Shots: 

• Recently, at UEGW 2024, Lilly presented histologic and combined histologic-endoscopic outcomes from the VIVID-1 Phase III study, which evaluated the safety and efficacy of mirikizumab in adults with moderately to severely active Crohn’s disease 

• A key finding reported during UEG Week highlighted the interactions between mirikizumab and ustekinumab, particularly regarding histologic response and remission, as well as combined endoscopic-histologic responses and remissions 

• Today at PharmaShots, Mark Genovese shares insights into the study design, outcomes, and the safety profile of mirikizumab 

Saurabh: Would you like to share the study design of VIVID-1?  

Mark: VIVID-1 is a Phase 3, randomized, double-blind, treat-through study that evaluated the safety and efficacy of mirikizumab compared with placebo and an active control (ustekinumab) in adults with moderately to severely active Crohn's disease. Patients randomized to mirikizumab were administered 900 mg of mirikizumab intravenously every four weeks from Week 0-12, then 300 mg subcutaneously every four weeks from Weeks 12-52. In this study, 49% of patients taking mirikizumab or placebo had experienced a prior biologic failure. 

VIVID-1 is the first Phase 3 study for any approved or investigational treatment in Crohn's disease to report histologic and combined histologic-endoscopic outcomes that were evaluated using a systematic assessment of five bowel segments (four colonic and one ileal) and strict definitions consistent with the recently published European Crohn's and Colitis (ECCO) position statement on mucosal histopathology. 

Saurabh: What primary endpoints did you target in patients administered with Mirikizumab?  

Mark: In VIVID-1, mirikizumab demonstrated statistically significant and clinically meaningful improvements versus placebo in both of the following co-primary composite endpoints: 

• Proportion of participants achieving clinical response by patient reported outcomes (PRO) at Week 12 and endoscopic response (defined as ≥50% reduction from baseline in Simple Endoscopic Score – Crohn's Disease [SES-CD] Total Score) at Week 52 compared to placebo  

• Proportion of participants achieving clinical response by PRO at Week 12 and clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] Total Score <150) at Week 52 compared to placebo  

• Clinical response by PRO: defined as ≥30% decrease in stool frequency and/or abdominal pain, and neither score worse than baseline   

• SES-CD: a scoring method used in colonoscopies to measure healing and health of the gut 

• CDAI: a tool used to quantify the symptoms of patients with Crohn’s disease   

These results showed more than half of patients on mirikizumab achieved clinical remission as measured by CDAI at one year. Furthermore, mirikizumab demonstrated robust efficacy across subgroups and particularly in mirikizumab patients for whom prior biologic therapy had failed.  

The data disclosed at UEG Week specifically evaluated the impact of mirikizumab on histologic response, histologic remission, and combined endoscopic-histologic response and endoscopic-histologic remission at Weeks 12 and 52. Key endpoints evaluated included: 

• Histologic response, as measured by the absence of epithelial neutrophils, epithelial damage, erosions, and ulceration; or ≥50% decrease in both, active Robarts Histopathology Index (RHI) and active Global Histologic Disease Activity Score (GHAS) 

• Histologic remission, as measured by complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions and ulcers 

• Combined endoscopic-histologic response, as measured by achieving both, endoscopic response (≥50% decrease from baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) total score) and histologic response 

• Endoscopic-histologic remission, as measured by achieving both, endoscopic remission (SES-CD Total Score ≤4 and ≥2-point reduction versus baseline and no subscore >1 in any individual variable) and histologic remission 

In VIVID-1, mirikizumab achieved nominally statistically significant improvements across all histologic and histologic-endoscopic endpoints versus placebo at Weeks 12 and 52, and versus ustekinumab on the following endpoints:  

• A greater number of patients that achieved histologic response were observed with mirikizumab at Week 52 in the overall population (58.2% versus 48.8%; p=0.0075).  

• In patients with active histologic disease at baseline and with at least one prior biologic failure, mirikizumab also showed greater histologic response at Week 52 (56.5% versus 41.3%; p=0.0064) and endoscopic-histologic response at Week 52 (39.6% versus 27.8%; p=0.024) 

Saurabh: The result of the study looks promising. Would you like to share the outcomes of the study observed so far?    

Mark: The data disclosed at UEG Week specifically evaluated the impact of mirikizumab and ustekinumab on histologic response and remission and combined endoscopic-histologic response and remission at Week 52 in all patients with and without prior biologic failure in VIVID-1. 

