Vertex Pharmaceuticals reported positive results Tuesday for two Phase 3 trials testing the efficacy and safety of pain compound VX-548 compared to either placebo or opioid-based treatment.
While both studies met the primary endpoint, the data prompted some analysts to question the asset’s commercial relevance.
VX-548 led to a statistically significant, roughly 50% reduction versus placebo in moderate-to-severe-pain in both studies, one after abdominoplasty and one following surgical removal of bunions. Findings were similarly positive in a single-arm safety and effectiveness study involving subjects with a range of pain conditions, both surgical and non-surgical.
The late-stage results suggest the agent’s benefit-risk profile may “fill the gap between medicines with good tolerability but limited efficacy and opioid medicines with therapeutic efficacy but known risks, including addictive potential,” stated Vertex CEO Reshma Kewalramani in a company announcement.
With breakthrough and fast-track designations in-hand, the drugmaker plans to submit a new drug application by mid-year, Kewalramani added, and a broad label in moderate-to-severe acute pain is anticipated.
VX-548, a highly selective NaV1.8 pain signal inhibitor, is a cornerstone of the company’s effort to transform a pain treatment landscape dominated by non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. For years, these treatment options were over-marketed and over-prescribed despite their strong link between acute use and chronic dependency and addiction.
There hasn’t been a novel MOA for acute pain in two decades. “One need look no further than the opioid crisis to recognize the gravity of this situation,” Kewalramani said on a conference call to go over the results.
She said the company envisions NaV1.8 or 1.7 inhibitors being used as first-line therapy. They’re poised to enter a multi-billion-dollar, mostly generic market, in which 80 million American patients per year are prescribed a drug for acute moderate-to-severe pain.
More than 80% of patients in Vertex’s single-arm trial rated VX-548 as good, very good or excellent in treating pain.
Skeptics remain
However, as underscored by their cool reception to the Phase 3 trial data, some in the analyst community aren’t sold.
VX-548 met the bar for approval, “however, the devil is in the details,” cautioned Raymond James analyst Danielle Brill in a Tuesday investor note. “We continue to question the commercial viability of VX-548 for the treatment of post-surgical acute pain.”
For one, the agent’s efficacy profile appears “modest,” explained Brill, adding that it’s worse than opioids and in-line with NSAIDs. VX-548 failed to demonstrate comparable efficacy to the active opioid control — a drug similar to Vicodin — in the bunionectomy study.
Moreover, as pain is usually worse early on in the post-op period, time is of the essence. Still, the investigational drug’s rate of onset, as measured by a secondary endpoint, “time to meaningful pain relief,” may not be ideal for a pain treatment.
VX-548 separated from placebo more quickly than the opioid control in abdominoplasty, but “it separated more slowly in the bunionectomy trial,” observed Leerink Partners’ David Risinger in an investor note Tuesday.
In other words, the agent offered greater initial pain relief relative to the opioid option in the tummy tuck cohort, while those in the bunion group saw similar pain relief to placebo over the first eight hours.
“It’s very valuable to look at the overall data set – the bunionectomy as well as the abdominoplasty [cohorts],” the CEO suggested when asked about the time-to-onset differential. “In both studies with the placebo, it’s about 8 hours to a…clinically meaningful change. And with ‘548, it’s much less than that — 2 hours in abdominoplasty and 4 hours in bunionectomy.”
Moreover, she continued, the full data set — to be released at a future medical meeting — shows subjects in the two trials experienced a minimal level of pain relief after just 30 and 60 minutes, respectively.
Payers are the unknown
What will the payer reception be like? They’re likely to be open to coverage, given the new drugs’ efficacy and safe, non-addictive profile, said Vertex COO Stuart Arbuckle, also during the call.
“We know payers don’t like opioids, but reluctantly that’s the only [effective] thing that really is available right now to treat acute pain,” he contended.
Arbuckle also shared that he expects more of the ongoing “sea change” away from legislation and medical guidelines restricting opioids and more toward encouraging non-opioid options.
He pointed to 2022’s passage of the NOPAIN Act, which, starting in 2025, provides separate Medicare reimbursement for non-opioid medicines in outpatient surgical settings.
“We’re going to see more legislation like that,” Arbuckle predicted, as well as advancement of policies to reduce barriers to consideration of non-opioids, like equalizing co-pays between brand and generic medicines.
Then again, Brill pointed out, “From what we can tell, VX-548 is no more potent than generic NSAIDs which already provide a non-addictive treatment option for those patients at increased risk.”
Thus, she concluded that in the organization’s opinion, “the risk for addiction in the post-surgical acute pain setting is not a significant enough concern to justify paying premium branded pricing.”
The analysts haven’t completely lost enthusiasm for Vertex’s pain program, though.
VX-548’s clean safety profile may justify some use in the minority of patients that can’t tolerate opioids or NSAIDs, noted Brill. Indeed, VX-548 was safe and well-tolerated in all three Phase 3 studies, the company said, with no concerns regarding addiction.
Although the acute-pain opportunity remains “highly uncertain,” to the extent the drugmaker can replicate the findings in chronic pain, Brill does “see a role for a new non-addictive pain med in that setting. Still, we do not think the modest efficacy results presented today de-risked the chronic pain program in any way.”
As the firm seeks to gain approval in the peripheral neuropathic pain area, too, it also initiated a second Phase 2 neuropathic pain trial in lumbosacral radiculopathy, following positive Phase 2 results among subjects with diabetic peripheral neuropathy.
To that end, additional NaV1.8 and NaV1.7 inhibitors, for use alone or in combination, will be advanced, Vertex said.
Regarding speed of onset, Risinger highlighted two possibilities that could yield better performance.
The first is administering VX-548 the day before surgery to accelerate pain relief in the postoperative period. The second is developing an intravenous formulation of next-gen candidate VX-993 — also a NaV 1.8 inhibitor — that could be administered throughout the perioperative period.
