On December 19, 2024, Vertex announced that its non opioid painkiller suzetrigine (VX-548) had achieved the primary endpoint of significantly reducing pain in the Phase 2 Sciatica (LSR) study. However, the placebo group also showed significant pain relief (about 2 points), and the difference between the treatment group and the placebo group was not significant.

Affected by this news, Vertex's stock price plummeted by 11.37%.

01. Background
VX-548 is a selective NaV1.8 pain signal inhibitor under development, aimed at blocking the transmission of pain signals to the brain by specifically blocking sodium channels in peripheral nerves. Due to its mechanism of action being limited to the peripheral nervous system, VX-548 does not pose an addiction risk to opioid drugs.

Previously (December 2023), Vertex retrieved phase 2 clinical data on VX-548 for chronic pain, which showed that its efficacy was comparable to that of the control group Pregabalin. This study further demonstrated that VX-548 does not enter the central nervous system, theoretically avoiding possible central nervous system side effects.

Therefore, VX-548 is regarded as a non addictive analgesic drug with the potential to replace opioid drugs and is highly anticipated by the market.

This time, Vertex released the research results of VX-548 for LSR. Due to doubts about its efficacy, investor confidence has been shaken, adding a bit of uncertainty to the future of this highly anticipated "non addictive painkiller". The specific data is as follows.

In terms of effectiveness, the treatment group receiving VX-548 showed a decrease of -2.02 in pain scores compared to baseline at week 12, achieving the primary endpoint of the study, which was the weekly average change in daily leg pain intensity on the Digital Pain Rating Scale (NPRS) relative to baseline within the group at week 12.

This was originally good news, but the problem lies in the fact that the placebo group also showed similar therapeutic effects. The placebo group decreased by -1.98 during the same period. The p-value for both groups is<0.0001.

Although Vertex emphasized in the press release that this study was not designed to directly compare the differences between VX-548 and placebo, i.e. there is no need to worry about placebo outcomes.

But if even a placebo can achieve similar analgesic effects, why use VX-548? Did clinical trial design or operational factors affect the final results? Does the efficacy data of VX-548 still have credibility?

Vertex's post hoc analysis found that there were differences in placebo response among different study locations. Meanwhile, in approximately 40% of locations with lower placebo response, the pain relief effect was greater in the VX-548 group, and the separation from the placebo group was more pronounced.

In terms of safety, Vertex has good tolerability, with an incidence of adverse events (AEs) of 22.9%, compared to 32.4% in the placebo group. Most AEs are mild to moderate, with no serious adverse events (SAEs) related to VX-548, and there have been no cases of treatment interruption caused by AEs.

Vertex will make improvement measures for the "high placebo effect" in the future, including limiting the number of trial sites, strengthening training for researchers and patients, and adopting the "placebo adjustment" strategy to address the placebo response issue, and pushing the LSR study to the third phase.

02. Analysis
Since 1999, over 190000 people in the United States have died from overdoses of OxyContin and other similar painkillers. According to incomplete statistics, there are 25 deaths from opioid drugs per 100000 people in the United States, with over 80000 deaths in 2021. The number of deaths caused by opioid addiction exceeds that of car accidents.

The Opium Crisis in the United States gave rise to a massive 'blue ocean market'. In 2020, the number of prescriptions for opioid analgesics in the United States exceeded 140 million. In the eyes of Wall Street analysts, "the pain market has the potential to become the next weight loss drug market." According to Zhiyan Consulting, the global painkiller industry market size in 2022 is approximately $91.14 billion. If VX-548 can be replaced, its value is self-evident.

So, can VX-548 achieve such value? Paul Matteis, an analyst at investment bank Stifel, believes that the research results of LSR are harmless. Even if the indication cannot be approved, the commercialization ability of VX-548 is still considerable, and it is expected that the annual revenue will reach $5 billion by 2035. (Mainly for chronic pain indications)

Baird analyst Brian Skorney expressed concerns about the quality of the trial data and the company's prospects, believing that the drug's performance was far below expectations and even questioning whether critical research could continue.

Currently, the fastest developing NaV1.8 inhibitor globally is VX-548. Other options include Vertex's VX-150 (clinical phase II termination); Pfizer's PF-04531083 (clinical phase II termination); HRS4800 (clinical phase II) from Hengrui, etc.

Source: https://pharm.jgvogel.cn/c1475143.shtml