Optimizing Treatment Strategies to Manage Inflammatory Bowel Disease - Episode 13
Expert gastroenterologists review the unmet needs in IBD management.
Remo Panaccione, MD, FRCPC: Ed, we’ve been at this for 21 years, as far as the biologic era has evolved, but there are still a lot of unmet needs in IBD [irritable bowel disease] management. Why don’t you outline what you think those unmet needs are, what the trends are, and where the field is going?
Edward Loftus Jr., MD: We’ve come a long way. Bill and Siddhartha Singh—their group recently did a nice meta regression on surgical rates comparing prebiologics to postbiologics, and there has been a significant reduction in both Crohn [disease] surgery rates and UC [ulcerative colitis] colectomy rates. We’ve made progress. The biggest unmet need is still on the efficacy side. Despite that, we’ve seen efficacy, and the reason is that we don’t have good predictive biomarkers. Everything is largely an empirical decision as to which drug to pick first. If we have a highly effective treatment—and Bill alluded to this earlier—then the more effective the drugs become up front, the less this whole issue of predictive biomarkers becomes because then, the drugs are just more effective in larger groups of patients. Efficacy is still the biggest unmet need. Related to that, there’s the biomarker piece, and we haven’t been able to find actionable items there to use on a regular basis.
Remo Panaccione, MD, FRCPC: Jessica, you’re the youngest of us, so you’re living in Candy Land. You weren’t in the era of only conventional therapy, which Bill is sprinkling in. Let’s talk about a little bit of cyclosporine, a little bit of tacrolimus—those are the good old days. But now, it has been 20 years, and I agree with Ed that we haven’t seen a lot of incremental efficacy gains. Is there anything else that you think we still need to address better, outside of pure efficacy?
Jessica Allegretti, MD, MPH: With improved efficacy, we also need improved safety. Some of our limitations can also be around safety profiles and convenience of dosing, which we’re really moving toward. To Bill’s earlier point, it’s a matter of the right patient and the right drug. We know that, if you get it right the first time, you’re much more likely to have improved outcomes and durability. To what Ed was just discussing, we really need biomarkers and testing to identify who’s going to respond to what up front, so that we’re not doing this hypothesis, this guess generating—“I guess we’ll start with this and then try.” That’s where the field is moving, and I certainly hope we get there in the near future so that we can identify which pathway is driving that person’s disease. We can get them on the right therapy early and then hopefully give them a lot of disease-free time. That’s really, in my opinion, the biggest unmet need in our space, because we’re going to have a lot of new mechanisms coming down the line. We’re going to have a lot of new agents, but if we’re still cycling through 9 agents instead of 3, we haven’t made a ton of headway.
Remo Panaccione, MD, FRCPC: Bill, we always hear the same shopping list of the things we want. Are we any closer to seeing a biomarker-driven treatment decision algorithm, or are we just dreaming in Technicolor?
William Sandborn, MD: We are going to see it. It comes in spades to oncology, and it’s going to come to autoimmune diseases sooner than you think. People always say that you should never underestimate how slowly change will occur and how massive the change will be when it gets there. It has been a long, slow slog for precision medicine, in the treatment of autoimmune diseases, particularly in IBD, but it is going to end eventually. The big unmet need is efficacy. The fact remains that even some of the drugs we’re talking about today that have the biggest efficacy signals that we’ve seen—you’re talking about 25% remission rates in ulcerative colitis on a drug and 5% on a placebo. That’s the best we’ve ever seen. That means 75% of patients aren’t going into remission. That’s the need. How would you get there? Taking into account what Jessica said, it could be predictive biomarkers and precision medicine. It could be combination therapy. Remo, your group and our group recently published about an experience of combining biologics where, for the most part, patients had failed all the individual biologics. In the treatment of Crohn disease, we were able to get up to 40% of patients into clinical remission, which is surprising and somewhat remarkable. It needs much more replication, and we have to better assess the safety, but that looks feasible to me. Then the third issue is this organ specific delivery system.
There must be 20 drugs; some are parenterally administered. Many are orally administered, and they are targeting the gut. That, without a doubt, will improve safety, and you might be able to have 2 or 3 gut-targeted drugs in combination with a systemic drug. The efficacy increase could go 2 ways. It could be combinations, and then organ-specific delivery as a portion of the combination, which will be critical. The other thing is it could be that you see 60% or 70% efficacy or—let’s not be greedy—50% efficacy in a predictive biomarker defined population, and you see 10% efficacy per remission in the biomarker-negative group. Maybe the biomarker-positive is only 25% of patients, but if you can get 50% efficacy in 25% of patients, that will be the first-line drug for those patients. You’ll take half the patients off the table in that group. If you chip away at it, and you get 3 of 4 of those, suddenly you would have half the patients who you would have a really highly effective drug to go to out of the gates. The first trials that are going to do exactly that—test exactly that strategy—will start in a month or 2 in the third quarter. We’ll get a feel over the next couple of years if that can work.
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.