Reaction to FDA’s Approval of Upadacitinib for Crohn’s Disease

The FDA recently approved upadacitinib (Rinvoq) for treating Crohn’s disease, the first Janus kinase (JAK) inhibitor indicated for the condition, based on findings from the U-EXCEED and U-EXCEL induction studies along with the U-ENDURE maintenance study. Analyses of the trials were presented during the recent Digestive Disease Week (DDW) conference.

In this first of four exclusive roundtable episodes, MedPage Today brought together three expert leaders in the field — moderator Jason K. Hou, MD, of Baylor College of Medicine in Houston, is joined by Shirley Cohen-Mekelburg, MD, of Michigan Medicine in Ann Arbor, and Jill Gaidos, MD, of Yale School of Medicine in New Haven, Connecticut — for a virtual roundtable discussion of the data on upadacitinib in Crohn’s disease.

Following is a transcript of their remarks:

Hou: Hello everybody. Welcome to the DDW 2023 IBD [inflammatory bowel disease] Roundtable. I’m Dr. Jason Hou, a gastroenterologist associate professor at Baylor College of Medicine, and a staff member of the Houston VA [Veterans Affairs] Medical Center. It’s my pleasure to introduce our two presenters for this session. The first is Dr. Shirley Cohen-Mekelburg — she’s assistant professor of medicine at the University of Michigan and the director of IBD at the Ann Arbor VA. Also, I’d like to introduce our other presenter, Dr. Jill Gaidos, associate professor of medicine at Yale University and Director of Clinical Research at Yale University.

Well, I’d like to jump into the conversation discussion with our first abstract with Dr. Cohen-Mekelburg. The first abstract will be on endoscopic and clinical outcomes of upadacitinib in patients with moderately to severely active Crohn’s disease by number and type of prior biologics. Dr. Cohen-Mekelburg?

Cohen-Mekelburg: Thank you, Jason. So this was a post-hoc analysis of the phase III upadacitinib trials for Crohn’s disease. They included U-EXCEL and U-EXCEED, which were the two induction trials for upadacitinib 45 milligrams daily versus placebo for 12 weeks induction. And patients who achieved the clinical response were then re-randomized in a third trial, U-ENDURE, to upadacitinib 15 milligrams daily, upadacitinib 30 milligrams daily, or placebo, and this was for 52 weeks maintenance.

They then went on to examine clinical endoscopic and safety outcomes by number and type of biologic exposures. And the three studies included a total of 733 study participants with similar numbers of patients in each subgroup by number of prior biologics. And so there were 279 participants who’d been exposed to one biologic, 223 that were exposed to two, and 231 who were exposed to three or more biologics.

And basically if you look at the patient characteristics, those patients who received three or more biologics were more likely to have a longer disease duration as well as they were more likely to have received steroids. And basically when it comes to the study findings, upadacitinib response as compared to placebo was found to be lower, as the number of biologics that a participant experienced rose. And this was regardless of the type of biologic — whether it was an anti-TNF [tumor necrosis factor], an anti-integrin, or an anti-IL [interleukin] 12/23.

It was also noted that adverse effects were higher in those patients with a history of higher number of biologic exposures, and I think it is pretty consistent with what we see in our clinical practice. Patients with a higher number of biologic exposures are more likely to have poorly controlled disease, more likely to have IBD complications leading to more steroid use and adverse effects. And the longer disease duration, the more likely that you have an opportunity to receive a higher number of biologics.

And so what they concluded is that upadacitinib is effective in moderate to severe Crohn’s disease as compared to placebo, with most benefit and fewer adverse effects in those participants who failed fewer biologics. And I think to me this means that the treatment effect is actually lower the more biologics that someone is exposed to. And with that, any thoughts on that, Jill?

Gaidos: I think it’s useful because we sort of had the understanding that the JAK inhibitors were just as good, sort of at any time point. And so I think this really clarified as we think about positioning of therapies. Like you said with any of our other medications, we know that the earlier we can treat a patient, the better the response will be, sort of regardless of the biologic or advanced therapy — in this case with the small molecules.

