Snigdha Dey1, Netravat Pendsey1, Goutam Nair1, Prakash Packirisamy1, Tanvi Joshi1, Maithreye Rengaswamy1, Rukmini Kumar1
1Vantage Research Inc
Objectives: In this poster, we have calibrated and validated a Quantitative Systems Pharmacology (QSP) model of Ulcerative Colitis (UC) to predict the efficacy of a novel therapeutic combination in a Phase 3 clinical trial of UC patients. Background and Motivation: UC is an autoimmune disease of the bowel (categorized as an Inflammatory Bowel Disease, or IBD) with an annual incidence rate of 10.5 to 46.14 per 100,000 in Europe [1]. IBD presents an unmet treatment need, with patients losing response to treatment (biologics) over time; one study reported that over half of UC patients were not in remission at 12 months, while a third showed inadequate response [2]. Hence, it is imperative to find novel therapies and combinations that can provide alternatives to existing therapies. QSP modeling can facilitate this process by predicting the impact of novel therapies and combinations using Virtual Populations to simulate clinical outcomes. Methods: We modified a published model of UC [3] to include a representation of clinically relevant outcomes for UC, i.e., the Mayo score. Like prior approaches in AutoImmune disease modeling [4,5], the UC score is modeled semi-mechanistically to be dependent on key cell types & cytokines, epithelial cell numbers (to represent barrier function), and calibrated to match multiple clinical trials simultaneously. Results: 1) We created and calibrated an allcomers (anti TNF-alpha responder and non responder mixed) Virtual population consistent with the baseline patient characteristics and %response and %remission to therapy as reported in Phase 3 induction trials for Adalimumab (10% / 9.3% from ULTRA-1), Vedolizumab (21.9% / 11.5 % from GEMINI-1), Ustekinumab (30.5% / 10.2% from UNIFI, higher dose), and Mirizikumab (21.3% / 10.9% from LUCENT-1) [6-8] with a 2% tolerance. 2) We predicted the efficacy of a combination of two approved monotherapies, Vedolizumab and Ustekinumab, in an induction Phase 3 clinical trial with a similar all-comers population. Conclusions and Next Steps A calibrated and validated QSP model can be used to obtain predictions of Phase 3 efficacy of novel therapies and combinations in IBD. Additional areas for increasing model robustness may be to add other therapies attempted in UC (Tofacitinib, Etrolizumab, etc.), re-calibrating for Crohn’s Disease clinical outcomes, etc. Further work can be carried out as follows: 1) To predict therapeutic efficacy in specific subpopulations of interest, for example, anti-TNF-alpha non-responders or, 2) for predicting efficacy of novel therapies, e.g., anti TL1A.
[1] Caron B, Honap S, Peyrin-Biroulet L. Epidemiology of Inflammatory Bowel Disease across the Ages in the Era of Advanced Therapies. J Crohns Colitis. 2024 Oct 30;18(Supplement_2):ii3-ii15. doi: 10.1093/ecco-jcc/jjae082. [2] Bokemeyer B, Picker N, Kromer D, Rosin L, Patel H. Rates of clinical remission and inadequate response to advanced therapies among patients with ulcerative colitis in Germany. Int J Colorectal Dis. 2023 May 8;38(1):116. doi: 10.1007/s00384-023-04397-7. [3] Rogers KV, Martin SW, Bhattacharya I, Singh RSP, Nayak S. A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 1 – Model Framework. Clin Transl Sci. 2021 Jan;14(1):239-248. doi: 10.1111/cts.12849. Epub 2020 Aug 21. [4] Bedathuru D, Rengaswamy M, Channavazzala M, Ray T, Packrisamy P, Kumar R. Multiscale, mechanistic model of Rheumatoid Arthritis to enable decision making in late stage drug development. NPJ Syst Biol Appl. 2024 Nov 4;10(1):126. doi: 10.1038/s41540-024-00454-1. [5] Whittaker DG, Shaliban A, Roy M, Packrisamy P, Rengaswamy M, Damian V, Gupta A; Leveraging in vitro data from novel drug candidates to prioritize antibody combinations in autoimmune disease using a QSP model of IBD. Whittaker DG, Shaliban A, Roy M, Packrisamy P, Rengaswamy M, Damian V, Gupta A; Presented at PAGE 2023 [6] Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, Kron M, Tighe MB, Lazar A, Thakkar RB. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012 Feb;142(2):257-65.e1-3. doi: 10.1053/j.gastro.2011.10.032. [7] Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, Van Assche G, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant T, Xu J, Parikh A; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013 Aug 22;369(8):699-710. doi: 10.1056/NEJMoa1215734. [8] Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, Adedokun OJ, Li K, Peyrin-Biroulet L, Van Assche G, Danese S, Targan S, Abreu MT, Hisamatsu T, Szapary P, Marano C; UNIFI Study Group. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2019 Sep 26;381(13):1201-1214. doi: 10.1056/NEJMoa1900750.
Reference: PAGE 33 (2025) Abstr 11485 [www.page-meeting.org/?abstract=11485]
Poster: Drug/Disease Modelling - Other Topics