Parambir Dulai, MD on Anti-Interleukins: 12/23 and Beyond

Dr Dulai reviews his presentation from the Advances in Inflammatory Bowel Diseases regional meeting in Chicago on existing and emerging anti-IL-12/23 and anti-IL-23 agents for the treatment of IBD.

Parambir Dulai, MD, is an associate professor of medicine at Northwestern University in Chicago, Illinois.

TRANSCRIPT:

Hi, I'm Parambir Singh Dulai, an associate professor at the Northwestern University in Chicago, Illinois. I just gave my talk at the Chicago AIBD Regional, and I wanted to leave you with a few key highlights from today's topic of anti-interleukins, 12/23 and beyond.

This is a promising class of therapies for us in IBD, both for Crohn's disease and ulcerative colitis, and we reviewed several really important clinical trials that were recently completed, or have recently been completed and presented at conferences.

I'm going to start by just highlighting the recent SEAVUE trial, which compared ustekinumab to adalimumab in Crohn's disease in nearly 400 biologic naive, moderate-to-severe Crohn's patients who were early in their disease duration.

The real key take-home point here was that the overall remission rates for both ustekinumab and adalimumab were around 60%, and nearly equivalent between these 2 drugs, showing parity, potentially, between these two therapies. But ustekinumab did have a lower rate of side effects.

And so, the IL 12/23 class as a whole looks to be at least comparable to anti-TNF agents early in Crohn's disease with a good safety profile.

Now, when we think about the IL 12/23 class, and considerations for some of the new therapies, it's important to understand what the 12/23 pathway means.

So, IL 12 has a P40 subunit, as well as IL 23 has a P40 subunit, which are targeted by ustekinumab. So, ustekinumab blocks both IL 12 and IL 23, whereas IL 23 also has a P19 subunit, which is what's being targeted now with more recently developed IL 23-specific inhibitors.

The reason for this more specific inhibition is that there's some thought that IL 12 may actually have some anti-inflammatory components, and therefore the true benefits of this pathway aren't fully achieved unless we selectively block IL 23.

Some of the recent notable IL 23 inhibitors that have come to market are risankizumab, which is now approved for Crohn's disease, guselkumab, which has completed some important phase-two clinical trials, which I'll discuss, and mirikizumab.

So, thinking about risankizumab, which has just completed the large phase 3 clinical trial program and is now FDA approved for treatment in Crohn's disease; the ADVANCE and MOTIVATE induction trials, randomized over 1,500 patients; and the FORTIFY maintenance trial, followed over 500 patients as a follow-up to understand induction response and remission; and what you'll see in the clinical trial data is that risankizumab had a significantly higher rate of clinical remission, both using the CDAI and stool frequency and abdominal pain, as well as endoscopic response. This is an important endpoint that's going to progressively be involved in some of our clinical trials.

And when they looked at the subgrouping of patients based on prior bile failures and non-bile failures, it looked like it worked really well in both subpopulations, both for induction and maintenance of remission. And so, I think this is a very promising therapy, the IL 23 inhibitors for Crohn's disease.

And when we think about how we want to position these IL 23 selective inhibitors against what's already available, which is the IL 12/23 inhibitor ustekinumab, the GALAXY trials have shown us that there might be some incremental benefit.

So, the GALAXY trial looked at guselkumab compared to placebo, but also looked at guselkumab compared to ustekinumab. And the induction studies were significantly positive, and already published. But what was recently presented was the follow-up maintenance data, where 65% of Crohn's disease patients treated with guselkumab achieved clinical remission at week 48.

And there was a nearly 10% delta difference with guselkumab being favored over ustekinumab. Now, this wasn't set up to be a superiority trial, but this does help us begin to understand if this selective inhibition of IL 23 might be beneficial, and more beneficial, over the inhibition of both 12 and 23.

Switching gears to ulcerative colitis, mirikizumab should be FDA approved soon, but the LUCENT trials have shown us that this has significant benefit in terms of efficacy for ulcerative colitis, both for induction and maintenance of remission.

Most notably for the maintenance of remission, they saw that the remission rates for both clinical and endoscopic remission were up to 50-60%. A really important part of that study was that they added a new urgency subscore, a symptom that's very important for patients, and sometimes often neglected, which showed that mirikizumab was significantly better than placebo for improving urgency within the first few weeks of treatment.

And so, I think this class and these selective inhibitors of IL 23 have a very promising physician in our therapies, and these trials have begun to incorporate more symptom-based etiologies and considerations that are important for patients.

So, thank you for taking the time to hear us, and hopefully you'll be able to join us for another one of our AIBD sessions at another location. Thank you.