With the world in an opioid crisis, the development of non-opioid analgesics has become more urgent. A series of Phase 3 clinical trials into a novel oral, non-opioid painkiller has found that it’s effective in treating acute pain in both surgical and non-surgical settings.
Voltage-gated sodium channels are key determinants for regulating the generation and spread of neuronal action potentials, or nerve impulses, electrical charges that travel along a neuron’s membrane. There are different types of sodium channels; NaV1.8 plays a critical role in pain signaling in the peripheral nervous system.
Vertex Pharmaceuticals Inc. recently reported the results of Phase 3 clinical trials to test its oral, non-opioid NaV1.8 inhibitor, VX-458. The trials found that the drug effectively treats moderate-to-severe acute pain in surgical and non-surgical conditions.
The trials included two randomized, double-blind, placebo-controlled, pivotal trials examining the effect of VX-458 following surgical procedures: abdominoplasty, commonly called a ‘tummy tuck,’ and bunion removal (bunionectomy). A pivotal trial is designed to gather statistically significant evidence of efficacy and safety to obtain marketing approval by regulatory authorities. Abdominoplasty was chosen because it’s a model of soft-tissue pain, while bunionectomy is a model of bone pain. In addition, there was a single-arm Phase 3 trial into the drug’s safety and efficacy in treating various surgical and non-surgical pain conditions.
Results following abdominoplasty and bunionectomy surgery
In both the abdominoplasty and bunionectomy trials, patients were given oral doses of either VX-458, a combination of hydrocodone and acetaminophen (Vicodin), or a placebo over 48 hours. VX-458 was given at an initial dose of 100 mg, followed by 50 mg every 12 hours, whereas hydrocodone/acetaminophen 5 mg/325 mg was given every six hours.
The abdominoplasty trial involved 1,118 patients aged 18 to 80 with moderate-to-severe pain following surgery; the bunionectomy trial involved 1,073 patients. In both trials, based on patients’ reported pain intensity difference from baseline, statistically significant pain relief was observed compared to the placebo. The hypothesis that VX-458 would provide superior pain relief to hydrocodone/acetaminophen was not supported in either trial.
VX-458 had a more rapid onset than the placebo, producing a sustained, two-or-more-point (i.e., ‘meaningful’) reduction in pain rating within two hours and four hours in abdominoplasty and bunionectomy patients, respectively, whereas the median time to meaningful pain relief for the placebo was eight hours.
Safety and effectiveness study: surgical and non-surgical acute pain
The third of the Phase 3 trials evaluated treatment with VX-458 for up to 14 days in 256 patients with a range of other surgical and non-surgical acute pain conditions, using the same dosing regimen as in the preceding studies.
Surgical patients included those who’d undergone orthopedic, plastic, urologic and general surgery. Non-surgical patients included those with upper and lower extremity pain, orofacial pain, and multiple concurrent pain conditions. Measured by a Patient Global Assessment (PGA) at the end of treatment, 83.2% of participants rated the drug as ‘good’, ‘very good’ or ‘excellent’ at treating pain.
Adverse events in all three clinical trials
VX-458 was found to be safe and well-tolerated across all three trials. The majority of adverse events were mild-to-moderate, and no serious adverse events were reported.
In general, adverse events in the two randomized controlled trials were consistent with the surgery performed. The number of adverse events with VX-458 was lower than that seen with the placebo: 50.0% versus 56.3% following abdominoplasty and 31.0% versus 35.2% following bunionectomy.
“We are very pleased with the results from the VX-458 pivotal program, which demonstrate a compelling and consistent combination of efficacy and safety across multiple acute pain conditions and settings,” said Reshma Kewalramani, CEO and President of Vertex. “The VX-458 benefit-risk profile ideally positions it to potentially fill the gap with good tolerability but limited efficacy and opioid medicines with therapeutic efficacy but known risks, including addictive potential.”
Next steps
Vertex plans to submit a New Drug Application for VX-458 to the US Food and Drug Administration (FDA) by mid-2024, seeking approval to treat moderate-to-severe acute pain.
The company had previously undertaken smaller Phase 2 clinical trials into VX-458’s effectiveness in treating acute pain in post-operative patients (abdominoplasty and bunionectomy) and a Phase 2 study assessing its effectiveness in treating peripheral neuropathic pain caused by diabetes. They’ve also initiated a Phase 2 study using VX-458 to treat peripheral neuropathic pain in patients with lumbosacral radiculopathy caused by impairment or damage to nerve roots in the area of the lumbar spine.
“With FDA Breakthrough and Fast Track Designations in hand, we are working with urgency to file the New Drug Application for VX-458 and bring this non-opioid medicine to the millions of patients who suffer from acute pain each year in the US,” said Kewalramani.
Source: Vertex Pharmaceuticals
