Saurabh Mehandru, MD, on Durability of Response to p19 Inhibitors in IBD

Dr. Mehandru reviews the results of 3 pivotal clinical trials on p19 inhibitors where the drug effect was found to be sustained for a long time after drug withdrawal.

Saurabh Mehandru, MD, is professor of gastroenterology and head the Mehandru Laboratory for the study of mucosal immunology at the Icahn School of Medicine at Mt Sinai in New York, New York.

TRANSCRIPT:

My name is Saurabh Mehandru. I'm a professor of gastroenterology at the Icahn School of Medicine Mount Sinai, New York. This is about a recent presentation that I made at the Crohn's and Colitis meeting in Denver where I was asked to talk about an interesting topic, which is, do some of the newer IBD medications, particularly the p19 drugs, have a more durable response after the drug is discontinued? And if so, what could be the speculative mechanisms?

Just as a further point of introduction about myself, I run a laboratory of mucosal immunology. My group is interested in how the intestines behave during inflammation, and we do some detailed analysis of the various cell types that go up and down with inflammation. With this, in terms of the introduction, I was asked to elaborate on p19 drugs. These are among the new drugs that are in Crohn's disease and hopefully in the future for ulcerative colitis as well.

And then to speculate on why, if there is a durability of the drug response after stoppage of drugs, then what the mechanisms could be. In terms of actual data, it comes from a pivotal study or a set of studies that was published last year in the journal, Lancet. There were 2 studies named ADVANCE and MOTIVATE, and these were induction trials with this P19 drug that is called risankizumab, where patients who had severely active Crohn's disease were treated with a single dose of intravenous risankizumab or a placebo and risankizumab was given in 2 doses, either 600 milligrams or 1200 milligrams, or the patients were treated with a placebo. And the primary endpoint of this study was clinical remission at week 12, as well as patient reported outcome data and endoscopic response.

The trial was successful in the sense that in patients with moderate to severe Crohn's disease, a significantly greater proportion of patients, they achieved the coprimary endpoints of clinical remission and endoscopic response with risankizumab treatment than with placebo at week 12. And a conclusion of the study was that risankizumab may be beneficial as first-line therapy in newly diagnosed patients with moderate to severe Crohn's disease.

The next study, which is a maintenance trial, so what the investigators did, was that they took the patients who had responded to the induction therapy trial, so all the treatment responders in the ADVANCE and MOTIVATE induction studies, were then randomly assigned to receive either risankizumab 118 milligrams or risankizumab 360 milligrams, or they were withdrawn from risankizumab to a subcutaneous placebo. Essentially the treatment responders from the induction therapy trials, but then those who wanted to participate were assigned to these 3 groups, either 3 groups of risankizumab treatment or to a placebo group. And then they were followed over 52 weeks.

The very interesting thing was that of course, patients who got randomized to risankizumab, they did well. And the coprimary endpoints of CDAI, clinical remission, and endoscopic response to week 52 were met with the drug and stool frequency and abdominal pain score remission was achieved at week 52 as well. The conclusion of this study was that risankizumab was effective as a maintenance drug for patients with Crohn's disease after they had demonstrated an initial response.

The part that was very intriguing is that the patients who were treated with placebo, in those patients objective parameters such as C-reactive protein and fecal calprotectin, they continue to be suppressed, even at week 15, so they demonstrated very long-term suppression. And I won't go into the details in the trial, I elaborated data from dermatology literature, as well as data from other p19 drugs in IBD where this is a recurring theme that p19 drugs, they seem to have even after the drug is taken away, the effects, the beneficial effects of the drug, they persist.

What I ended up then discussing are some very high resolution mucosal data that are arising from our group where we've looked with some of the newer technologies such as single cell RNA sequencing as well as spatial transcriptomics, to study what happens to the lining of the intestines when there is inflammation. And what we found was that there are 2 predominant cell populations that go up. One is a T-cell population called Th17 cells, and the other is a myeloid cell population called inflammatory monocytes and macrophages. And these 2 populations are the populations that actually are targeted by risankizumab.

It's a drug that basically blocks the IL-23 pathway and prevents the generation of a pathogenic T-cell type called Th17 cell. And what we and others have found is that it's these Th17 cells as well as the myeloid cells like monocytes and macrophages that produce IL-23. Those are increased in patients with intestinal inflammation. We speculate, and of course this is speculative because right now, there is no primary data, but we speculate that risankizumab or p19 directed drugs may be targeting some of the key cells that go up during inflammation.

And how that translates into durable mucosal response, again, this is speculative, but it may be that after these cells are targeted, it leads to sort of a remodeling of the intestines so that there is some of the maladapted immune pathways, they seem to perhaps, be resetting leading to durability of the immune response.

And then towards the end of my presentation, again, this is not based on data and I speculated whether these groups of drugs could potentially be what we'd call as disease modifying drugs, and I was calling them DMIDs or disease-modifying IBD drugs, where they may be impacting on some fundamental aspects of the biology to then reset the immune clock a little bit. Of course, all of this is ripe for further studies and I was hopeful that the talk that would've spawned not only some discussion, which it did, but also that it would actually pique the interest of both people who do lab-based studies and people who do clinical studies to try and address the exact mechanisms behind this observation.