Vertex has reported a phase 2 win that still dented confidence in its pain prospect suzetrigine. The trial linked the near-approval molecule to a significant improvement from baseline, but placebo performed similarly, triggering a 12% drop in Vertex’s share price in premarket trading.
The study tested the NaV1.8 pain signal inhibitor suzetrigine in 102 people with painful lumbosacral radiculopathy (LSR). A further 100 people received placebo. However, the primary endpoint looked at the change on the numeric pain rating scale (NPRS) from baseline, not compared to placebo. That allowed the trial to hit its primary endpoint despite a performance that was startlingly similar to placebo.
Mean NPRS fell 2.02 points after 12 weeks of treatment with suzetrigine, causing the trial to meet its primary endpoint with a p-value of 0.0001. In comparison, mean NPRS fell 1.98 points after 12 weeks of treatment with placebo, meaning the trial found placebo had a statistically significant effect on pain as measured using NPRS.
Vertex didn’t design or power the trial to detect a difference between the suzetrigine and placebo arms. But the near-identical reduction in NPRS in the arms invited comparisons between the cohorts—and investors didn’t like what they saw. Vertex’s share price dropped below $400 for the first time in months in premarket trading Thursday from a Wednesday closing price of $447.50.
Running a placebo-controlled trial could have avoided the uncertainty created by the phase 2 results. Vertex’s chief operating officer Stuart Arbuckle discussed the trial design at a Stifel event in November, explaining that the placebo group was intended to show how a sugar pill performs in a well-controlled LSR population without taking on the burden of running a controlled study.
“The other way of doing a comparison with placebo would need a very, very large study, which would take a very, very long time, and that's not what we are interested in doing in phase 2. We want to do a fast, efficient study, which helps us predict whether ... suzetrigine is going to work in this patient population and allows us to size the phase 3 study,” Arbuckle said.
The biotech ran post hoc analyses to understand what happened, uncovering variability in the placebo response across study sites. In the roughly 40% of sites with lower placebo responses, there was “greater separation” between the suzetrigine and placebo arms. The press release makes no mention of the level of separation or why it split out 40% rather than, say, 30% or 50%, of sites for the analysis.
Vertex said the analyses “suggest that trial design innovation may better control the placebo response and separate the treatment effect of suzetrigine from placebo in future studies.” The company plans to talk to regulators about designing a phase 3 trial that will incorporate insights from the phase 2 data and post hoc analyses.
The lack of treatment options for LSR, a condition that Arbuckle said affects around 4 million people, could strengthen the case for advancing suzetrigine on the basis of mixed midphase data. Multiple molecules have failed in LSR. Vertex is betting suzetrigine will fare better because it blocks the pain signal from the peripheral sensory neurons rather than just changing how the pain is perceived.
Validating that hypothesis is central to Vertex’s plans for suzetrigine. Around 10 million patients in the U.S. have peripheral neuropathic pain (PNP) as their primary diagnosis, Arbuckle said. Vertex is advancing the asset in LSR and diabetic peripheral neuropathy, indications that account for about 60% of cases. If suzetrigine works in those two settings, the FDA may sign off on a broad PNP label.
William Blair analysts said they were “unsure about the validity of moving into phase 3 in LSR based on today’s data.”
“We assume the decision to move forward is likely due to Vertex’s commentary about securing a broad neuropathic pain label for suzetrigine, which it cannot do in painful diabetic neuropathy alone,” the analysts added in a Dec. 19 note.