Tag Archives: Mirikizumab

Efficacy of Mirikizumab in Moderate-to-Severe Crohn’s Disease (VIVID-1 Study)

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M Ferrante et al. The Lancet 2024; https://doi.org/10.1016/S0140-6736(24)01762-8. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study

Methods: VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study which enrolled 1150 patients with moderate-to-severe Crohn’s disease. There were three treatment groups: mirikizumab group, ustekinumab group, and placebo group. In each group, 48-49%were considered “biologic-failures” including 45-46% who were anti-TNF failures.

Key findings:

Discussion points:

Early treatment effect: “Symptomatic improvement was evident as early as week 4 accompanied by a statistically significant reduction in high-sensitivity CRP and faecal calprotectin, and endoscopic response was seen at week 12.”

Compared to ustekinumab: “Mirikizumab reached non-inferiority versus ustekinumab for clinical remission by CDAI at week 52…mirikizumab showed statistically significantly greater improvements from baseline in fecal calprotectin and CRP compared to ustekinumab.
In addition, a greater percentage of patients reached the combination endpoint of endoscopic response and clinical remission by CDAI at week 52.”

Comparison across treatment trials: “. At week 52, 45∙4% of patients treated with mirikizumab met the endpoint of clinical remission by CDAI in the treat-through analysis with composite endpoint, 54∙1% met the endpoint in the treat-through analysis, and 64∙3% met the endpoint in the responder analysis. This example, with a range of nearly 20% percentage points depending on analysis type, shows the profound limitations in comparing
unadjusted outcomes across phase 3 trials.” The authors note other differences in trial design between VIVID-1 and SEQUENCE (risankizimab) and state “no conclusions on
relative efficacy can be drawn.”

My take: This study shows that mirikizumab is effective in adults with moderate-to-severe Crohn’s disease with and without prior biologic treatments. Pediatric studies are underway.

In Trials: An Oral IL-23 Antagonist Peptide

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R Bissonnette et al. NEJM 2024; 390: 510-521.An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis

While this study shows that an oral IL-23 antagonist was effective for plaque psoriasis, this is exciting news for the GI physicians as biologic agents that target IL-23 have been shown to be very effective for inflammatory bowel disease (IBD) (eg. Ustekinumab, Risankizimab, Mirikizumab). This “FRONTIER” study shows how to achieve similar results as these biologic therapies.

Biologics are large monoclonal antibodies which cannot be orally absorbed and must be administered either intravenously or as an injection. However, “JNJ-77242113 is an oral interleukin-23–receptor antagonist peptide that selectively and potently blocks interleukin-23 proximal signaling and the production of downstream cytokines such as interleukin-17.” This medication needs to be taken on an empty stomach (this could effect real-world results).

My take: I am expecting that this medication will undergo trials for IBD and suggests that an oral effective therapy is in the therapeutic pipeline.

New Therapy for Crohn’s Disease: Mirikizumab

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Because our office is one of the centers participating in a mirikizumab study for adolescents, I was particularly interested in seeing the published results of a phase 2 study in 191 adults.

BE Sands et al. Gastroenterol 2022; 162: 495-508. Open Access: Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease

Summary Video Link (worth a watch!): Summary of Mirikizumab Study (4:25 minutes)

Background: “Mirikizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4)–variant monoclonal antibody that binds specifically to the p19 subunit of IL23 and has demonstrated efficacy in psoriasis and ulcerative colitis, and is currently in phase 3 testing for psoriasis, ulcerative colitis, and CD. We evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderately-to-severely active CD”

Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12.

**approximately two thirds of participants had received biologic therapy and approximately half of all patients in this trial having experienced at least 1 biologic failure

Key findings:

  • At Week 12, endoscopic response was significantly higher for all mirikizumab groups compared with placebo (PBO) (200 mg: 25.8%, P = .079; 600 mg: 37.5%, P = .003; 1000 mg: 43.8%, P < .001; PBO: 10.9 %). 
  • Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C (combined IV groups) and SC (subcutaneous) groups , respectively. See 4th and 6th slides below which show that those with response at 12 weeks continued with response at 52 weeks.
In the Non-Randomized group which included non-improvers and placebo, they received
the highest dose, 1000 mg. A significant number of non-improvers responded at week 52.

My take: In this study of adults, with moderate to severe Crohn’s disease, Mirikizumab showed good efficacy and safety at both 12 weeks and 52 weeks. Because about half of the participants were biologic failures, this indicates that this agent shows promise in those with refractory disease.

