Optimizing Treatment Strategies to Manage Inflammatory Bowel Disease - Episode 14

Novel Agents Being Investigated for IBD Treatment

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William Sandborn, MD, discusses various novel agents being investigated for the management of IBD.

Remo Panaccione, MD, FRCPC: Maybe I’m not as patient as I should be with some of the newer mechanisms of actions that we’ll talk about going forward, but I do think that a combination or some combination will be the path forward, with a lot of the different mechanisms of action and especially the oral targeted small molecules, where it may not be a combination forever. It may be an episodic combination, on demand with different algorithms, so you don’t have to have the cost associated with continuous drug therapy.

I’m looking forward to that evolution. The clinical trials to evaluate that and assess that robustly are difficult just by the nature of how they need to be designed, because there are considerations in induction and in maintenance. At least it seems that there’s an appetite from different sponsors around the world to start testing this.

William Sandborn, MD: Just think of some of the stuff that Jessica has been working on. You could imagine looking for a loss of diversity in patients with ulcerative colitis in the microbiome and selecting patients for whom there’s a loss of diversity. You have a cocktail of that. You’ve tested a microbiome product—ideally, it’s synthetic stool as opposed to donor stool—that’s targeted to that group of patients. Then there are a bunch of strategies for increasing regulation T cells [T-regs], whether you’re topically administering that targeted IL-10 or you’re giving a mutant low-dose IL-2—maybe low-dose IL-2 tagged to an antibody to MADCAM1 that tethers it to the gut. That’s in clinical development, to recruit IL-2 cells or cell therapy, where gut-targeted cells are secreting IL-2 or even tethered cell-therapy T-regs that are tethered to the gut.

There are a bunch of strategies that could have the effect of ultimately increasing T-regs in the gut. Then you could mix that with the stabilizer that’s locally delivered or a topical JAK inhibitor. They’re gut-targeted oral alpha(4)beta(7) [LPAM], which looks like they might work. You could imagine 3 or 4 of those altogether. Now, the cost of it—if they’re all proprietary, you’d have to figure that out. There would be a way forward if a combination like that would work, and I could imagine a multitargeted combination of the gut like that really being profound.

Remo Panaccione, MD, FRCPC: Why don’t you review 3 or 4 of the ones you think are furthest along and that we can expect to see in the clinic in the next, say, 24 months—or even before? You already talked about Zeposia [ozanimod] as an S1P1 inhibitor. Where are we now? What’s over the horizon?

William Sandborn, MD: You have ozanimod, which was just approved in the United States; the phase 3 study will be published soon. Behind it, you have etrasimod, which will finish clinical development at the end of this year. You have amiselimod, and that’s motoring along. There are 2 other S1P modulators with favorable pharmacokinetic characteristics that are entering phase 2 now. That class of drugs is for ulcerative colitis, and it’s going to be a big deal. Ozanimod has a long-acting but correlated metabolite in the range of 7 or 8 days. It’s a long accumulation period, to maximize the clinical benefit, and they are dose-titrating up to mitigate first-dose heart rate reduction.

By contrast, some of these other drugs that are coming behind don’t have a long-acting correlated metabolite. Their half-life is about 1 day, so you can be at steady state in a week, then run a 12-week trial, and you have a long runway. The efficacy of that class of drugs may be even better than what you could see with ozanimod, given its characteristics and how we design the trial. That class of drugs is coming. We only have an open-label study of ozanimod in Crohn disease, so we don’t have a good feel for S1P modulators in the treatment of Crohn disease. I guess they’ll work, but we need to see. Then you have the JAK inhibitors like tofacitinib, but the dosages go up to 10 mg twice a day and just did not work for Crohn disease. We know that 15 mg twice a day, with some limited experience, was better than 10 mg, but you just couldn’t go high from a safety perspective.

It wouldn’t surprise me if 15 or 20 mg twice a day of tofacitinib in Crohn disease would work, but you can’t go there from a safety perspective. The JAK1 selective drugs, upadacitinib and filgotinib, are really interesting. They potentially have a better safety profile and, because of their selectivity, you can dose them more intensively. It looks like you get a ramp up in efficacy. Then you have this evolving—there are clinical trials recruiting for deucravacitinib, which is a selective TYK2 inhibitor. You can almost think of that as an oral anti–IL-23, and that’s revolutionary in the treatment of psoriasis. It’s supereffective and analogous to what you see with anti–IL-23 blockaded parenterally in psoriasis. That’s being tested for treating ulcerative colitis and Crohn.

There’s another trial that will come out at ECCO [European Crohn’s and Colitis Organisation Congress] that looks at a JAK1 TYK2 vs a placebo and then separately a JAK3 TYK2, so tyrosine kinase 2; watch for that. It’s all 1 trial, so you have 2 active trials with dose finding compared with a placebo, and these selective molecules within the JAK universe are going to incrementally get better. That’s going to be huge in our field in the years to come. We’ve mentioned repeatedly, fewer anti–interleukin 23, so blocking P19 instead of blocking P40, that blocks both interleukin 12 and 23. In psoriasis, the P19 blockade—so pure interleukin 23 blockade—is flat-out superior to blocking interleukin 12 and 23, which is a little counterintuitive to me. It’s unequivocal, but it’s true. I’ve seen it in several trials.

We have a bit of that sense in Crohn disease, that fewer anti–interleukin 23 blockades in patients with anti-DNF [distant or regional node] failure is just very robust. I do not know that it will have psoriasis-like efficacy, but it may be the best in class for that population of patients. That’s really interesting. Then we’re much earlier in understanding pure anti–interleukin 23 in ulcerative colitis. There are a bunch of studies going on. One of the trials of mirikizumab has been finished. They said that the top-line data were positive, but all the data has not been released. To me, those are the 3 big classes that should be progressively coming into practice over the next 3 years. Everything else is a bit further back.

Remo Panaccione, MD, FRCPC: Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. I’m sure you’ll see the folks in front of you on future programs. Thank you very much.

Transcript edited for clarity.