As Vertex’s pivotal pain readout looms, non-opioid drug development faces a reckoning

Many drug developers have abandoned the search for new pain medicines. But the outlook of the field, experts say, could change from a pair of late-stage clinical trials testing Vertex Pharmaceuticals’ non-opioid compound.

There hasn’t been a new class of pain drug in decades, according to a Vertex press release. Vertex’s drug stands as one of the few in late-stage studies, with results expected later this year or early next year. If successful, the data readout could reinvigorate pain drug development after the likes of Biogen, Roche and Pfizer exited the space.

Michael Oshinsky

“If it succeeds, you’re going to see a whole bunch of other companies start to develop therapeutics,” said Michael Oshinsky, director of the NIH’s NINDS Office of Preclinical Pain Research. He pointed to the closely-related field of migraine drugs as a model — where a new class of drugs called CGRP inhibitors has seen a stream of approvals since 2018.

“There was a rush to market,” Oshinsky exclaimed.

Successful data readouts could open up what Vertex projects is a $4 billion market in acute pain, and more importantly, reignite the wider quest for non-opioid medicines amid the overdose crisis claiming over 100,000 US lives in each of the last two years — marking the worst span on record.

But full results from Vertex’s Phase II studies, which were published in the New England Journal of Medicine Wednesday evening, raise old questions about pain clinical trials — many of which Vertex will have to face again in its pivotal trials.

In Phase II, a high dose of Vertex’s pain candidate VX-548 significantly reduced scores on a pain scale compared to placebo after bunion surgery or an abdominoplasty, or a tummy tuck. However, the low doses of the drug did not meaningfully separate from placebo. Vertex previously shared the topline results from the two Phase II trials last year.

In addition, fewer patients who received Vertex’s drug stopped treatment because it wasn’t effective. In the bunion surgery trial, about 8% discontinued the high dose of Vertex’s drug from lack of efficacy, compared to 23% in the placebo and 25% in the hydrocodone-acetaminophen arm. In the tummy tuck study, 3% discontinued the high dose of Vertex’s drug from lack of efficacy, compared to 8.5% and 10% of the placebo and hydrocodone-acetaminophen groups, respectively, according to the full study results.

Vertex is currently studying the treatment in Phase III studies for pain following the same two surgeries, but with more than three times the amount of patients — the two Phase II studies featured around 300 patients each, whereas the Phase III studies are projected to enroll around 1,000 patients each, according to a federal clinical trials database.

Placebo effect

Reshma Kewalramani

Vertex’s CEO Reshma Kewalramani said during the company’s second-quarter call that she has “high confidence in the outlook” of the Phase III trials. Analysts from Jefferies and Leerink Partners have also been optimistic on the Phase III readouts, projecting a 75% chance the trials succeed.

But Mark Wallace, a professor of anesthesiology at the University of California, San Diego, isn’t as sure. While he believes the drug holds promise, he’s concerned that a large placebo effect — a common issue in trials studying pain drugs — could thwart the Phase III trials, as placebo effects often make results from pain clinical trials harder to interpret. “A lot of times it’s the placebo that kills it,” he said.

“It’s a classic issue in pain studies,” Oshinsky added. “When you’re put into a clinical trial, interacting with these people with their nice, new white coats and interacting with the potential for something to be different and safe and beneficial, that just builds that placebo effect tremendously.”

Another concern, Wallace and Oshinsky both noted, is the measurement that pain trials use as a primary endpoint. It is relatively one-dimensional, asking participants to mark their pain on a scale, but failing to capture how the medicines might actually be helping people in their day-to-day lives.

Mark Wallace

“The pain experience is much more than just a number,” Wallace said. “I have patients that will start treatment and their pain score is eight out of 10. Then when I come back, maybe four months later, their pain score is still eight out of 10.”

But, he said, these patients are sleeping better and are more active. That increased activity brings their pain levels up, but they are only able to be active because of their pain medications — something that isn’t captured in pain studies. Scientists are currently investigating new ways to capture pain in clinical studies, though current studies tend to use the more standard endpoints.

Wallace said he hopes regulators can adopt a more flexible approach toward pain drugs, especially ones that are safe and show a significant impact in Phase II, given the need for new, non-addictive treatments. “Perhaps our expectations are too high in trials of new agents for acute pain,” he wrote in an editorial in NEJM published alongside the study.

Wallace, who’s been involved in pain clinical trials for three decades, added, “It’s quite frustrating. It’s been quite frustrating to see for pain therapeutics how difficult it has been to get into the market.”

A safe option

One of the main causes of drug addiction is exposure to opioids after injury or surgery, Wallace noted. A drug option that could cut down the use of opioids after surgeries would be very significant against that backdrop.

Unlike opioids, which are addictive in large part because they trigger reward centers in the brain, Vertex’s drug targets peripheral neurons. The drug blocks a sodium channel important for pain signaling called NaV1.8. It’s the less popular sibling to another sodium channel NaV1.7, which drugmakers rushed after over a decade ago.

The initial excitement stemmed from scientists that found people who had mutations in the gene for NaV1.7 experienced either incredible pain, or little pain at all. Having evidence in actual humans — as opposed to mice or cells — was compelling for the industry.

Stephen Waxman

“That attracted the biopharma industry to invest a lot more effort in NaV1.7 than NaV1.8,” said Stephen Waxman, a neurologist at Yale whose lab is behind much of the pioneering research behind the sodium channels and pain.

But Roche, Teva and Biogen all tried and failed to develop drugs for NaV1.7.

Biogen officially stopped work on its candidate vixotrigine at the end of 2022, citing “regulatory, development and commercialization challenges” after numerous delays in the start of a Phase III trial.

For Waxman, Vertex’s Phase II successes show that blocking sodium channels still has promise for pain treatment, despite failures with NaV1.7.

VX-548 is Vertex’s fourth attempt at a NaV1.8 sodium channel blocker in the clinic. A previous candidate also passed Phase II trials, but Vertex ended up only moving VX-548 forward. Vertex is also studying VX-548 in chronic pain, where the biotech company expects a Phase II readout in diabetic peripheral neuropathy around the end of this year or early next year as well.

Stuart Arbuckle

Even if Vertex’s drug succeeds in Phase III trials in acute pain and wins approval from the FDA, insurance coverage could be another hurdle as currently available drugs are generic and cheap, Wallace said. But Vertex COO Stuart Arbuckle said on an analyst call that he believes existing pain treatment guidelines and policies, such as the NO PAIN law, will support a non-opioid pain medicine like VX-548.

He also said that policy initiatives in states and hospitals in the past few years have largely focused on restricting opioid prescriptions, but that focus is shifting to support non-opioid options like Vertex’s medicine. “And I think that that’s a very welcome systemic change,” Arbuckle said.

“I used to say to patients, ‘I think there may — in the future — be a new class of non-addictive pain medications that target peripheral sodium channels,” Waxman said. “A few years prior to this, even prior to this New England Journal of Medicine study, I changed my wording to say that I’m confident that sooner or later, there will be a new class of non-addictive pain medications.

“This is a real advance,” he added, “but how long it’s going to take to translate that into actual bedside medicine, I can’t say.”

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