Marla Dubinsky, MD, is chief of the division of pediatric gastroenterology and nutrition and co-director of the Susan and Leonard Feinstein IBD Clinical Center, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine.

Marla Dubinsky, MD

The recent US Food and Drug Administration approval of Lilly’s mirikizumab (Omvoh) for the treatment of moderately to severely active Crohn’s disease (CD) expands the interleukin(IL)-23p19 antagonist’s impact on 

 care, building upon its 2023 approval for 

The January 15, 2025, decision was based on positive results from the phase 3 VIVID-1 study in adults with moderately to severely active CD who had an inadequate response, loss of response, or intolerance to corticosteroids, immunomodulators, and/or biologics. Both primary endpoints were achieved, with 53% of patients treated with mirikizumab achieving clinical remission at 1 year versus 36% on placebo (

<.001) and 46% of patients treated with mirikizumab experiencing visible healing of the intestinal lining at 1 year versus 23% on placebo (

For additional insight into the need for effective therapies in CD and the significance of now having mirikizumab as a treatment option, the editorial team of 

 spoke with Marla Dubinsky, MD, chief of the division of pediatric gastroenterology and nutrition and co-director of the Susan and Leonard Feinstein IBD Clinical Center, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine.

 Can you explain what CD treatment has historically looked like and what unmet needs exist for effective therapies?

The introduction of anti-TNF therapies in the late 1990s revolutionized treatment. We quickly learned that TNF was not the right target for all patients. At first, we believed all roads led to TNF no matter the disease state or pathway, so we were okay with going very downstream.

Then, we realized there are primary nonresponders to TNF for whom that is not the right target. We also learned that over time, a significant amount of patients were losing response to anti-TNF, so the durability was in question.

This was more at the beginning when we were using episodically and there were anti-drug antibodies. The dosing on label was based on whether someone felt better. For UC, there was always an endoscopic component to outcomes for clinical trials. In Crohn’s disease, we started with “Do you feel better over the last 7 days?”

We know that for patients who don't have inflammation but have more sort of disorders of gut-brain interaction, maybe an IBS overlay, when you answer the CDAI, it can overlap significantly with some of our patients who also have these functional symptoms or patient-reported outcomes.

In the SONIC trial, about 50% of patients who said clinically they felt great on either infliximab monotherapy or infliximab plus a thiopurine or a thiopurine alone and met the CDAI score change of less than 150 had ulcerations on their colonoscopy that we were blinded to. The other 50% said they didn’t feel well. They had a CDAI score that met that disease activity, their scope was normal.

That disconnect between objective and subjective is so paramount to us understanding why, despite having incredible treatments and using them early, we still had a significant amount of patients going to the operating room. A lot of that was because we were following symptoms only. We were not using the TNFs correctly from a dosing standpoint, because we started off with episodic infliximab and the exposure response was so far off.

 What are some of the issues with anti-TNFs that merited the clinical development of IL-23 antagonists? How does the mirikizumab approval build upon this?

TNF is an incredible target, and when anti-TNF is used correctly and used early, there’s not much else you need. But there’s a group of patients where we just can't get enough of the dosing. They need more than what's on label, even if we use it escalated or optimized. TNF is not their primary cytokine, and by waiting far down the line to TNF, we may be missing an upstream opportunity to get better disease control and not wait for TNF to overwhelm the system.

We also had some realizations about safety. When I tell my patients there is a Black Box warning around TNFs, particularly when I talk about pregnancy or pediatric utilization, there's a fear about the safety hits it comes with. We know that, but to be fair, it is probably the class with the highest denominator on the planet compared to all of our other drugs, where although there are warnings around infection and lymphoma risk and other serious warnings, it is still the most utilized target we have.

That's all a lot of work and a lot of gymnastics, so we would like an easier button. When risankizumab first came out and endoscopy was part of the primary outcome, we learned that IL-23 works very well in naive patients, the same as what you see with mirikizumab. We also noted that there is no warning, there are very good pharmacokinetics, and these drugs appear to be extremely durable. You don't need to use a thiopurine with it, so you're not increasing the risk.

