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

Abstract

Objective: To evaluate the analgesic potential, safety, tolerability, and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects.

Design: This was a randomized, double-blind, placebo-controlled, crossover study in healthy subjects.

Subjects: Twenty healthy male subjects with an age of 18-55 years, inclusive, were enrolled. Eligibility was based on general fitness, absence of current or previous medical conditions that could compromise subject safety, and a training assessment of pain tolerance across pain tests to exclude highly tolerant individuals whose tolerance could compromise the ability to detect analgesic responses. All dosed subjects completed the study.

Methods: Subjects were randomized 1:1 to one of two sequences receiving a single VX-150 dose and subsequently placebo, or vice versa, with at least 7 days between dosing. A battery of pain tests (pressure, electrical stair, [capsaicin-induced] heat, and cold pressor) was administered before dosing and repetitively up to 10 h after dosing, with blood sampling up to 24 h after dosing. Safety was monitored throughout the study. Data were analyzed with a repeated-measures mixed-effects model.

Results: VX-150 induced analgesia in a variety of evoked pain tests, without affecting subject safety. Significant effects were reported for the cold pressor and heat pain thresholds. Maximum median concentration for the active moiety was 4.30 µg/mL at 4 h after dosing.

Conclusion: Results of this proof-of-mechanism study are supportive of the potential of VX-150, a highly selective NaV1.8 channel inhibitor, to treat various pain indications.

Keywords: Experimental Pain; NaV1.8-Selective Inhibitor; VX-150.

Figure 1.

Study design. Twenty subjects were randomized and equally allocated to one of the two treatment sequences. n = number of subjects.

Figure 2.

Primary evoked pain test endpoints, represented as change from baseline in percentages (%). Baseline has been defined as the average of two pre-dosing measurements of that occasion, except for the capsaicin-induced PDT. For this test, the second pre-dosing assessment served as baseline, given that there was no capsaicin applied before this assessment. Values on the y-axis represent the least-squares means change and the 95% CI. Time is shown in hours on the x-axis. (A) Cold pressor PTT. (B) Electrical stair PTT. (C) CPM PTT. (D) Pressure PTT. (E) Heat PDT on capsaicin-treated skin (“capsaicin heat PDT”). (F) Heat PDT on untreated skin (“normal heat PDT”). °C = degrees Celsius; CPM = conditioned pain modulation; mA = milliamperes; PDT = pain detection threshold; PTT = pain tolerance threshold.

Figure 3.

Pharmacokinetics results. Mean concentration of VX-150’s active moiety and of its major circulating metabolite (in µg/mL, on the x-axis) after single oral doses of 1,250 mg VX-150 over time (in hours, on y-axis). Data are represented on a linear scale.

Figure 4.

Analgesic profile of 1,250 mg VX-150. Visualization of the effect size of VX-150 for each pain modality, defined as the ED between the least-squares means of the contrast placebo—VX-150. Round markers for heat pain PDT and cold pressor PTT indicate a significantly different treatment effect of VX-150 vs. placebo over the complete time course, before dosing up until 10 h after dosing (P < 0.05). Percentage ranges provided in parentheses reflect the range of responses reported across a battery of analgesics summarized in an earlier report of this profile model, except for the cold pressor PTT, which had to be increased from 0–50% to 0–60% to reflect the larger effect size of VX-150 observed in this study [19]. For cold pressor PTT and pressure PTT, the ED as included in Table 3 was used, as the data for these end points were log-transformed for analysis and therefore already presented in percentages. For other end points, as those were not log-transformed, the ED was divided by the first least-squares mean of the contrast (i.e., of placebo) and multiplied by 100 to allow the effect size to be reported as percentages, as well.