But I think it’s important to realize that we shouldn’t wait until the very end to throw in a JAK inhibitor. So maybe if we have somebody who’s already been exposed to a TNF, we could use it earlier in the disease course and hopefully get a better response.

Cohen-Mekelburg: Definitely. I think that’s interesting. Some notes of caution, and this is mentioned in the abstract as well, but to just interpret some of these subgroups with caution, meaning that particularly those patients, there are very few patients who are actually anti-TNF naive. I believe it was actually 29 participants. And so some of this data can’t necessarily be generalized to the TNF-naive crowd.

But at least in its current practice, that would be off-label use. And I believe that one of the induction trials, actually one of the inclusion criteria was a failure of at least one biologic, which was most likely an anti-TNF.

So yeah, note of caution, but yeah, I agree. This data is very reassuring as far as the effect of upadacitinib in these subgroups, particularly with Crohn’s disease now that it was recently FDA approved.

Gaidos: I think one other key point is just as we get more information about the safety of these drugs, again like you said, this is sort of a re-analysis of the same data, but again, they saw no non-melanoma skin cancers, no major adverse cardiovascular events, or no thromboembolic events reported.

So again, as we talk to our patients, we get more and more use of these therapies, particularly the JAK inhibitors. Being able to share more information about the safety, I think, makes the decision and that shared decision-making conversation a little bit easier to have more information.

Cohen-Mekelburg: Definitely. And now that it’s approved, I super look forward to the real-world data, particularly the limitations on kind of the inclusion criteria by age. And so I think it’ll be interesting to see when is this being used for patients who are, let’s say, older adults who wouldn’t have been included in the trial.

Hou: Shirley and Jill, thanks for that discussion. One thing I just wanted to add or question to pose to both of you: Jill, you mentioned this earlier, some of the data supported or suggested that the JAK inhibitors may be good regardless of their prior exposure to a biologic, which was a nice contrast from our other traditional biologic agents.

We’ve seen this both with tofa [tofacitinib (Xeljanz)] as well as upa [upadacitinib] in UC [ulcerative colitis]. So I found that a little interesting with this abstract, maybe in Crohn’s disease the JAK inhibitors may act more like the other biologics in terms of our concern with prior exposure.

Gaidos: I mean, I don’t think we have much information about … it’s unclear if it’s just the disease and possibly some underlying fibrosis that we’re treating and not true inflammation, or if it’s some change in the pathway that’s triggering the inflammation — so if it’s some sort of change in the mechanism behind the inflammation that’s driving that. But I think as we get some more real-world data, these patients will get a better understanding of where to position these therapies and who it works best in.

Cohen-Mekelburg: And just to go off what Jill was saying, I think it’s interesting in the sense that if you look at the study design of the trials, the randomization was stratified by steroid use, endoscopic disease severity, and the number of prior biologics. However, they divided that into zero, one, or more than one biologic, rather than the subgroups that are included in this post-hoc analysis, which is like one, two, or greater than three.

And that probably counts for why you do see some of the differences that we’re seeing — let’s say by disease duration or by steroid use. And so you do wonder, is this an issue with confounders or is this an issue of truly those patients who are exposed to three or more, all other things being matched, are they truly less likely to respond?

Hou: That’s a great point, Shirley. Yeah, so just to conclude and summarize. A really interesting study; I think we have more to see, obviously as they go into this and it goes into full manuscript and we see the details of this. There’s obviously a lot of adjustment that needs to be taken into consideration, whether some of these differences pan out or not.

But I found this abstract to be interesting. Again, in JAK inhibitors, Crohn’s is going to be a different animal. We know obviously with tofa, it didn’t make it in phase II trials, times two. So it’ll be interesting to see. The devils are in the details. But very encouraging overall that they were still seeing response despite their exposure rates.

A key question, you may say whether how relevant some of this is, because as you mentioned, Shirley, as per labeling, these really should be TNF inhibitor exposed by labeling. And I think a key challenge as you also pointed out, the minority of the patients in these studies were TNF-exposed — only 29.

So that again, as both of you mentioned, very interesting to see how this pans out in further studies in the real world. Thanks.