A closely watched non-opioid painkiller succeeded in two large clinical trials, raising hopes the drug might offer an alternative to powerful but addictive medicines like OxyContin or Vicodin.
Results showed the drug, developed by biotechnology company Vertex Pharmaceuticals, eased pain after surgery by significantly more than a placebo. Relief also came faster, with participants who received Vertex’s treatment in the trials reporting reduced pain in a few hours.
There were also few side effects to treatment, supporting Vertex’s case that its medicine, a pill called VX-548, could be widely used.
In a statement Tuesday, Vertex said it plans by mid-year to ask the Food and Drug Administration for approval of VX-548 in moderate-to-severe acute pain.
“For years, our goal has been to make a medicine with clinically meaningful pain relief for moderate-to-severe acute pain, with a safety and tolerability profile that’s better than an opioid,” said David Altshuler, Vertex’s top scientist, in an interview. “We will file for approval with urgency.”
The results aren’t without blemish, however. VX-548 didn’t prove superior to a combination of the widely prescribed opioid hydrocodone bitartrate and Tylenol, falling short on a key secondary goal Vertex had set in both trials.
Still, the main findings are rare good news in a long history of mostly futile efforts to develop drugs that can extinguish pain without the destructive dependency opioids elicit. The pharmaceutical industry’s failure on this score has been especially stark amid a continuing crisis of opioid abuse and overdose in the U.S.
VX-548 was seen as having a better chance of success. Many years in development, the drug is built upon research showing the role cellular gates known as sodium channels play in relaying pain signals.
Certain types of these gates are found only in peripheral nerve cells — an important feature, because sodium channels are vital for many functions and blocking them broadly would come with unacceptable side effects. VX-548 inhibits one of these peripheral channels, dubbed Nav1.8, to tamp down pain signaling from nerve cells to the brain.
Promising results from mid-stage trials of VX-548 in 2022 encouraged Vertex to push the drug into the two Phase 3 studies from which data were disclosed Tuesday.
Enrolling about 1,100 participants each, the trials tested VX-548 against placebo as a treatment for acute pain following either bunion surgery or an abdominoplasty, also known as a “tummy tuck” procedure. A third group in each study received hydrocodone bitartrate and Tylenol.
Using a 10-point rating scale, researchers assessed participants’ pain intensity at a series of time intervals over 48 hours. The difference from baseline was assessed at each point, weighted by the amount of time elapsed and then added together to yield a score known as SPID48. Higher SPID48 scores represent greater pain reduction.
On this measure, treatment with VX-548 significantly lowered pain intensity compared to placebo in both the bunionectomy and abdominoplasty studies.
Vertex described the reduction in pain as clinically meaningful. The data show that, on the 10-point scale, participants rated their pain about half as intense after 48 hours than at the study’s start.
When comparing SPID48 scores, VX-548 didn’t statistically outperform hydrocodone bitartrate and Tylenol in either trial. And in the bunionectomy study, VX-548 appeared to offer less relief than the combination.
Graphs of pain intensity over time shared by Vertex Tuesday show the curves for VX-548 and the combo treatment roughly overlap, with a greater difference in the bunionectomy study.
Vertex has emphasized VX-548’s safety, however, particularly compared to treatments that carry the risk of addiction as well as other serious side effects.
“The unmet need in the management of pain isn’t increasing on opioid efficacy,” said Vertex’s Chief Commercial Officer Stuart Arbuckle, in an interview. He described VX-548 as solving the trade-off physicians and patients face when weighing the efficacy of opioid painkillers against their risk.
In both trials, rates of adverse events were lower in the VX-548 arms than in the placebo groups. The most commonly reported adverse events were nausea, constipation, headache and dizziness, but, in almost all instances, occurred less frequently among participants given VX-548 than either placebo or the combination treatment.
Vertex only disclosed a summary of the safety results in its press release Tuesday.
The company also ran a third, smaller Phase 3 trial of about 250 people with a “broad range” of non-surgical and surgical acute pain who received VX-548 for up to two weeks. More than 80% of participants rated VX-548 either “good,” “very good” or “excellent” in treating their pain, Vertex said.
According to Altshuler, this study was designed to support Vertex’s efforts to secure wide approval of VX-548 by showing its use in different types of pain and in different settings.
The positive findings are a boost for Vertex, which has put VX-548 at the center of a plan to expand beyond the cystic fibrosis drugs that made it one of the largest biopharmaceutical companies by value. It’s also investing in diseases like sickle cell, for which it recently won a landmark approval of the first CRISPR-based drug, and Type 1 diabetes.
Company CEO Reshma Kewalramani recently touted VX-548’s potential to investors, pointing to the large market for a potent, safe and non-addictive analgesic. Analysts agree, with some predicting billions of dollars in peak annual sales if Vertex succeeds.
Experts, meanwhile, have viewed VX-548 as the first of what could be a new class of pain drugs. “In my view, it’s like the very first stage of the development of the statins,” said Stephen Waxman, director of the Center for Neuroscience and Regeneration Research at Yale University, on an Aug. 3 podcast hosted by The New England Journal of Medicine to discuss earlier VX-548 data.
While another expert described the pain relief offered by Vertex’s drug in earlier testing as modest, its success in Phase 3 offers firmer evidence.
Vertex is also conducting trials of VX-548 in chronic pain, and has a number of successor molecules in earlier stages of testing. Late last year, the company released initial data from a mid-stage study of VX-548 in diabetic nerve pain.
However, on the NEJM’s podcast, Waxman noted how chronic pain, which is associated with changes in the brain, could be more challenging to treat.
