Aprotinin(Bayer Ag)

Pictured: An illustration of a woman overlooking a field with pill-shaped sheep/Nicole Bean for BioSpace† A medication called VX-548, developed by Vertex Pharmaceuticals, proved superior to placebo in two small Phase II clinical trials for two types of post-surgical pain, according to a study published in The New England Journal of Medicine in early August. Though the effect was modest, “these trials represent an early foray into an exciting new class of drugs in a difficult field,” Mark Wallace, a physician at UC San Diego’s division of pain medicine who was not involved in the research, wrote in an accompanying editorial. The medication heads now to two Phase III trials with 1,000 participants each, plus an open-label study with 250 participants. The results couldn’t come at a better time, as the opioid epidemic continues to ravage the U.S., with 50,000 people dying each year from overdose, and 10 million abusing the highly addictive medications annually. The U.S. Department of Health and Human Services (HHS) officially declared opioid abuse a public health emergency in 2017, but until there is a safe and effective alternative to opioids, acute and chronic pain present a silent scourge of their own. “There is an immense unmet need for new pain medications, even without the opioid epidemic,” Stephen Waxman, a Yale neuroscientist who penned another editorial accompanying the recent NEJM study, told BioSpace. At least one other firm is pursuing the same target as Vertex, while others are exploring different pain-blocking approaches. “There hasn’t been a new class of pain medicine in more than 20 years,” Vertex spokesperson Heather Nichols told BioSpace in an email. “We believe we could redefine the treatment of pain with the first new mechanism of action in decades.” Meanwhile, other companies are looking to make opioids themselves safer by removing their addictive qualities. Vertex Therapeutic Helps Quell Acute Pain Vertex researchers zeroed in on two distinct, repeatable sources of pain: bunionectomy (a type of foot surgery) and abdominoplasty (tummy tuck), both of which necessitate analgesic medication for acute, post-operative pain. The design allowed for a homogenous patient population, where specific pain was triggered by the same injury. A total of 274 participants were enrolled in the bunionectomy trial, and 303 participants in the abdominoplasty trial. Participants rated their pain at 19 time points on a scale of zero (no pain) to 10 (the worst pain one can imagine). This led to an overall score known as sum of the pain-intensity difference, or SPID, a measurement the FDA recommends as a primary endpoint in acute pain trials. Though a moderate dose of VX-548 did not show a significant improvement over placebo, a high dose did. In fact, the high dose acted rapidly, within the first hour of treatment. At 48 hours, the high dose offered more patients at least a 30% reduction in the score on the pain rating scale than placebo did. Side effects such as nausea, headaches or constipation were mild or moderate, and temporary. Participants on the high dose were less likely to stop medication early because they felt it wasn’t helping than patients on placebo or given a common painkiller that combines hydrodocone bitartrate and acetaminophen. The new molecule is the end result of decades of research into peripheral voltage-gated sodium channels, often referred to as NaV channels, which are found in sensory neurons outside the brain and are responsible for detecting painful or noxious stimuli. There are nine different types of voltage-gated sodium channels in the body (NaV1.1 to NaV1.9); Vertex’s new medication targets NaV1.8, which is expressed exclusively in sensory neurons of the peripheral nervous system and not the brain. Researchers have raised concerns about the results, including the fact that the trials were small, and that a higher (thus more effective) dose of acetaminophen/oxycodone was not tested. Nonetheless, Waxman, whose work on peripheral voltage-gated sodium channels has been widely published, pointed out that the study was a proof-of-concept trial. “It wasn’t necessarily a home run,” he told BioSpace, “but it showed that blocking peripheral gated sodium channels does reduce pain, without central nervous system side effects and without addictive potential.” Waxman added that he is hopeful that these findings will eventually lead to broadly effective treatments for chronic pain as well. Vertex is already conducting a Phase II trial on diabetic neuropathy, with a study completion date in spring of 2024. Other Approaches in Development for Pain Management Vertex is not alone in its quest. “It’s been a race for the holy grail,” commented Waxman. “In 2006, we established very clearly that NaV1.8 is a major controller of the repetitive firing of pain signaling in neurons and if you could block it you would reduce pain.” In Finland, Orion Pharmaceuticals is working on developing a non-opioid pain therapy dubbed JMKX000623 that also blocks the NaV1.8 sodium channel. This experimental therapy is in Phase I trials. And here in the U.S., Virpax Pharmaceuticals is looking at other pain targets and approaches. One of its new analgesics is a liposomal, long-acting, injectable formulation of bupivacaine, a potent local anesthetic similar to lidocaine. It is intended for post-operative pain management and Virpax is developing the formulation in conjunction with the U.S. Army, which is studying its potential in battlefield wounds. The company is also planning Phase I safety trials on two intranasal sprays that would target pain centers in the brain—one is a peptide called enkephalin, and the other, a pharamaceutical-grade cannabidiol. Meanwhile, in an entirely different approach, biotech startup Ensysce Biosciences has developed a novel chemistry that modifies how opioids are released when taken in order to make them safer. The platform, called TAAP (trypsin activated abuse protection), uses the body’s own digestive enzyme, trypsin, to trigger release of the opioid. That means the pills won’t work if they crushed in order to be snorted or injected—the kind of recreational abuse that is common. The opioid can only be activated in the stomach in the presence of trypsin. In addition, overdose protection is ensured by adding a tiny amount of trypsin inhibitor to every dose. “If you take the prescribed amount, the amount of trypsin inhibitor is negligible so nothing happens,” explained chemist Lynn Kirkpatrick, CEO at Ensysce Biosciences. “But if you take more than you should, there is enough inhibitor to shut down the activation.” The company’s molecule is called PF614 and is currently in Phase II clinical trials, and fast tracked by the FDA. It is a prodrug of oxycodone, with a safety pro to other traditional opioids, but a 12-hour half-life once ingested, which is longer-acting than current opioids. “We are talking to the FDA about Phase III plans,” Kirkpatrick told BioSpace. If all goes as planned, she said, the company might have an NDA submitted to the agency by 2025. Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.