As the world descends into an opioid crisis, the development of non-opioid analgesics has become even more urgent. A series of Phase 3 clinical trials of a new oral non-opioid analgesic found it to be effective in treating acute pain in both surgical and non-surgical settings.

Voltage-gated sodium channels are key factors in regulating the generation and propagation of neuronal action potentials, or nerve impulses (charges that move along neuronal membranes). There are many types of sodium channels, and NaV1.8 plays a key role in pain signaling in the peripheral nervous system.

Vertex Pharmaceuticals recently reported results from a Phase 3 clinical trial of its oral, non-opioid NaV1.8 inhibitor VX-458. The trial found the drug was effective in treating moderate to severe acute pain in both surgical and non-surgical settings.

The trials included two randomized, double-blind, placebo-controlled pivotal trials that examined the effects of VX-458 after surgical procedures: abdominoplasty (commonly known as a "tummy tuck") and hallux valgus resection (removal of the hallux valgus). Pivotal trials are designed to gather statistically significant evidence of efficacy and safety to obtain marketing approval from regulatory agencies. Abdominoplasty was chosen because it is a soft tissue pain model, whereas bunionectomy is a bone pain model. Additionally, a single-arm Phase 3 trial was conducted on the drug's safety and effectiveness in treating a variety of surgical and non-surgical pain.

Results after Abdominoplasty and Hallux Valgus Removal Surgery

In the abdominoplasty and bunionectomy trial, patients took VX-458 (a combination of hydrocodone and acetaminophen) or placebo by mouth over 48 hours. The initial dose of VX-458 is 100 mg, followed by 50 mg every 12 hours, and hydrocodone/acetaminophen 5 mg/325 mg every 6 hours.

The abdominoplasty trial included 1,118 patients aged 18 to 80 years with moderate to severe postoperative pain; the bunionectomy trial included 1,073 patients. In both trials, significant pain relief with VX-458 was observed compared with placebo, based on differences in patient-reported pain intensity from baseline. The hypothesis that VX-458 is more effective than hydrocodone/acetaminophen for pain relief was not supported in either trial.

VX-458 worked more quickly than placebo, with sustained reductions in pain scores of 2 or more points (i.e., "meaningful") within 2 hours and 4 hours in patients undergoing abdominoplasty and hallux valgus resection, respectively, compared to a median of 8 hours for placebo.

Safety and Effectiveness Studies: Surgical and Nonsurgical Acute Pain

The third Phase 3 trial evaluated VX-458 treatment for up to 14 days in 256 patients with other surgical and non-surgical acute pain conditions, using the same dosing regimen as the previous studies.

Surgical patients included patients who underwent orthopedic, orthopedic, urological, and general surgical procedures. Nonsurgical patients include those with upper and lower extremity pain, orofacial pain, and multiple comorbidities. In the Patient Global Assessment (PGA) conducted after treatment, 83.2% of participants rated the drug's effectiveness in treating pain as "good," "very good," or "excellent."

Adverse events in three clinical trials

In all three trials, VX-458 was safe and well-tolerated. Most adverse events were mild to moderate, and no serious adverse events were reported.

Overall, adverse events in both RCTs were consistent with the procedures performed. Adverse event rates were lower with VX-458 than with placebo: 50.0% versus 56.3% after abdominoplasty and 31.0% versus 35.2% after bunionectomy.

Reshma Kewalramani, CEO and President of Vertex, said: "We are very pleased with the results from our pivotal program for VX-458, which demonstrate compelling and consistent efficacy and safety across a variety of acute pain conditions and conditions. VX-458's benefit-risk profile gives it the potential to fill the gap between opioids that are well tolerated but have limited efficacy and those that have efficacy but known risks, including the potential for addiction."

next step

Vertex plans to submit a new drug application for VX-458 to the U.S. Food and Drug Administration (FDA) by mid-2024, seeking approval for the treatment of moderate to severe acute pain.

The company has previously conducted smaller Phase 2 clinical trials to study the effectiveness of VX-458 in treating acute pain in post-operative patients (abdominoplasty and hallux valgus resection) and a Phase 2 study to evaluate its efficacy in treating peripheral neuropathic pain caused by diabetes. They have also initiated a Phase 2 study using VX-458 to treat peripheral neuropathic pain in patients with lumbosacral radiculopathy caused by damage or damage to the lumbar nerve roots.

Kewalramani said: "We have received breakthrough designation and fast track designation from the FDA and are rushing to submit a new drug application for VX-458 to provide this non-opioid drug to the millions of acute pain patients in the United States each year."