Advances in The Management of Inflammatory Bowel Diseases - Episode 19
Miguel Regueiro, MD: Bill, you've done a lot of work in clinical trials over the years; you have a good finger on the pulse of what's to come. What other novel agents are in clinical trial now and how do these drugs work? Focus on 2 or 3 of your top hits for what you think is to come.
William J. Sandborn, MD: There are 3 classes of drugs that are furthest along and have the most promise. One is, and Marla alluded to this earlier, the pure anti–interleukin-23 antibodies or anti-p19 antibodies. There are multiple of those in development: risankizumab, mirikizumab, brazikumab, and guselkumab. They're being studied for the most part in Crohn disease and ulcerative colitis. We have less information in ulcerative colitis, but in Crohn disease, there are now 3 trials in heavily or entirely anti-TNF [tumor necrosis factor] failure patient populations with solid rates of clinical and endoscopic response and remission. That class of drugs for anti-TNF failures is going to be good, and they are revolutionary in psoriasis. They're better than anti-p40 drugs, so they will fit all those dermatology indications in our field as well. They're not thought to be of great utility for arthritis, so they're like potent ustekinumab. That class of drugs is very interesting for Crohn disease, and it is evolving for ulcerative colitis.
Then, you have the selective JAK1 [Janus kinase 1] inhibitors. Tofacitinib is a pan-JAK inhibitor that only works at the doses that were studied in ulcerative colitis and comes with some safety considerations. My general feeling is that, with the selectivity on JAK1, you can go to doses that would be equivalent to much higher tofacitinib doses because of the selectivity. For the same or better safety, you get more potent JAK1 selectivity, and it's as if you were giving mega-dose tofacitinib, which you could never give from a safety perspective.
We have a couple of drugs in development now: upadacitinib and filgotinib in that arena. They look good in refractory Crohn disease, so that will be another option, an alternative to the anti-p19s in the future that are oral. Then you see this nice dose response with upadacitinib in ulcerative colitis, so you get nice effects as you push up the doses with JAK1 selective drugs. They have a good arthritis effect. They've got a reasonable psoriasis dermatology effect. That's a useful class.
Then the ones that are new will be the S1P [sphingosine 1-phosphate] modulators. Ozanimod finishes clinical trials this summer, so we should see data this fall with the phase 3 program in ulcerative colitis. There's also amiselimod and etrasimod that are in development for IBD [inflammatory bowel disease]. There are at least 3 drugs in that class. As was noted earlier, they work as well in multiple sclerosis. They're being evaluated for atopic dermatitis and some dermatology indications. That class of drugs is oral, and it looks like a good maintenance of remission drug that's oral. That'll be interesting, to see that play out. Those are the 3 big classes.
There are some topicals in play. There's a topical JAK inhibitor; it's a pan-JAK inhibitor but with very little systemic absorption that's being tested in ulcerative colitis and Crohn disease. It was recently published: a 4-week translational medicine study that showed that you could accumulate drug in the target tissue and effect phospho-stat3 signaling, which tells you you're blocking JAK in the tissue. It's too short and too small of a trial to see what the full magnitude of the efficacy is going to be, but if you can get, with longer dosing, full JAK inhibitor efficacy with topical therapy, that'll be cool. We'll have to see about that.
Miguel Regueiro, MD: Bill, thank you. I knew I called on the right person to ask this question because that was a wonderful overview. For our patients, there's great hope, not only for more selective therapies, but new MOAs [mechanisms of action] coming out down the line.
William J. Sandborn, MD: One more thing not to forget is additional selective anti-integrin agents. We have etrolizumab that blocks beta-7 and anti–MAdCAM-1 antibody. Those are also in late-phase clinical trials and would be other drugs in the general vedolizumab class, so those are coming too.
Transcript Edited for Clarity