I think there's always a need for innovation. There is a need to understand the overlap between skin conditions and rheumatic conditions and GI. We tend to follow the lead like we did with risankizumab from psoriasis data. Interestingly, mirikizumab was only tested in the IBD space. The goal was not to first get it approved in a joint or skin condition, but instead to go straight to IBD, and it has had its approval for ulcerative colitis for a while now. I think all of that results in patients and physicians and any stakeholder wanting a drug that they can have confidence in that has proof of endoscopic remission and healing.

We know with mirikizumab, for example, that we had a significant amount of patients who not only met clinical deep remission versus placebo, but also met the mucosal aspect with healing of the intestinal lining being double the percentage that we saw with placebo.

Overall, we are entering an era where confidence and safety matters. I think mirikizumab represents a positive and forward movement in this class, where we are able to help patients feel better, both with the healing of their lining and also from an emotional perspective. We don't talk enough about the importance of urgency or fatigue. The fact that we've advanced our therapies to look at the whole person is really the new era of looking at drug efficacy, value, and validity.

Brooks A. FDA Approves Mirikizumab (Omvoh) for Crohn’s Disease. 

. January 15, 2025. Accessed January 17, 2025. 

https://www.hcplive.com/view/fda-approves-mirikizumab-omvoh-for-crohn-disease

Articles

Lilly's mirikizumab (Omvoh) has been approved by the FDA for treating moderately to severely active Crohn’s disease, following its prior approval for ulcerative colitis. This decision was based on the VIVID-1 study, which demonstrated significant clinical remission and intestinal healing in patients. Historically, anti-TNF therapies have been pivotal but have limitations, including nonresponse and safety concerns. Mirikizumab, an IL-23 antagonist, offers a promising alternative with favorable safety and efficacy profiles, marking a significant advancement in inflammatory bowel disease management.

Dubinsky describes the evolution from anti-TNF therapies to IL-23 antagonists and the significance of mirikizumab’s approval for Crohn’s disease.

Marla Dubinsky, MD: Ushering In a New Era of Crohn’s Disease Treatment with Mirikizumab

Experts in gastroenterology discuss treatment selection in special situations of CD, such as age, women considering pregnancy, extra-intestinal manifestations.

Selecting CD Treatment in Special Scenarios

This is a video synopsis/summary of a panel discussion involving Marla Dubinsky, MD; David Rubin, MD; Miguel Regueiro, MD; Remo Panaccione, MD, FRCPC; and Sara Horst, MD, MPH.

The discussion revolves around advanced therapies for Crohn's disease, focusing on specific scenarios and the choice of treatments. The participants discuss their preferences based on various patient characteristics and conditions.

The conversation begins with considerations for patients previously exposed to anti-TNF (tumor necrosis factor) therapies. Natalizumab is deemed less effective in this population, and risankizumab is suggested as a preferable option over upadacitinib due to similar data outcomes. The need for speed in specific cases, such as those with extra-intestinal manifestations, is highlighted, making upadacitinib an attractive choice.

The panel discusses the importance of personalized medicine, considering factors like inflammatory joint problems, spondyloarthropathy, or other manifestations. Choices are tailored to individual patient profiles, with IL (interleukin)-23-based strategies favored for certain scenarios.

Pregnant women are advised on the importance of disease control, with emphasis on the safety of IL-23 and IL-12/23, alongside traditional anti-TNF options. The potential use of JAK (Janus kinase) inhibitors for quick induction of deeper remission is acknowledged.

The safety profile of JAK inhibitors is addressed, dispelling misconceptions and encouraging broader utilization in IBD (inflammatory bowel disease) management. The discussion concludes with a rapid-fire round where each participant shares their first-line therapy preferences for specific patient scenarios.

In closing, the participants express hope for the future of Crohn's disease management, emphasizing the evolving landscape of precision medicine, advancements in fibrosis treatment, the paradigm shift in disease monitoring, and the promise of combination therapies. The concept of treating Crohn's disease earlier in its course is highlighted as a future goal, providing optimism for improved patient outcomes.

