First Non-Addictive Painkiller Application Submitted in 20 Years

On August 20, 2024, Scientific American reported that Vertex Pharmaceuticals (VRTX.US) has developed a novel painkiller capable of reducing acute pain levels by approximately 50% without the risk of addiction. On July 30, 2024, Vertex announced that the U.S. Food and Drug Administration (FDA) had accepted a New Drug marketing application for the drug and granted priority review status. The drug, VX-548, is used to treat moderate to severe acute pain. If approved, VX-548 will be the first non-opioid acute pain medication to hit the market in two decades, marking a significant milestone in pain management.

Previous research has identified the mechanisms behind pain onset: widely distributed pain-sensing neurons detect stimuli and generate impulses that transmit pain signals along nerve fibers to clusters of dorsal root ganglion cells at the spinal cord, ultimately relaying the signals to the brain. Voltage-gated sodium channels (NaV) are central to this neural pathway and also regulate the electrical impulses that power the heart and brain. Blocking sodium channels is an ideal target for paining treatment, provided it does not compromise essential functions. Scientists have pinpointed three sodium channels in peripheral sensory neurons that are frequently involved: NaV1.7, NaV1.8, and NaV1.9, with NaV1.7 and NaV1.8 playing critical roles in pain signal transmission.

Pain is primarily categorized into acute and chronic pain. While pain does not directly threaten life like other diseases, it can significantly diminish quality of life and may lead to serious issues such as suicide, Alzheimer's disease, and depression and anxiety. However, pain management has not kept pacing with demand. Existing medications for alleviating human pain are markedly insufficient, contributing to the ongoing opioid crisis, which has resulted in over 730,000 overdose deaths. Research into new painkillers faced significant challenges. The NaV channel family consists of nine closely related members that share over 50% of their genetic sequences. 

Vertex scientists developed the E-VIPR (Electrostimulation Voltage Ion Probe Reader) system in the early 21st century, enabling rapid testing of multiple compounds on a single channel. In 2015, Vertex initiated the first clinical trial of a NaV1.8 inhibitor, discovering that a compound named VX-548 successfully alleviated pain in a small group of patients. The company conducted larger studies in 2022.

On January 30, 2024, Vertex released positive results from two large pivotal clinical trials. Approximately 1100 patients undergoing abdominal plastic surgery and carpal tunnel release surgery were recruited to receive either a placebo, VX-548, or a combination of acetaminophen (Vicodin). Pain relief was measured on a scale from 0 to 10, revealing that both VX-548 and Vicodin reduced pain levels by about 3 points, with VX-548 posing no addiction risk. Among patients recovering from abdominal surgery, VX-548 provided faster pain relief than Vicodin. When assessed using different pain scales, VX-548 was less effective for carpal tunnel release patients compared to Vicodin; however, patients taking VX-548 reported fewer side effects (such as nausea and headaches) than those on placebo, indicating that this treatment is safe.

Chronic pain patients outnumber those with acute pain. Therefore, Vertex is also testing the effects of VX-548 on chronic pain. The company’s scientists believe that the mechanisms of chronic and acute pain are similar, suggesting that VX-548 may also be effective for chronic pain. A small study released by Vertex on December 13, 2023, indicated that the drug showed good efficacy and safety in treating diabetic peripheral neuropathy, prompting Vertex to plan for Phase III trials.