Economic Burden of Inflammatory Bowel Disease, Fewer Operations and Emerging Treatments

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Pouillon, L., Travis, S., Bossuyt, P. et al. Head-to-head trials in inflammatory bowel disease: past, present and future. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-0293-9 (Thanks to KT Park for this reference)

An excerpt:

This Perspective provides an overview of the past, current and future concepts in IBD trial design, with a detailed focus on the role of comparative research and the challenges and pitfalls in undertaking and interpreting the results from such studies.

Related blog posts:

GR Lichenstein et al. Clin Gastroenterol Hepatol 2020; 18: 889-97.  Using Truven MarketScan Insurance Claims data (2008-2015) from more than 160,000 patients with inflammatory bowel disease (IBD), the authors estimated economic burdens from Crohn’s disease (CD) and ulcerative colitis (UC).

  • For CD, lifetime incremental cost was $416,352 on average, but was $707,711 if diagnosis was established between 0-11 years of age. The lifetime costs, $622,056, consisted of $273,056 for outpatient care, $164,298 for inpatient care, $163,722 for pharmacy costs, and $20,979 for emergency room care.
  • For UC, lifetime incremental cost averaged $230,102, but was $369,955 if diagnosis was established between 0-11 years of age. The lifetime costs, $405,496, consisted of $153,670 for outpatient care, $123,190 for inpatient care, $105,142 for pharmacy costs, and $13,493 for emergency room care.
  • The lifetime costs for UC and CD were both greater than that for rheumatoid arthritis ($100,273) and for type 2 diabetes ($89,064).
  • Related blog post: IBD Shorts 2020  Cost of IBD Care is Increasing. From Healio Gastro: Chronic inflammatory disease expenditures nearly double over last 2 decades

T Shinagawa et al. Clin Gastroenterol Hepatol 2020; 18: 898-907.  In this study from Japan with 1871 patients with CD, the 5- and 10-year reoperation rates were 23.4% and 48.0% respectively.  However, reoperation rates were significantly lower after 2002 than prior with HR 0.72.  Postoperative use of immunomodulators (OR 0.60) and anti-TNF therapy (HR 0.71) were associated with a reduced the risk of reoperation.

Pipeline Medications for Ulcerative Colitis (Part 2)

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To continue with topic of new medications for ulcerative colitis started yesterday -two more articles:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 537-49
  • S Danese. Gastroenterol 2020; 158: 467-70 (commentary)

The first reference describes a randomized phase 2 study of mirikizumab with 249 patients.  Mirikizumab is a monoclonal antibody to the p19 subunit of IL23. A similar agent, ustekinumab is a monoclonal antibody directed at the p40 subunit of IL23 and IL12; thus mirikuzumab is more selective targeting of IL23. the authors examined response to the study drug at 3 doses: 50 mg, 200 mg, and 600 mg and compared to intravenous placebo.  All patients received dosing at weeks 0, 4, and 8. A subset of patients continued with subcutaneous treatment starting at week 12, with 47 receiving 200 mg every 4 weeks and 46 receiving 200 mg every 12 weeks. 63% of patients in this trial had previous exposure to biologics.

Key findings:

  • At week 12, 15.9% (50 mg), 22.6% (200 mg), and 11.5 % (600 mg) in the treatment groups achieved clinical remission compared to 4.8% of the placebo group
  • Clinical responses occurred in 41.3%, 59.7%, and 49.2% in the respective treatment groups compared to 20.6% in placebo group
  • At week 52, clinical remission was achieved in 46.8% of SC every 4 weeks and 37.0% every 12 weeks.

In the commentary, Danese reviews the pipeline of new drugs emerging for ulcerative colitis.  Full Text Link: New Drugs in the Ulcerative Colitis Pipeline: Prometheus Unbound

A couple of key points:

  • “Like Prometheus, who gave fire to humans and paid with the price of eternal torment, so the gift of new drugs in ulcerative colitis brings the consequence of patients with heterogeneous disease being cycled indiscriminately through similarly modestly effective agents.”
  • “Predictive biomarkers are needed” to optimize treatment and avoid ineffective and potentially harmful treatments

My take: The emergence of new treatments is welcome given the frequent loss of response or lack of response to current therapies.  Two questions: How will we decide which agent(s) is the best one to use? When will pediatric studies be available?