What is VX-548?

VX-548 (suxetrigine) is an experimental analgesic (pain-relieving medicine) that works by selectively blocking an ion channel called Nav1.8. It is currently undergoing investigational trials to assess its ability to relieve moderate to severe acute pain or peripheral neuropathic pain.

How does VX-548 work?

Advances in understanding the physiology behind pain has led to a better appreciation of the role ion channels play in this process. There are many different types of ion channels including transient receptor potential (TRP) channels, voltage-gated ion channels (Nav) channels, calcium channels (CaV), Acid-sensing ion channels (ASICs), Piezo channels, and Purinergic receptor ion channels (P2X).

VX-548 is a highly selective inhibitor of Nav1.8, one of three Nav channels (Nav1.7, Nav1.8, Nav1.9) that have been identified as excellent targets for pain management as they are vital for the voltage changes across the nerve membrane and the transmission of painful stimuli in the peripheral nervous system. VX-548 works by blocking only the Nav1.8 channel, and research to date has presented positive results and a well-tolerated side effect profile. Many non-selective Nav channel blockers such as carbamazepine, lacosamide, and mexiletine are already being used off-label for various pain conditions.

Vertex has other Nav1.8 and Nav1.7 inhibitors that it is also investigating.

How is VX-548 taken?

VX-548 is an oral tablet that is taken every 12 hours after an initial loading dose.

The dose used in the phase 3 clinical trials was a loading dose of 100mg followed by 50mg every 12 hours.

What are the side effects of VX-548?

Nausea, constipation, headache, and dizziness were the main side effects reported with VX-548 by 5% or more participants in the clinical trials. There were no serious side effects reported.

How effective is VX-548 (suxetrigine)?

Results from phase 3 clinical trials conducted by Vertex included two randomized controlled trials (RCT) and one single-arm safety and effectiveness study.

• Statistically and clinically meaningful improvements in pain intensity and pain reduction in baseline compared to placebo (an inactive pill) were reported after 48 hours with the two RCTs – one of which was conducted following abdominoplasty (a “tummy tuck”) and the other following bunion removal.
• The mean difference in the SPID48* was 48.4 (95% CI: 33.6, 63.1; P<0.0001) with abdominoplasty and 29.3 (95% CI: 14.0, 44.6; P=0.0002) after bunion removal.
• Both trials also investigated whether VX-548 was superior to hydrocodone bitartrate/acetaminophen, but results indicated that this secondary endpoint was not met (meaning that VX-548 was not more effective than hydrocodone bitartrate/acetaminophen).
• Another secondary endpoint was the median time to meaningful pain relief which was reported as 2 hours for abdominoplasty (P<0.0001) and 4 hours for bunion removal (P<0.0016) compared with 8 hours for placebo.

With regards to peripheral neuropathic pain (nerve pain that affects the hands and feet and other areas outside the spinal cord), the results of phase 2 studies have been positive.

*SPID48: time-weighted sum of the pain intensity difference from 0 to 48 hours

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Is VX-548 (suxetrigine) FDA-approved?

VX-548 is not yet approved by the Food and Drug Administration (FDA) but Vertex is planning to submit a New Drug Application by mid-2024 for VX-548 to be used for moderate to severe acute pain (acute pain is pain that lasts less than 3 months).

VX-548 currently has both Fast Track and Breakthrough Therapy designations – these are processes designed to expedite the development of drugs that offer a substantial improvement on current therapy or address an unmet need – for this indication. Current treatment options rely heavily on opioids which have serious side effects including the potential for addiction and dependence.

Vertex is also planning to seek a label for peripheral neuropathic pain.

Vertex has other Nav1.8 and Nav1.7 inhibitors that it is investigating.

Who makes VX-548?

VX-548 is made by Vertex Pharmaceuticals Incorporated.