Vertex VX-993 Misses Primary Endpoint in Mid-Stage Trial, Ending Investigation for Acute Pain

Vertex Pharmaceuticals announced Monday that its investigational NaV1.8 inhibitor, VX-993, did not meet the primary efficacy endpoint in a phase 2 dose-ranging study evaluating the drug for acute pain following bunionectomy surgery.¹

In the randomized, double-blind, placebo-controlled trial involving 367 participants, none of the 3 doses of VX-993 evaluated showed a statistically significant improvement over placebo in the time-weighted Sum of the Pain Intensity Difference over 48 hours (SPID48), the study's primary endpoint. In contrast, study participants in a reference arm who received a hydrocodone /acetaminophen combination experienced superior analgesic efficacy.¹

Mean SPID48 scores were 50.2 for placebo, 54.0 for low-dose VX-993, 71.5 for the mid-range and 74.5 for the high-dose formulations. The high-dose group showed a mean SPID48 difference from placebo of 24.3 (95% CI, –6.3, 54.9; P =.1190), while the hydrocodone/acetaminophen group reached 94.4, with a statistically significant mean difference from placebo of 44.2 (95% CI, 14.0, 74.4; P = .004), according to a Vertex statement.¹

“This proof-of-concept study was powered to test whether VX-993 would result in higher clinical efficacy than previously demonstrated with the NaV1.8 pathway,” Carmen Bozic, MD, Vertex executive vice president, global medicines development and affairs, chief medical officer, said in the statement.¹ “Based on these results, as well as the totality of preclinical data and results from our previous bunionectomy clinical studies, VX-993 is not expected to be superior to our existing NaV1.8 inhibitors and therefore we will not be advancing it as monotherapy in acute pain.”¹

VX-993 was generally well tolerated at all doses tested, with an adverse event profile similar to placebo. No serious adverse events related to the drug were reported. Common adverse events included nausea (4.1% in VX-993 groups vs 11.3% placebo), headache (2.7% vs 1.4%), dizziness (1.4% vs 1.4%), and vomiting (1.4% vs. 2.8%). No participants receiving VX-993 discontinued the study due to adverse events.¹

The development of VX-993 follows January's landmark approval by the FDA of the company's original NaV1.8 ion channel inhibitor suzetrigine (Journvax).² Suzetrigine, welcomed by the medical community as the first analgesic with a new mechanism to treat acute pain in more than 20 years, is indicated to treat moderate to severe acute pain in adults.²

The VX-933 phase 2 failure was revealed on the same day that Vertex announced second-quarter earnings, according to BioSpace.³ During a call with media and investors, the company said recent talks with the FDA put a damper on the potential for an expanded label for suzetrigine to treat lumbosacral radiculopathy.³ While scuttling plans for a new study in pursuit of that indication, however, Vertex will now prioritize ongoing research on, and future regulatory approval for, the use of suzetrigine to treat painful diabetic peripheral neuropathy.² The company is also pursuing application of the first FDA-approved NaV1.8 inhibitor for other types of neuropathic pain, Vertex said.¹

References

1. Vertex announces results from phase 2 study of VX-933 for the treatment of acute pain. News release. Vertex. August 4, 2025. Accessed August 5, 2025. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-results-phase-2-study-vx-993-treatment-acute

2. Halsey G. FDA approves Journavx, first-in-class nonopioid analgesic for moderate-to-severe acute pain. Patient Care. January 30, 2025. https://www.patientcareonline.com/view/fda-approves-journavx-first-in-class-nonopioid-analgesic-for-moderate-to-severe-acute-pain

3. Samorodnitsky D. Trial failure of Vertex's next-gen pain drug mars strong Q2 earnings. BioSpace. August 5, 2025. https://www.biospace.com/business/trial-failure-of-vertexs-next-gen-pain-drug-mars-strong-q2-earnings