Edward Loftus Jr., MD

A discussion on how evolving endpoints—such as endoscopic, transmural, and histologic remission—provide a more accurate reflection of therapeutic efficacy compared to traditional clinical measures.

Overcoming the Placebo Effect in IBD Studies

The Peers & Perspectives series episode on Optimizing Therapeutic Strategies in Inflammatory Bowel Disease opens with a discussion on redefining remission. Traditional endpoints, such as symptom improvement, are increasingly being supplemented with objective measures like endoscopic and histologic healing to better capture treatment effectiveness. The conversation highlights how deeper healing correlates with sustained remission and improved quality of life, while also addressing the practical challenges of implementing these advanced endpoints in clinical practice—balancing diagnostic precision, resource availability, and patient accessibility.

Building on this foundation, the program transitions to an analysis of early intervention strategies and their impact on disease trajectory. Recent research underscores that initiating advanced therapy earlier in the disease course can significantly enhance both short- and long-term outcomes. The discussion delves into the importance of identifying high-risk individuals before the onset of severe symptoms and tailoring therapy based on disease phenotype, risk profile, and treatment goals. Comparisons are drawn between established and emerging agents—including biologics, JAK inhibitors, S1P receptor modulators, and IL-23 inhibitors—to help clinicians navigate evolving treatment algorithms with confidence.

In its closing section, the program looks ahead to the future of IBD management, focusing on the role of predictive medicine and the integration of novel biomarkers, genetic insights, and multi-omics data. These tools are expected to transform how clinicians diagnose, stratify, and monitor patients—enabling more personalized, preventative, and data-driven approaches to care. The discussion concludes with a forward-looking perspective on clinical research priorities, emphasizing the need for continued innovation in treatment endpoints, combination therapy trials, and patient-centered outcome measures that define the next generation of IBD care.

Videos

An overview of the changing IBD treatment landscape, highlighting how deeper remission targets and emerging therapies are redefining patient care and treatment goals.

Evolution of Healing Targets in Inflammatory Bowel Disease

 Does anything else catch your eyes, Ed or Jessica?

 I’m most excited for, at the current moment, the selective JAKs to be coming down the line, especially for Crohn disease. That’s really what I have my eye on, in addition to, as Bill just mentioned, the IL-23 inhibitors. Those are the things that are coming the soonest, and I’m excited to have more hopefully safe and efficacious options when treating Crohn disease. Those are what I have my eye on, in addition to, of course, my personal biases: the microbiome therapeutics, of which there are several under investigation. We did see some intriguing initial data from Seres Therapeutics in 1 of their agents in the treatment of ulcerative colitis, although these are still very early days. We also know there are several companies working on FMT [fecal microbiota transplantation]–like products, but really more selective microbiome therapeutics. I’m very excited for those. The positioning of microbiome therapeutics earlier or in combination with other advanced therapies is really exciting.

 Ed, do you have any final words on therapies?

 Some of the etrolizumab UC [ulcerative colitis] results were clearly mixed and somewhat disappointing, but don’t forget, we still have a Crohn [disease] trial out there. At some point, we’re going to have some anti-integrin data, and more on Crohn, so there may be something. There are a few other molecules in that realm, so who knows what will happen?

 In that same vein, there’s an orally systemically bioavailable alpha(4) beta(7) [LPAM] inhibitor that’s a small molecule. Think of it as oral vatelizumab. That’s in phase 1 testing. Then there’s another that’s a short peptide that gets down into the more distal gut, and you can think of it as inside out instead of outside in. We always knew that vatelizumab didn’t work solely the way it was proposed because, at doses and drug concentrations that are one-tenth of what’s required for clinical efficacy, you can completely saturate the alpha(4) beta(7) receptors on the appropriate lymphocytes in the periphery. If the entire mechanism of action of vatelizumab is blocking lymphocyte trafficking from the periphery to the gut, then that should be sufficient for efficacy, and it’s not. It makes you think that there’s some other mechanism beyond that, possibly with an antibody in the tissue affecting cell-cell interactions of cells that have already trafficked. With this inside-out peptide, you can see efficacy, and they saw it in a pilot study in the clinic, as well as in animal models, at concentrations where you got some into the blood but only to the point that it was 60% saturating the receptor in the periphery. You wouldn’t expect that to work, yet it did. Anyway, I’m with that. We’re going to see an evolution in anti-integrins and maybe oral therapies. Wouldn’t that be cool?

 That’s a lot to unpack and look forward to. With that, I want to thank everyone for the rich and informative discussion. Before we conclude, I’d like to get some final thoughts from each of you about what you’d like to say to our clinical colleagues. What should they be striving for in treatment and looking for the future? Jessica, why don’t we start with you?

 As we’re evolving in this space, it can potentially feel a bit overwhelming. There are almost too many potential choices coming down the line, so what I would tell my colleagues is to assess your patients. Look for prognostic factors to help you make those treatment decisions, pick targets that you’re going to follow, and do that systematically with your patients every time. It’s going to be different for every patient, but really that’s a way to keep things straight and organized. Stay attuned to the data and all these exciting developments coming down the pipeline. Remember, you can always lean on some of your colleagues at IBD [irritable bowel disease] centers if you’re unsure about therapies or want assistance. For example, I’m always happy to have discussions with my colleagues about which agent we should be choosing, why, or if they’re uncomfortable with potential therapeutic options, because until you have a lot of hands-on experience with some of these drugs, it takes a bit to get comfortable with them. That would be some of my advice to anybody out there treating IBD, but it’s starting to feel a bit overwhelming by all these new advances coming down.

 I’m going to a total side thing. We’re seeing patients with complicated diseases. One of our jobs is to stay rational but also project confidence and hope. Sometimes, we see these patients who have lost hope. Usually, for almost every patient, there’s something you can do to improve their quality of life. Just keep that in mind.

 We’re at the end of the beginning of the revolution of IBD therapy. Buckle up—a lot of new stuff will come, but we have an amazing repertoire of therapies that we can use today. Be students of the field and the craft, and learn to use those therapies and, as Ed said, improve the lives of your patients.

 I always say to the fellows here [Cumming School of Medicine at the University of Calgary], “We need to demand more.” We need to demand more of ourselves to help the patients, demand more of science to push things forward to improve the lives of the patients and to pay attention to those little things that we’ve all talked about tonight. Ed summed it up nicely, that even if you’re on your fourth biologic or advanced therapy, there’s something you can do for that patient that will make tomorrow better for them. Always look at what you can do for that individual patient. With that, to all of you, this was just fantastic stuff. I hope the audience enjoyed it.

 If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming 

 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.

Jessica Allegretti, MD, MPH, and Edward Loftus Jr., MD, review emerging agents in the later phases for the management of IBD.

Emerging Treatments Over the Horizon for IBD

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?

 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.

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?

 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.

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?

 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.

Expert gastroenterologists review the unmet needs in IBD management. 

Edward Loftus Jr., MD

Articles