Mirikizumab Up Regulates Genes Associated With Mucosal Scarring In Ulcerative Colitis For Up To One Year In Phase 2 Study

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Category: Antibodies

Posted on Friday 09 July 2021 18:23

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INDIANAPOLIS, IN, USA I July 9, 2021 I Eli Lilly and Company (NYSE: THERE IS) announced new phase 2 data showing that changes in gene expression induced by mirikizumab in patients with ulcerative colitis (UC) during 12 week induction therapy were maintained up to a year. These gene transcript changes, which were unique in those who responded to mirikizumab compared to placebo, were associated with scarring of the mucosa, indicating that mirikizumab affects a distinct molecular healing pathway, compared to spontaneous recovery that occurs. ‘is produced in those who responded to placebo.

Mirikizumab is being studied in Phase 3 trials for UC and Crohn’s disease (CD), two forms of inflammatory bowel disease that can cause severe and debilitating symptoms as well as disturbances everyday.

A separate analysis of patients with moderate to severe UC assessed significant improvement in bowel urgency, a common symptom of UC that is associated with higher levels of disease activity, decreased productivity in the body. work and a worse quality of life. These results are presented virtually at the Congress of the European Organization for Crohn’s Disease and Colitis (ECCO), July 8-10, 2021.

Mirikizumab has shown early and sustained gene expression changes associated with mucosal healing in UC for up to a year

In a previously published Phase 2 study evaluating patients with UC, mirikizumab downregulated several gene transcripts associated with inflamed mucosa and upregulated gene transcripts correlated with healthy mucosa and markers of functional scarring. after 12 weeks, as defined by clinical disease endoscopy and histology indices.

In this analysis, a set of differentially expressed genetically transcripts was identified in patients who responded to mirikizumab that were not found in those who responded to placebo at 12 weeks. Of the modulated genes, 71% (n = 63) were present only in patients who responded to mirikizumab, 5.6% (n = 5) were present only in those who responded to placebo, and 23.6% (n = 21 ) were present in both groups. Effect size estimates were also examined to account for differences in sample size and associated power between treatment groups. The set of gene transcripts regulated by mirikizumab correlated with indices of UC activity, demonstrating the consistency of these molecular changes across symptomatic, clinical, endoscopic and histological indices of UC activity.

Results observed at 12 weeks were maintained for up to one year in patients receiving mirikizumab. For methodology, see “About the studies” section below.

“In the first clinical study of an anti-IL-23p19 treatment in ulcerative colitis to assess gene expression on this large scale, mirikizumab demonstrated an ability to downregulate gene transcripts associated with inflammation and upregulate transcripts associated with mucosal scarring in ulcerative colitis, with changes maintained for up to one year, ”said Walter Reinisch, director of the IBD Clinical Study Group, Department of Gastroenterology and hepatology, Vienna Medical University. “These results support the continued development of mirikizumab as a potential treatment option for ulcerative colitis, given the importance of mucosal healing and functional scarring as key therapeutic goals for this difficult-to-treat disease. “

UC Patients Reported on Definition of Significant Change in Bowel Emergency

Bowel urgency, the sudden or immediate urge to have a bowel movement, is one of the most distressing symptoms experienced by patients with UC. In this qualitative study of patients with moderate to severe UC, patients defined both the severity of the bowel emergency and what would be a significant improvement in the bowel emergency based on a numerical rating scale. (NRS) at 11 points.

In this study, half of patients with UC (50%, n = 10) reported that a one-point change on the NRS emergency would be a significant change, indicating improved emotional well-being and greater confidence to leave home or do their job. job.

A quarter of respondents (25%, n = 5) indicated that a 2 point improvement in the NRS emergency was needed to be considered significant, and another 25% of respondents (n = 5) indicated that a change of 3 or more points was needed to improve quality of life.

It is important to note that among the 75% of patients who approved a 1 to 2 point change in the NRS emergency, the initial scores on the NRS emergency ranged from 2 to 9, indicating that this amount of change was significant. regardless of the severity of an individual’s bowel emergency. . For methodology, see “About the studies” section below.

“We are very pleased to present these results to ECCO, which provide one of the first analyzes from a patient perspective on the impact of bowel emergency and what would constitute a significant change,” said Prentice Stovall, Jr. ., Global Development Manager, Immunology at Lilly. “Given the impact of bowel emergency on an individual’s ability to work and overall quality of life, this analysis will help us better understand the experience of people with UC and the potential impact of our treatments for this heavy and debilitating symptom. “

About the studies

• Mirikizumab-induced transcriptome changes in biopsies from patients at week 12 are maintained through week 52 in patients with ulcerative colitis
  Patients who achieved a clinical response at 12 weeks, measured by a decrease in the 9-point Mayo sub-score (rectal bleeding, stool frequency, endoscopy) of ≥ 2 points and ≥ 35% from baseline, with either a decrease in rectal bleeding sub-score of ≥ 1 or an RB sub-score of 0 or 1) continued on maintenance treatment with mirikizumab. Patients who received an induction placebo and achieved a clinical response continued with the placebo during the maintenance period. In this study, colonic biopsies from 52 patients were obtained at weeks 0, 12 and 52 from the most affected area ≥ 30 cm from the anal margin (mirikizumab, n = 31, placebo, n = 7). Of these patients, 31 were responders to 200 mg mirikizumab and seven responded to placebo. Transcription changes at week 12 from baseline in the placebo and mirikizumab arms were pooled into differentially expressed genes using the Bayesian Limma R package. Differentially expressed genes that maintained their level of expression from week 12 through week 52 in the placebo and mirikizumab arms were identified and referred to as similarly expressed genes. Overall, the safety profile at 52 weeks was consistent with that of mirikizumab in UC studies and with class.
• A qualitative study exploring significant improvement in bowel urgency in adults with moderate to severe ulcerative colitis
  In this qualitative study evaluating significant improvement in bowel urgency based on an NRS, in-depth interviews were conducted in the United States with 20 adults with clinician-confirmed moderate to severe UC. Using an 11-point NRS developed specifically to assess the severity of the bowel emergency, participants were asked to define levels of bowel urgency (where 0 = no emergency and 10 = worst emergency possible) . Participants were also asked to describe what would be a significant improvement based on the impact of this change on their daily lives.

About Mirikizumab
Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 interleukin 23 subunit. Mirikizumab is being studied for the treatment of immune diseases, including ulcerative colitis and Crohn’s disease.

About ulcerative colitis
Ulcerative colitis is a chronic inflammatory bowel disease that affects the colon. UC occurs when the immune system sends white blood cells into the intestinal lining, where they produce chronic inflammation and ulcerations. There is an unmet need for additional treatment options for UC that offer significant symptom relief, including bowel emergency, and provide sustained clinical remission.

About Eli Lilly and Company
Lilly is a global healthcare leader that combines compassion and discovery to create medicines that improve the lives of people around the world. We were founded over a century ago by a man determined to create high quality medicines that meet real needs, and today we remain true to that mission in all of our work. Around the world, Lilly employees strive to discover and bring life-changing medicines to those in need, to improve understanding and management of disease, and to give back to communities through philanthropy and volunteering. To learn more about Lilly, visit us at lilly.com and lilly.com/newsroom. P-LLY

SOURCE: Eli lilly