Vertex's non-opioid pain drug no better than placebo in sciatica study

Matthew Dennis

SOURCE: https://firstwordpharma.com/story/5922661

The quote “Insanity is doing the same thing over and over again and expecting different results” is often attributed to Albert Einstein, but it is likely apocryphal:

https://www.businessinsider.com/misattributed-quotes-2013-10

Published : December 19, 2024

Ref: Business Wire, Vertex Pharmaceuticals , Investor's Business Daily, Bloomberg

With an FDA decision due in a little over a month on its non-opioid drug suzetrigine in acute pain, Vertex Pharmaceuticals on Thursday unveiled mid-stage data that raises new questions about the oral NaV1.8 inhibitor's future in chronic settings. The results in people with painful lumbosacral radiculopathy (LSR) — also known as sciatica — sent the company's shares down more than 10%.

Vertex reported that the Phase II study met its primary endpoint, with suzetrigine demonstrating a significant and clinically meaningful reduction from baseline in pain as measured by the numeric pain rating scale (NPRS). Results showed that there was a mean change in NPRS at week 12 of -2.02, matching recent estimates from BMO Capital Markets analysts of a -2.0 to -2.25 point reduction.

'Similar' reduction on placebo

Although Vertex noted that the trial "was not designed nor powered for statistical comparison between suzetrigine and placebo," patients in the latter reference arm showed a "similar" reduction from baseline in pain with a mean change in NPRS at week 12 of -1.98.

"We did not see separation between the suzetrigine and the placebo arms. Yet our post-hoc analyses suggest that this could be due to the high placebo response in this study," remarked Carmen Bozic, chief medical officer at Vertex.

The pharma, noting that the placebo response is "a recognised issue in pain trials," suggested that post-hoc analyses showed that there was "variability" in the placebo response across study sites. "We remain committed to studying LSR and innovating our Phase III study design to control for the placebo effect as we advance suzetrigine into pivotal development for this condition," Bozic said.

In terms of safety, Vertex indicated that suzetrigine was well tolerated in the study, with an adverse-event rate of 22.9%, compared to 32.4% for placebo.

'Considerable risk' moving forward

RBC Capital Markets analyst Brian Abrahams called the efficacy results a "worst-case scenario" for suzetrigine, which "raise considerable risk" around its potential in chronic pain indications.

Meanwhile, William Blair analyst Myles Minter suggested that Vertex's decision to push ahead in LSR is likely due to hopes of securing eventual approval as a treatment for broad neuropathic pain. "We are unsure about the validity of moving into Phase III in LSR based on today's data and an effect size that appears very difficult to power a pivotal study for beyond potentially removing high placebo responder sites, which are nearly always present in pain trials," Minter said.

Vertex's application under review by the FDA seeks approval of suzetrigine — also known as VX-548 — to treat moderate-to-severe acute pain, with a decision expected by Jan. 30 next year. Meanwhile, a pivotal Phase III programme in patients with painful diabetic peripheral neuropathy (DPN) is also ongoing.

Abrahams noted that in patients with DPN during Phase II, suzetrigine improved pain as measured using NPRS by a similar amount as seen in the latest LSR trial. "We believe that today's data offers some hints as to the potential placebo response that could occur in the Phase III DPN study, setting a high bar for hitting [statistical significance] vs. a placebo comparator arm."