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 Nav1.8 inhibitor,in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Na_vs), such as Na_v1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Na_v1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na_v1.8 inhibitors as pain treatments.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective sodium channel (Na_v) inhibitors have been proposed as an alternative to opioids for pain management. Their potential, however, has yet to be confirmed, as none of the multiple selective Na_v inhibitors that have been investigated for pain management has reached the market.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We investigated the safety, tolerability, and initial analgesic effects of VX‐128, a novel and highly selective Na_v1.8 inhibitor, in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study to describe clinical data obtained on the highly selective Na_v1.8 inhibitor VX‐128, and the first to report analgesic effects of this selective Na_v inhibitor in humans. VX‐128 administered as a single dose was well‐tolerated, but dose‐limiting skin rashes occurred after multiple doses resulting in a premature study halt. Although the study had a parallel design and was not necessarily powered to detect pharmacodynamic effects, nociceptive test results suggest that VX‐128 leads to dose‐dependent analgesic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings substantiate research that is performed on evaluating selective Na_v1.8 inhibitors as treatment for pain, and suggests that the cold pressor‐ and pressure pain models are suitable to evaluate selective Na_v1.8 inhibitors.