Role of JAK Inhibitors and S1P Receptor Modulators for UC Treatment


Marla Dubinsky, MD, discusses the role of S1P receptor modulators and JAK inhibitors for the treatment of ulcerative colitis.

Miguel Regueiro, MD: Marla, we’re in the era of oral small molecules. We have the S1P. We have 1 S1P so far, ozanimod. I welcome you to talk about that and how we now have 2 JAK inhibitors. Talk to us about small molecules in general and those therapies specifically for ulcerative colitis [UC].

Marla Dubinsky, MD: It’s crazy to think that from 1998 until 2018, we didn’t have much. Now we have more than what we had for those 20 years. It’s an incredible thing to think about, and it’s becoming more impressive over the next couple of years. In 2018, we had our first approved small molecule with advanced therapy with tofacitinib, which was the first JAK inhibitor falling under the JAK1/3 pathways, which essentially means it goes after several cytokine pathways and other immune pathways. It first came out as a reminder. For anyone with moderate to severe ulcerative colitis, you just had to not respond to or tolerate conventional therapy. Those were the days. About a year later, at DDW [Digestive Disease Week], I got a notification in 2019 that the there was concern over increased rates of pulmonary emboli and even associated mortality in a rheumatoid arthritis [RA] study. I can take 90 minutes to walk through that study because that’s how complicated and unfortunate the information was that came out and applied to UC; however, that’s for another time.

The veno-thromboembolic events led to a label change with tofacitinib. To say a few things, 1) predominantly we now have to first fail an anti–TNF [tumor necrosis factor] therapy; 2), to consider using the lowest effective dose when you think you could dose de-escalate; for example, from 10 mg in maintenance to 5 mg—it was always 10 mg twice a day in induction; 3) you need to look for veno-thromboembolic risk factors. Those were the 3 key things that changed in 2019. That was triggered by things happening in RA, not based on the data we had with the registration trials or real world on risk of veno-thromboembolic events in UC; that’s a very important distinction that I’m making.

Fast-forward, and over time the further primary outcomes of this RA—what we call ORAL Surveillance A3921133 study, whose primary outcome was not those thromboembolic events but malignancy and MACE, major adverse cardiac events. They found that tofacitinib wasn’t deemed not-not inferior—that’s a bit of a complex thing—to TNF. Therefore, there were a couple of things that resulted. One, for the malignancy, MACE wording, and thromboembolic wording, the label was changed for tofacitinib. That same label was then applied to when upadacitinib was approved in the United States on March 16. That’s a JAK1 inhibitor. It’s not a JAK1/3, so there’s a slight distinction. We call it more selective, but that’s another discussion. The idea is that you’re blocking JAK1 in this state. The same label of failing at least TNF1, maybe TNF2. For any disease state that TNF was an option, the label is recommending that these drugs—tofacitinib or upadacitinib—not be used until after you failed at least 1, along with all the safety caveats that come along with it, and it’s recommending to consider using a lower dose unless the patient is refractory. It’s complicated because we’re taking label discussions that are specifically based on a study of patients with rheumatoid arthritis and applying them.

Unfortunately, for 1 of our most effective drug classes—I’ve saved multiple colectomies by using the JAK inhibitor class—we need to be clear on the safety and efficacy in IBD [inflammatory bowel disease] specifically. I hope this discussion will help people rethink where this information came from because before these JAKs were around, patients would have gone to colectomy. This is an important statement that I’m making. In the game for who could work quickest, it’s like name those data that my rectal bleeding score and my stool frequency are going to get better. We originally had a post hoc analysis for tofacitinib by day 3, when you already saw an improvement in the key patient-reported outcomes. We presented at ECCO [European Crohn’s and Colitis Organisation] that by day 1 with tofacitinib, you’re seeing an improvement in some of these qualities, including urgency.

There’s a lot going on in the space. I don’t want it to be seen only through the lens of safety when we have these discussions with patients. You can tell I’m all over the map on this because I’m obsessed with understanding the safety and efficacy of this class. I don’t want to withhold it from patients who really need it. I know we must fail TNF; that’s not an issue. Back to ozanimod, the first S1P, which was approved in June 2021, so we’ve had it for almost a year. That was shown to be effective in biologic-naïve and biologic failure. Although if you look at the data, it works better if you use it before an entity or a biologic. I think about positioning it, which we’ll get to, but this is the first oral small molecule that doesn’t have to fail at TNF. Understanding where all these small molecules go and their positioning is going to be critical for the future.

Miguel Regueiro, MD:That’s a wonderful overview of the oral small molecules. As you said, more to come on that.

Transcript Edited for Clarity

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