Novel Anti-Inflammatory Drug! Lilly's IL-23p19 Inhibitor Mirikizumab for Ulcerative Colitis (UC): Sustained Upregulation of Mucosal Healing-Associated Genes
Jul 10, 2021 02:46
CST Updated
02:46
Eli Lilly
Global Pharmaceutical R&D and Production Company
Inflammatory Bowel Disease (UC, CD, Image source: tahminahaqmd.com)
July 09, 2021 /BioonBIOON/ --Eli Lilly(Eli Lilly) recently announced new data from a Phase 2 study of the novel anti-inflammatory drug mirikizumab for the treatment of ulcerative colitis (UC), showing:Gene expression changes induced by mirikizumab in patients with ulcerative colitis during the 12-week induction therapy were sustained for one year.。These changes in gene transcripts were unique to patients responding to mirikizumab treatment compared with the placebo group and were associated with mucosal healing, indicating that, compared with the natural healing occurring in patients who responded to placebo,Mirikizumab affects a unique molecular healing pathway。
Mirikizumab is a humanized IgG4 monoclonal antibody targeting the p19 subunit of IL-23, and the drug is currently under development for various immune-mediated diseases, including in Phase 3.Clinical Trialin the treatment of ulcerative colitis (UC) and Crohn's disease (CD). UC and CD are two inflammatory bowel diseases that can cause severe and debilitating symptoms and interfere with daily life.
Another analysis conducted in patients with moderate-to-severe UC evaluated meaningful improvements in bowel urgency, a common symptom of UC associated with higher disease activity, lower work productivity, and poorer quality of life. These results were presented at the European Crohn's and Colitis Organisation (ECCO) Congress, held from July 8 to 10, 2021.
Inflammatory Bowel Disease: Therapeutic Targets (Image adapted from PMID 30478416)
1、Mirikizumab demonstrates early and sustained gene expression changes associated with mucosal healing in ulcerative colitis for up to one year.
In a previously published phase 2 study evaluating patients with UC, after 12 weeks of treatment, mirikizumab downregulated several gene transcripts associated with inflamed mucosa and upregulated gene transcripts associated with healthy mucosa and markers of functional healing, as defined by endoscopic and histologic clinical disease indices.
In this analysis, a set of differentially expressed gene transcripts was identified in patients responding to mirikizumab, whereas none were detected in patients responding to placebo at week 12. Among these modulated genes, 71% (n=63) were exclusive to mirikizumab responders, 5.6% (n=5) were exclusive to placebo responders, and 23.6% (n=21) were present in both groups. The analysis also evaluated effect size estimates to account for differences in sample size and associated statistical power across treatment groups. A set of gene transcripts modulated by mirikizumab correlated with UC disease activity indices, demonstrating concordance between these molecular changes and the symptomatic, clinical, endoscopic, and histological indices of UC disease activity.
In patients treated with mirikizumab, the results observed at Week 12 were maintained for one year.Walter Reinisch, Director of the Clinical IBD Research Group, Department of Gastroenterology and Hepatology, Medical University of Vienna, stated: “In the first clinical study evaluating an anti-IL-23p19 therapy for UC, which included a large-scale assessment of gene expression, mirikizumab demonstrated the ability to downregulate UC inflammation-related gene transcripts and upregulate UC mucosal healing-related gene transcripts, with these changes sustained for one year. Given the importance of mucosal healing and functional healing as key treatment goals in UC, these results support the continued development of mirikizumab as a potential treatment option for UC.”
2. UC patients reported meaningful changes in bowel urgency.
Bowel urgency (fecal urgency), defined as a sudden or immediate need to defecate, is one of the most distressing symptoms for patients with ulcerative colitis (UC). In this qualitative study of patients with moderately to severely active UC, patients used an 11-point Numerical Rating Scale (NRS) to define the severity of fecal urgency and what constitutes a meaningful improvement in this symptom.
In this study, half of the UC patients (50%, n=10) reported that a 1-point change in the urgency NRS would represent a meaningful change, indicating improved emotional well-being and greater confidence in leaving home or going to work.
One-quarter of the respondents (25%, n=5) indicated that a 2-point improvement on the urgency NRS should be considered meaningful, while another 25% of respondents (n=5) stated that a change of 3 points or more is required to achieve an improvement in quality of life.
Importantly,Among the 75% of patients who supported a 1- to 2-point change in the Urgency NRS, baseline Urgency NRS scores ranged from 2 to 9, indicating that this change is clinically meaningful regardless of an individual's baseline level of bowel urgency.
Eli LillyImmunologyHead of Global Development Prentice Stovall stated: “We are pleased to present these findings at ECCO, marking the first analysis to assess the impact of bowel urgency from the patient perspective and define what constitutes a meaningful change. Given the impact of bowel urgency on an individual’s work capacity and overall quality of life, this analysis will help us further understand the experiences of patients with UC and the potential impact of our treatment on this burdensome and debilitating symptom.” (Bioon.com)