Poster Number-49 - Selective Inhibition of NaV1.8 with VX-548 as a Targeted Treatment for Acute Pain

Selective Inhibition of Na_V1.8 with VX-548 as a Targeted Treatment for Acute Pain

Purpose:

Moderate‑to‑severe acute pain is a serious condition with significant individual and public health implications. Acute pain is often treated with opioids due to the absence of effective alternatives. Despite an urgent need for effective, non-opioid pain treatments, there has been a lack of progress in analgesic drug development in recent decades. Na_V1.8 is a voltage-gated sodium channel that is preferentially expressed in peripheral nociceptive neurons and plays a critical role in pain signaling. We hypothesized that selective inhibition of Na_V1.8 would effectively treat pain without the safety and tolerability concerns, including addiction, misuse, and abuse potential, associated with standard‑of‑care opioid therapies. VX-548, an orally bioavailable small molecule, is a highly selective inhibitor of Na_V1.8. We describe the preclinical characterization of VX-548 and report the results of two phase 2 clinical trials evaluating the efficacy and safety of VX-548 for treatment of acute pain after abdominoplasty or bunionectomy.

Methods:

The potency and selectivity of VX-548 was determined in vitro using patch-clamp electrophysiology techniques to quantify Na_V1.8 currents in recombinant cells and dissociated human dorsal root ganglia (DRG) neurons. Two phase 2 randomized, double‑blind, placebo‑controlled, clinical trials evaluated VX‑548 in participants with moderate or severe acute pain following abdominoplasty or bunionectomy. Following surgery, participants with moderate or severe acute pain, as determined by the Verbal Categorical Rating Scale (VRS) and pain ≥4 on the Numeric Pain Rating Scale (NPRS), were randomized to receive VX‑548 (one of two doses in the abdominoplasty trial or one of three doses in the bunionectomy trial), hydrocodone bitartrate/acetaminophen (HB/APAP; opioid reference), or placebo. VX-548 was administered orally at the following doses: 100 mg first dose followed by 50 mg every 12 hours (100 mg/50 mg q12h), 60 mg first dose followed by 30 mg every 12 hours (60 mg/30 mg q12h), or 20 mg first dose followed by 10 mg every 12 hours (20 mg/10 mg q12h) with the latter dose evaluated only in the bunionectomy trial; all VX‑548 doses were administered at 12, 24, and 36 hours after the first dose. HB/APAP was evaluated at a dose of 5 mg/325 mg administered orally every 6 hours (q6h) for 42 hours after the first dose. The primary endpoint was the time‑weighted sum of the pain intensity difference (SPID) as recorded on a NPRS 0 to 48 hours (SPID48) after the first dose of study drug; SPID48 was assessed at rest in the abdominoplasty trial. For the primary endpoint, statistical comparisons were made to placebo only; higher SPID48 values indicate greater improvements in pain relief. Secondary efficacy endpoints included time‑weighted sum of the pain intensity difference from the time of first dose to 24 hours (SPID24) as recorded on a NPRS and the proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at 48 hours after the first dose of study drug. Safety, tolerability, and pharmacokinetics were also assessed as secondary or other endpoints.

Results:

VX-548 potently inhibited Na_V1.8 currents in both dissociated human DRG neurons and recombinant cells with a half-maximal inhibitory concentration (IC₅₀) of approximately 0.7 nM and was highly selective for Na_V1.8 (≥31,000-fold) relative to other Na_V channels in recombinant cells. In both phase 2 trials, treatment with VX‑548 (100 mg/50 mg q12h) resulted in statistically significant superior pain reduction compared to placebo following abdominoplasty (SPID48 LS mean difference from placebo: 37.80, P = 0.0097) and bunionectomy (SPID48 LS mean difference from placebo: 36.79, P = 0.0251). In both trials, treatment with VX‑548 (100 mg/50 mg q12h) resulted in rapid (within 1 hour) and robust pain relief that was sustained throughout the duration of assessment. Notably, treatment discontinuations due to lack of efficacy were substantially lower in participants receiving VX‑548 (100 mg/50 mg q12h) compared to participants receiving placebo or HB/APAP. Results for secondary efficacy endpoints were generally supportive of results for the primary endpoint. VX-548 was generally safe and well tolerated at all doses in both trials. The majority of adverse events (AEs) were mild or moderate in severity and there were no serious adverse events (SAEs) related to VX-548. The most common AEs in ≥10% of participants in any treatment group were nausea, headache, constipation, dizziness, and vomiting in the abdominoplasty trial and nausea and headache in the bunionectomy trial. Two participants in the abdominoplasty trial discontinued VX‑548 due to AEs that were not related to treatment; there were no VX‑548 treatment discontinuations due to AEs in the bunionectomy trial.

Conclusion: Preclinical studies demonstrate that VX-548, a novel small molecule, is a potent and highly selective inhibitor of Na_V1.8. These data translated to a statistically significant and clinically meaningful benefit in two phase 2 clinical trials in acute pain and provide initial evidence that treatment with VX-548 represents an innovative, non-opioid, targeted approach for the treatment of people with acute pain.

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