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DOP32 Clinical and molecular characterisation of patients with durable response to ustekinumab induction therapy: Results from the UNIFI phase 3 studies in moderate-to-severe ulcerative colitis

K. Li, F. Yang, K. Hayden, D. Strawn, E. Wadman, S. Bhagat, C. Marano, J.R. Friednman

Janssen Research and Development- LLC, Immunology, Spring House, USA

Background

Ustekinumab (UST) is an effective therapy for moderate-to-severe ulcerative colitis (UC).1 A subset of patients responded to the induction dose of UST and achieved clinical remission at maintenance Week 44 (M-Week 44) following placebo (PBO) maintenance. The clinical and molecular characteristics of this group are unknown.

Methods

Three subsets of patients in the UNIFI phase 3 studies were compared: (1) UST induction Week 8 (I-Week 8) responders who achieved clinical remission at M-Week 44 following PBO maintenance (n = 32; referred to as 1UST-R); (2) UST I-Week 8 responders who did not achieve clinical remission at M-Week 44 following PBO maintenance (n = 87; 1UST-NR); (3) patients who had no clinical response following two doses of UST induction (n = 93; 2UST-NR). Clinical characteristics, histologic activity, inflammation burden, and genetic risk were compared among the three groups at induction baseline. Serum biomarkers related to the IL-12 and IL-23 pathways and/or UC in general (IFNg, IL-17A, IL-22, MMPs, SAA, and NGAL) were analysed in ~60% of patients within the three groups and compared with patients who achieved M-Week 44 clinical remission following UST maintenance and normal controls.

Results

1UST-R had lower disease activity and inflammation burden (CRP, faecal calprotectin, and faecal lactoferrin) at induction baseline than 1UST-NR and 2UST-NR. They had shorter disease duration, a lower frequency of biologic therapy failure, and a trend of lower polygenic genetic risk scores. Disease (MMPs and NGAL) and pathway-related biomarkers (IL17A and IL22) for this group were comparatively less elevated at induction baseline. Histologic measures of architectural change and chronic inflammation were higher in 2UST-NR than in 1UST-R or 1UST-NR at induction baseline. IFNg, IL17A, IL22, MMPs, and SAA in UC were partially normalised by UST induction and further improved with UST maintenance therapy. In contrast, there was no further improvement in these serum markers among the 1UST-R patients during the maintenance phase.

Conclusion

Patients with a durable response to UST induction had lower disease activity, serum biomarkers indicative of inflammation, and IL-12 and IL-23 pathway activity. Although the molecular effects of UST induction were retained through M-Week 44 in this group, the lack of further improvement suggests a molecular benefit of UST maintenance therapy.

Reference:

Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201–1214.

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