Eli Lilly and Company Indianapolis, IN, United States
Travis Johnson, PhD, MSPH1, Boyd Steere, PhD2, Pengyue Zhang, PhD1, Yong Zang, PhD1, Richard Higgs, PhD2, Klaus Gottlieb, MD, PhD, JD, MBA2, Walter Reinisch, MD, PhD3, Julian Panés, MD, PhD4, Venkatesh Krishnan, MSc, PhD2 1Indiana University Clinical and Translational Sciences Institute, Indianapolis, IN; 2Eli Lilly and Company, Indianapolis, IN; 3Medical University of Vienna, Wien, Wien, Austria; 4Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Catalonia, Spain
Introduction: Mirikizumab(miri), an anti-IL-23p19 monoclonal antibody, showed efficacy and was well-tolerated in Phase2 randomised trial in patients(pts) with moderate-to-severe ulcerative colitis(UC;NCT02589665). After 12 weeks(W) treatment, miri down-regulated several transcripts correlated with UC disease activity and implicated in anti-TNF resistance. We show W52 gene expression analysis from the induction responder cohort at W12 for miri and placebo(PBO) treated pt biopsy samples to identify sustained changes in gene expression.
Methods: Miri-treated pts achieving clinical response(decrease in 9-pt Mayo subscore[rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline[BL] with either a decrease of RB subscore of ≥1 or RB subscore of 0 or 1) or better at W12 were re-randomized to miri 200 mg administered subcutaneously every 4W or 12W through W52. Pts given PBO in induction achieving clinical response continued PBO in maintenance period. Colonic biopsies were obtained at W0, 12, 52 from the most affected area at least 30cm from anal verge(miri N=31,PBO N=7). Transcript changes at W12 from BL in PBO and miri arms were clustered into differentially expressed genes(DEGs) by Bayesian Limma R-package. Among the DEGs, similarly expressed genes(SEGs) were identified as those that maintained their W12 expression level through W52.
Results: Analysis of transcript changes at W52 in the W12 responders maintaining disease remission, identified a profile of DEG-SEGs in responders. Of these genes, 63(70.8%) were present only in miri responders, 5(5.6%) only in PBO responders, 21(23.6%) were present in both. Magnitude of transcript changes was greater at W12, and more consistent through W52, in miri responders compared to PBO responders. A separate cluster of DEG-SEGs correlated with disease activity indices(Robarts Histopathology Index [RHI], and modified Mayo; both r >0.5) were shown to be sustained in miri pts but not in PBO pts.
Discussion: In the sample of W12 PBO and miri responders, miri responders showed broader, larger, more sustained magnitude of changes at W52 than PBO responders. Qualitative description of transcripts suggests a distinct molecular healing pathway associated with miri treatment, as compared to spontaneous healing that occurred in PBO responders. A cluster of transcripts correlating with disease activity indices was identified, demonstrating consistency across molecular, endoscopic and clinical indices of miri-mediated healing in UC.
Travis Johnson indicated no relevant financial relationships.
Boyd Steere: Eli Lilly and Company – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Pengyue Zhang indicated no relevant financial relationships.
Yong Zang indicated no relevant financial relationships.
Richard Higgs: Eli Lilly and Company – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Klaus Gottlieb: Eli Lilly and Company – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).