Two decades ago, when two genetic mutations were discovered in Asia that gave scientists a better idea of how pain sensations traveled through the body and identified which part of the nervous system to target, the race was on in biopharma to develop a non-opioid pain relief medicine.
Despite the enlightenment, a laundry list of major drugmakers came up short in their attempts to develop a safe, painkilling drug and soon abandoned their efforts. But there was one company that kept at it.
Fast-forward to today, and Vertex Pharmaceuticals is on the verge of gaining an FDA approval for suzetrigine (VX-548), a nonaddictive oral treatment that is on track to become the first major shift in pain treatment for more than two decades. The U.S. regulator has established a target action date of Jan. 30.
To get here, Vertex examined data from studies run by other companies and speculated on the types of compounds that were being investigated. Its researchers believed that the process of “selective inhibition wasn’t being tested,” according to Vertex’s Paul Negulescu, Ph.D., who heads up the company’s research wing and guides its pain program.
“We tried to make those molecules ourselves and test them ourselves and just benchmark them against our compound,” Negulescu said in an interview with Fierce Biotech. “It was partially a belief in our hypothesis, but it was also an assessment that our failures weren’t disproving our hypothesis, so we kept going at it. In fact, I think (the failures were) further proving our hypothesis.”
The discoveries of the genetic mutations in China and Pakistan had uncovered the voltage-gated sodium channel Nav1.7 as the key transmitter of pain. If pain-signaling ions are blocked from passing through the Nav1.7 channel, they can never reach the brain. But the target was elusive. Because Nav channels have so much similarity, targeting one in particular isn’t easy.
As Vertex and other companies logged failure after failure, the Boston-based biotech continued to believe that it was on the right track. Bolstering that belief was its electrical stimulation voltage ion probe reader (E-VIPR).
While other companies were using patch-clamp electrophysiology—a method of measuring ion channel currents in cell membranes which was developed in the mid-1970s—Vertex employed its more advanced tool which uses electrical stimulation to identify compounds that inhibit specific sodium channels. E-VIPR allowed Vertex to test many more potential compounds and with greater efficiency.
“The level of selectivity that I believe is required to achieve pain-signal inhibition without effecting the other sodium channels and the other systems where those sodium channels play important roles is pretty large,” Negulescu said. “Many of the initial efforts—there were maybe tenfold, 100-fold selective—while we were like tens of thousands of folds selective.”
Another way that Vertex veered from the competition was to begin testing on the Nav1.8 channel, the function of which is closely related to the Nav1.7, helping supply its power. In three clinical trials, the first of which started a decade ago, Vertex’s Nav1.8 inhibitors failed to succeed. Two years ago, the company finally struck gold with VX-548 and moved it into later-stage trials.
Early this year, Vertex revealed the results of two phase 3 studies that met their primary endpoints, as suzetrigine topped placebo by a significant margin in relieving pain in the 48 hours after patients underwent tummy tuck and bunion removal procedures. The trials, however, failed to achieve their secondary endpoints, which aimed to show that suzetrigine was more effective than widely used painkiller Vicodin.
While the trials have set up suzetrigine to be approved for acute pain, Vertex is confident that it will eventually be approved for chronic pain as well. To investigate the potential in this indication, the company has kicked off a study in patients with diabetic peripheral neuropathy.
"The Nav1.8 target is expressed in these pain sensing neurons called nociceptors, which mediate pain under acute and chronic conditions. So, from a fundamental science, it should work in both conditions," Negulescu said. "And actually VX-150—the predecessor molecule—did show efficacy in both acute and chronic conditions."
Earlier this month, when Vertex broke down the results from the tummy tuck and bunion removal trials at the American Society of Anesthesiologists’ annual meeting, the principal investigator of the studies, Todd Bertoch, M.D., said it was the first time in more than 150 trials in which he has been involved that the drug had fewer adverse events than placebo.
Safety, of course, is the key differentiator between suzetrigine and the opioids with which it will compete. Leerink Partners has one of the most optimistic forecasts for the sales of suzetrigine, pegging it at $866 million in 2026.
Another differentiator between Vertex’s drug and opioids will be their price. For now, Vertex is working to make sure the drug can be accessed.
Passage of the Non-Opioids Prevent Addiction in the Nation (NOPAIN) Act last year was a major step in the right direction. The measure will increase patient and provider access in the hospital setting to non-opioid approaches to pain management for those enrolled in Medicare.
Another measure Congress is considering is the Alternatives to Prevent Addiction in the Nation (PAIN) Act, which would ensure that the 52 million seniors in the U.S. covered by Medicare Part D would pay no more out of pocket for a non-opioid than they would for an opioid prescription.
“There’s been a long-running public health emergency related to opioids. (Policymakers) have seen challenges that it has created with their constituents. They’re also looking at their budgets and realizing just how much the downstream consequences are costing them,” Matt Schumaker, Vertex’s chief of federal government affairs, said in an interview.
“When you put those things together, I think it’s driven a tremendous interest from policymakers to say: ‘Oh, wow we have a potential new tool here. How do we make sure that it’s an option for prescribers and for patients?’”