Video synopsis is AI-generated and reviewed by HCPLive editorial staff.

Videos

Experts in gastroenterology discuss treatment selection in special situations of CD, such as age, women considering pregnancy, and extra-intestinal manifestations.

Remo Panaccione, MD, FRCPC, provides an overview of the newest oral therapy approved for CD, upadacitinib.

Use of Upadacitinib in Treatment of CD

The discussion shifts to the newest drug for Crohn's disease, upadacitinib, a selective JAK (Janus kinase) 1 inhibitor. The speaker outlines the mechanism of upadacitinib, distinguishing it from other JAK inhibitors and emphasizing its selectivity for JAK1. The drug's impact on the JAK-STAT pathway and its role in modulating gene transcription for pro-inflammatory cytokines are discussed.

Upadacitinib is highlighted for its specificity in targeting JAK1 without significant effects on JAK2, which reduces the risk of off-target effects associated with myelofibrosis and erythropoiesis. The speaker explains that JAK inhibitors act as competitive agonists, binding to the intracellular side of the receptor and competing for STAT activation.

The drug's approval for Crohn's disease is discussed, with a comparison to another treatment mentioned earlier in the conversation. The speaker notes that the data for upadacitinib, an oral small molecule, aligns closely with the effects of the mentioned treatment, administered differently. The discussion emphasizes the drug's effectiveness in achieving clinical and endoscopic remission, with particular attention to its rapid action, possibly quicker than other options.

The speaker shares personal experiences, mentioning that upadacitinib is used as a first-line therapy for Crohn's disease in Canada for about 15% of patients. The drug is frequently used clinical practice, attributed to its quick efficacy and ability to rescue a significant number of patients. The convenience of an oral small molecule is underlined, especially in gastrointestinal diseases, addressing pharmacodynamic challenges associated with monoclonal antibodies in inflamed guts.

In summary, upadacitinib emerges as a remarkable and versatile drug, praised for its selectivity, efficacy, and oral administration. The speaker's experiences and the drug's potential as a first-line therapy contribute to its significance in the evolving landscape of Crohn's disease treatment.

panel discussion on a head-to-head sequence study of rizankizumab vs ustekinumab in the treatment of CD, as well as approaches to choosing first-line treatment.

Sequence Study of Risankizumab vs Ustekinumab in CD

The transcript discusses the findings of the sequence study, focusing on the comparison between two drugs, P41 (referred to as risankizumab) and P19 (referred to as IL (interleukin)-23 therapy). The study aimed to evaluate the efficacy of risankizumab in patients with Crohn's disease who had been exposed to TNF.

The results indicate that risankizumab-exposed patients were more likely to achieve clinical response, clinical remission, and endoscopic improvement compared to those on P40 (risankizumab with IL-12 and IL-23). The transcript emphasizes that the head-to-head comparison provides valuable insights, guiding clinicians in choosing the most effective therapy.

It highlights that risankizumab, along with its biosimilar, is an approved and effective option for Crohn's disease. The discussion touches upon the significance of the sequence study's second primary endpoint, endoscopic remission, and how it could be a pivotal moment in the field.

The conversation also touches on the evolution of clinical trials in Crohn's disease, emphasizing the importance of endoscopic outcomes and the progression from subjective measures to objective proof of efficacy. The participants express optimism about the potential impact of risankizumab, especially when used as a first-line therapy.

Furthermore, the transcript discusses the importance of early intervention in Crohn's disease, suggesting that initiating treatment early is more likely to result in a positive response and prevent further damage. The participants encourage setting higher expectations for patients and discuss the advantages of using risankizumab in biologic treatment-naive patients.

In conclusion, the discussion underscores the positive findings from the sequence study, positioning risankizumab as a promising option for Crohn's disease, particularly in terms of achieving endoscopic remission and improving patient outcomes. The participants stress the need for effective communication with patients about treatment options and the potential long-term benefits of early intervention.

David Rubin, MD, leads the panel discussion on a head-to-head sequence study of rizankizumab vs ustekinumab in the treatment of CD, as well as approaches to choosing first-line treatment.