Key endpoints evaluated included: 

• Histologic response, as measured by the absence of epithelial neutrophils, epithelial damage, erosions, and ulceration; or ≥50% decrease in both, active Robarts Histopathology Index (RHI) and active Global Histologic Disease Activity Score (GHAS) 

• Histologic remission, as measured by complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions and ulcers 

• Combined endoscopic-histologic response, as measured by achieving both, endoscopic response (≥50% decrease from baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) total score) and histologic response 

• Endoscopic-histologic remission, as measured by achieving both, endoscopic remission (SES-CD Total Score ≤4 and ≥2-point reduction versus baseline and no subscore >1 in any individual variable) and histologic remission 

These data show mirikizumab achieved nominally statistically significant improvements across all histologic and histologic-endoscopic endpoints versus placebo at Weeks 12 and 52, and versus ustekinumab on the following endpoints:  

• A greater number of patients that achieved histologic response were observed with mirikizumab at Week 52 in the overall population (58.2% versus 48.8%; p=0.0075).  

• In patients with active histologic disease at baseline and with at least one prior biologic failure, mirikizumab also showed greater histologic response at Week 52 (56.5% versus 41.3%; p=0.0064) and endoscopic-histologic response at Week 52 (39.6% versus 27.8%; p=0.024) 

These histologic data build on the growing body of evidence for mirikizumab, which may provide a greater depth of mucosal healing for those living with Crohn’s disease.   

Saurabh: Why was histological outcome considered as a significant factor in the study? How important is the shift from clinical remission to histological healing in indications such as Crohn’s Disease?  

Mark: These data broaden our understanding of the underlying inflammation that drives Crohn's disease at the cellular level—defined as histologic inflammation. This histologic inflammation persists even after treatment with standard of care therapies in up to one-quarter of patients with Crohn's disease despite evidence of endoscopic mucosal healing. 

For this reason, treatment strategies for Crohn’s disease must evolve beyond traditional measures of clinical remission and endoscopy to the evaluation of depth of intestinal healing.  

As the first company to report rigorous histologic and endo-histological outcomes in Crohn’s disease that align with the ECCO position statement, Lilly is setting a higher bar for the evaluation of long-term treatment response in inflammatory bowel disease that will provide clinicians the potential to make more informed treatment decisions. 

Saurabh: Can you shed some light on the safety profile of Mirikizumab?  

Mark: The overall safety profile of mirikizumab in patients with moderately to severely active Crohn's disease was consistent with the known safety profile in patients with ulcerative colitis (UC).  

The frequency of serious adverse events was greater in placebo than mirikizumab. The most common adverse events were COVID-19, anemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reactions. 

Saurabh: Is Mirikizumab being studied for other indications concerned with IL-23?  

Mark: Omvoh was approved by the United States Food and Drug Administration (FDA) in October 2023 as the first IL23p19 antagonist for the treatment of moderately to severely active UC in adults and is also approved in 44 countries around the world.  Lilly has additional ongoing trials to evaluate the efficacy and safety of mirikizumab in other populations with UC and Crohn’s disease, including studies in pediatric patients. Lilly is continuing to advance the science with an open-label UC trial studying two new endpoints in the assessment of bowel urgency with frequency and deferral time, both of which impact the quality of life for patients. Additionally, Lilly has a combination study in UC with mirikizumab and eltrekibart, a humanized monoclonal antibody that binds to the seven ligands that signal through the CXCR1 and CXCR2 chemokine receptors involved in neutrophil movement to sites of inflammation. There are also ongoing studies in both UC and Crohn’s disease with MORF-057, a selective oral small molecule alpha-4/beta-7 integrin inhibitor that may improve outcomes and expand treatment options for people with IBD.    

Image Source: Canva 

About the Author: 

Mark C. Genovese 

Mark C. Genovese, MD is the Senior Vice President (SVP) for Immunology Development at Eli Lilly, where he oversees development efforts across Rheumatology, Gastroenterology, Dermatology, and Allergy. Prior to joining Eli Lilly, he served as SVP for Clinical Development in Inflammation and Fibrosis at Gilead Sciences. 

Before transitioning to the industry, Dr. Genovese was the James W. Raitt Professor of Medicine and Clinical Chief of the Division of Immunology and Rheumatology at Stanford University. He earned his bachelor's degree from the University of Notre Dame and his medical degree from the Johns Hopkins University School of Medicine. He completed his internship, residency, and chief residency in the Department of Medicine at Stanford University, where he later pursued a fellowship in the Division of Immunology and Rheumatology before joining the faculty. 

Dr. Genovese led a clinical research program focused on translational medicine in autoimmune diseases. He has designed and led numerous investigator-initiated studies and international multi-center trials exploring novel therapies and therapeutic strategies for autoimmune diseases. 

He is the author of over 200 peer-reviewed articles and served as an editor for the 7th edition of Kelley’s Textbook of Rheumatology. Dr. Genovese received the prestigious Henry Kunkel Award from the American College of Rheumatology in 2008. 

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