VTX958 Misses Primary Endpoint for CDAI Change in Phase 2 Crohn’s Disease Trial

William Sandborn, MD

Credit: UC San Diego Health

Ventyx Biosciences has announced results from a phase 2 trial of VTX958 in patients with moderately to severely active Crohn’s disease (CD), revealing the primary endpoint for change from baseline in mean Crohn’s disease activity index (CDAI) score was not met in either VTX958 dosing group.¹

According to the July 29, 2024, press release, although both dose groups achieved nominal statistical significance on the key secondary endpoint of endoscopic response as measured by simple endoscopic score for Crohn’s disease (SES-CD), neither group met the primary endpoint for mean CDAI score change at week 12 due to a higher-than-anticipated placebo response. Based on these results, Ventyx Biosciences intends to conduct further analyses to better understand the discordance between symptomatic and endoscopic response data but does not anticipate conducting additional clinical trials of VTX958 with internal resources.¹

An oral, selective allosteric inhibitor of tyrosine kinase 2 (TYK2), VTX958 achieved positive results in a phase 1 single ascending dose and multiple ascending dose trial in 2022. TYK2 regulates both innate and adaptive immunity by mediating IFNα, IL-12, and IL-23 signaling, which have been clinically validated as relevant in the treatment of a broad range of immune-mediated diseases, including psoriasis, psoriatic arthritis, CD, ulcerative colitis, and lupus. At the time, Ventyx Biosciences indicated plans to advance VTX958 into multiple phase 2 trials for psoriasis, CD, and psoriatic arthritis.²

“We believe that our ability to achieve TYK2 target coverage throughout the day at levels typically associated with biologic therapies may position VTX958 for success in disease indications that are expected to require higher therapeutic doses, such as Crohn’s disease. We look forward to advancing VTX958 into multiple Phase 2 trials, including psoriasis, Crohn’s disease and psoriatic arthritis, beginning in the fourth quarter of 2022,” William Sandborn, MD, former president and chief medical officer of Ventyx Biosciences, said in a press release at the time of the topline phase 1 data announcement.²

On November 6, 2023, Ventyx announced the discontinuation of phase 2 trials of VTX958 in plaque psoriasis and psoriatic arthritis based on results from a 16-week, randomized, double-blind, placebo-controlled, dose-ranging phase 2 trial evaluating the efficacy and safety of 4 oral doses of VTX958 in patients with moderate to severe plaque psoriasis. Although the trial achieved its primary endpoint, the magnitude of efficacy observed did not meet Ventyx’s internal target to support VTX958’s advancement in plaque psoriasis. Accordingly, the company opted to terminate ongoing activities in the phase 2 plaque psoriasis trial and also elected to terminate the ongoing phase 2 trial of VTX958 in psoriatic arthritis.³

At the time of its discontinuation in plaque psoriasis and psoriatic arthritis, Ventyx noted the ongoing phase 2 trial of VTX958 in CD would continue to enroll and an interim efficacy analysis would be conducted in the first quarter of 2024.³ It included 109 participants randomized to VTX958 225 mg twice daily, VTX958 300 mg twice daily, or placebo for a 12-week induction treatment period followed by a long-term extension period. The primary endpoint was the change in the mean CDAI score from baseline to week 12, and a key secondary endpoint was endoscopic response, defined as a 50% reduction in the SES-CD.¹

According to a release from Ventyx, the trial did not meet its primary endpoint for change in mean CDAI score from baseline to week 12 due to a higher-than-anticipated placebo response. A dose-dependent treatment effect was observed on the key secondary endpoint of endoscopic response, at both the 225 mg (P <.05) and 300 mg (P < .01) doses. Both doses of VTX958 also showed a greater magnitude of decrease compared to placebo in 2 key biomarkers of inflammation, C-reactive protein, and fecal calprotectin. VTX958 was well tolerated with an overall safety profile consistent with previously conducted trials of VTX958.¹

As described in the release, based on these results, Ventyx Biosciences intends to conduct further analyses of the data to better understand the discordance between symptomatic and endoscopic response data. At this time, Ventyx does not anticipate conducting additional clinical trials of VTX958 with internal resources.¹

References

1. ^{Ventyx Biosciences. VENTYX BIOSCIENCES ANNOUNCES RESULTS FROM THE PHASE 2 TRIAL OF VTX958 IN PARTICIPANTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE. News Releases. July 29, 2024. Accessed July 29, 2024. https://ir.ventyxbio.com/news-releases/news-release-details/ventyx-biosciences-announces-results-phase-2-trial-vtx958-0}
2. ^{Ventyx Biosciences. VENTYX BIOSCIENCES ANNOUNCES POSITIVE TOPLINE PHASE 1 DATA FOR ITS SELECTIVE ALLOSTERIC TYK2 INHIBITOR VTX958. August 15, 2022. Accessed July 29, 2024. https://ir.ventyxbio.com/news-releases/news-release-details/ventyx-biosciences-announces-positive-topline-phase-1-data-its-0}
3. ^{Ventyx Biosciences. VENTYX BIOSCIENCES ANNOUNCES RESULTS FROM THE PHASE 2 TRIAL OF VTX958 IN PATIENTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS AND PROVIDES CORPORATE UPDATE. November 6, 2023. Accessed July 29, 2024. https://ir.ventyxbio.com/news-releases/news-release-details/ventyx-biosciences-announces-results-phase-2-trial-vtx958}