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

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 inflammatory bowel disease (IBD) care, building upon its 2023 approval for ulcerative colitis (UC).

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

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 HCPLive Gastroenterology 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.

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

Dubinsky: 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.

HCPLive: 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?

Dubinsky: 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.

References

Brooks A. FDA Approves Mirikizumab (Omvoh) for Crohn’s Disease. HCPLive. January 15, 2025. Accessed January 17, 2025. https://www.hcplive.com/view/fda-approves-mirikizumab-omvoh-for-crohn-disease