DOP099 Prolonged Pharmacodynamic Effects of Risankizumab Following Withdrawal in Patients with Moderately to Severely Active Ulcerative Colitis
Authors: Rubin D T , Allegretti J R , DeMasi R , Crowley J , Chen S , Winzenborg I , Guay H , D'Cunha R , Long M 
Published: January 2025

Abstract

Background
Risankizumab (RZB) is a high-affinity humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine, thereby inhibiting its interaction with the IL-23 receptor.1 RZB was intentionally designed with modifications to the antibody that could contribute to prolonged half-life, low immunogenicity, and increased stability and bioavailability.1 The objective of this post-hoc analysis was to characterise the pharmacokinetic (PK) and pharmacodynamic (PD) effects of RZB following withdrawal in patients with moderately to severely active ulcerative colitis (UC).

Methods
In the UC maintenance trial (COMMAND, NCT03398135), 272 patients who responded to 12 weeks of intravenous (IV) RZB 1200 mg induction therapy were re-randomised to receive subcutaneous (SC) RZB maintenance dosing (180 mg or 360 mg) or placebo (PBO; RZB withdrawal).2 This analysis evaluated clinical endpoints, PK, and biomarkers of the SC PBO/withdrawal. Change from baseline in partial modified Mayo score, serum RZB concentrations and levels of high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) were assessed at each predetermined study visits throughout the maintenance trial.

Results
A total of 90 patients were re-randomised to receive PBO (withdrew from RZB induction) in COMMAND. Predicted PK profiles of exposure over time in the PBO/withdrawal group showed that, following the third and final RZB induction dose, residual RZB concentrations lasted for at least 16 weeks before complete washout.3 The PBO/withdrawal group did not have meaningful increases from baseline in partial modified Mayo score until after about week 24 of maintenance (36 weeks since the last dose of RZB) (Figure). Levels of hs-CRP and FCP in the PBO/withdrawal patients remained low throughout maintenance and did not meaningfully increase until week 52.

Conclusion
Patients with moderately to severely active UC who received IV RZB 1200 mg induction therapy and were re-randomised to PBO exhibited continued response to RZB as demonstrated by disease activity and biomarkers for at least 6 months, exceeding the time of PK washout. hs-CRP and FCP did not increase until week 52 of maintenance and remained below baseline values. This durability of response may have important clinical implications and warrants continued investigation.

References
1.Singh S, Kroe-Barrett RR, Canada KA, et al. Selective Targeting of the IL23 Pathway: Generation and Characterization of a Novel High-Affinity Humanized Anti-IL23A Antibody. mAbs. 2015;7(4):778–791. doi:10.1080/19420862.2015.1032491.
2.Louis E, Schreiber S, Panaccione R, et al. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA. 2024;332(11):881–897. doi:10.1001/jama.2024.12414
3.Thakre N, Goebel A, Winzenborg I, et al. Population Pharmacokinetic and Exposure-Response Modeling to Inform Risankizumab Dose Selection in Patients With Ulcerative Colitis. Clin Pharmacol Ther. 2024;116(3):847-857. doi: 10.1002/cpt.3330.