OP40 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double-blind, placebo-controlled dose-ranging, basket trial (RELIEVE UCCD)
Authors: Jairath V , Kierkus J , Duvall G A , Danese S , Sands B E , Ratiu-Duma B , Singh R , Barkay H , Raphael G , Reinisch W 
Published: January 2025

Abstract

Background
Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 Few data are available for the potential of anti-TL1A therapies in Crohn’s disease (CD). A phase 2b induction basket trial (NCT05499130)2 assessed the efficacy, safety and tolerability of duvakitug in adults with moderately to severely active ulcerative colitis and CD.

Methods
RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The CD cohort comprised of adults with moderately to severely active disease with documented inadequate response, loss of response or intolerance to conventional and/or advanced therapies (ATs). Patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 Primary endpoint was endoscopic response (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) at week 14. Safety and tolerability were assessed by adverse event (AE) reporting and laboratory monitoring.

Results
In total, 138 patients with CD were randomised, treated and included in the analysis (n=46 per arm). Demographics and baseline characteristics were similar across arms (Table 1). Both duvakitug doses achieved the primary endpoint (26% [450 mg], 48% [900 mg] versus 13% [PBO]; PBO-adjusted rates: 13% [450 mg], 35% [900 mg]) with statistically significant endoscopic responses based on the prespecified Bayesian analysis, with a &gt;0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was similar for duvakitug 900 mg (43%) and PBO (48%), and lower than duvakitug 450 mg (67%). Incidences of AEs leading to discontinuation were 2% each for duvakitug 900 mg and PBO, and 9% for duvakitug 450 mg.

Conclusion
These are the first data reported for a double-blind, randomised, PBO-controlled induction study of an anti-TL1A antibody in patients with CD. Duvakitug demonstrated statistically significant and clinically meaningful endoscopic response versus PBO with no emergent safety signals observed. These results support further development of duvakitug as a treatment option for patients with moderately to severely active CD.

Funding
Duvakitug is being developed in partnership between Teva and Sanofi.

References
1. Clarke AW, et al. MAbs. 2018;10:664–77.
2. Reinisch W, et al. 19th Congress of European Crohn’s and Colitis Organization (ECCO) 2024; 21–24 February 2024; Stockholm, Sweden. Abstract P998.