain Management With Nonopioid Analgesics and Techniques: A Review. JAMA Surg. 2017; 152(7):691-697. DOI: 10.1001/jamasurg.2017.0898. View

Jarvis M, Honore P, Shieh C, Chapman M, Joshi S, Zhang X . A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007; 104(20):8520-5. PMC: 1895982. DOI: 10.1073/pnas.0611364104. View

Jones J, Correll D, Lechner S, Jazic I, Miao X, Shaw D . Selective Inhibition of Na1.8 with VX-548 for Acute Pain. N Engl J Med. 2023; 389(5):393-405. DOI: 10.1056/NEJMoa2209870. View

Kitano Y, Shinozuka T . Inhibition of Na1.7: the possibility of ideal analgesics. RSC Med Chem. 2022; 13(8):895-920. PMC: 9384491. DOI: 10.1039/d2md00081d. View

CLARE , Tate , Nobbs , ROMANOS . Voltage-gated sodium channels as therapeutic targets. Drug Discov Today. 2000; 5(11):506-520. DOI: 10.1016/s1359-6446(00)01570-1. View

Hijma H, van Brummelen E, Siebenga P, Groeneveld G . A phase I, randomized, double-blind, placebo-controlled, single- and multiple dose escalation study evaluating the safety, pharmacokinetics and pharmacodynamics of VX-128, a highly selective Na 1.8 inhibitor, in healthy adults. Clin Transl Sci. 2021; 15(4):981-993. PMC: 9010276. DOI: 10.1111/cts.13215. View

10.

Dybkova N, Ahmad S, Pabel S, Tirilomis P, Hartmann N, Fischer T . Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart. Cardiovasc Res. 2018; 114(13):1728-1737. DOI: 10.1093/cvr/cvy152. View

11.

Khera T, Rangasamy V . Cognition and Pain: A Review. Front Psychol. 2021; 12:673962. PMC: 8175647. DOI: 10.3389/fpsyg.2021.673962. View

12.

Ahmad S, Tirilomis P, Pabel S, Dybkova N, Hartmann N, Molina C . The functional consequences of sodium channel Na 1.8 in human left ventricular hypertrophy. ESC Heart Fail. 2018; 6(1):154-163. PMC: 6352890. DOI: 10.1002/ehf2.12378. View

13.

Mullard A . Vertex's non-opioid painkiller passes phase III tests. Nat Rev Drug Discov. 2024; 23(3):162. DOI: 10.1038/d41573-024-00029-z. View

14.

Odening K . The Role of Nav1.8 in Cardiac Electrophysiology-a Matter of the Heart or the Nerve?. Cardiovasc Drugs Ther. 2020; 33(6):645-647. DOI: 10.1007/s10557-019-06931-8. View

15.

Faber C, Lauria G, Merkies I, Cheng X, Han C, Ahn H . Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012; 109(47):19444-9. PMC: 3511073. DOI: 10.1073/pnas.1216080109. View

16.

Gil-Gouveia R, Goadsby P . Neuropsychiatric side-effects of lidocaine: examples from the treatment of headache and a review. Cephalalgia. 2009; 29(5):496-508. DOI: 10.1111/j.1468-2982.2008.01800.x. View

17.

Gan T, Habib A, Miller T, White W, Apfelbaum J . Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin. 2013; 30(1):149-60. DOI: 10.1185/03007995.2013.860019. View

18.

Anderson B . Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008; 18(10):915-21. DOI: 10.1111/j.1460-9592.2008.02764.x. View

19.

Alsaloum M, Higerd G, Effraim P, Waxman S . Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat Rev Neurol. 2020; 16(12):689-705. DOI: 10.1038/s41582-020-00415-2. View

20.

Raja S, Carr D, Cohen M, Finnerup N, Flor H, Gibson S . The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020; 161(9):1976-1982. PMC: 7680716. DOI: 10.1097/j.pain.0000000000001939. View