Edward Loftus Jr., MD

 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.

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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. 

Unmet Needs in IBD Management

In the pivotal studies, we were missing endoscopies for patients on both vedolizumab and ustekinumab, so you’re treating symptoms and we didn’t have that piece of information. The SEAVUE trial came out recently, and it showed similar outcomes with adalimumab in the treatment of Crohn, which we know is a good drug. Ustekinumab is also an option, including similar rates of endoscopic healing. We know that class of drugs and ustekinumab are safer, so that strengthens my way of thinking. If you have a patient that has significant alteration, or somebody whom you would ordinarily give a TNF [tumor necrosis factor] blocker or 2—that trial, to me, says, “If you wanted to emphasize safety, you could give ustekinumab as a first-line treatment and expect the similar amount of efficacy that you’re going to get with the TNF blocker.” I like that. I agree, the positioning by payers is problematic part of the time, but in a perfect world, that’s a great fit for first-line therapy because of the mixture of safety and efficacy.

We already touched on the SEAVUE trial, but we should unpack it and address the significance that it may have in clinical practice. The SEAVUE trial was a head-to-head trial of ustekinumab and adalimumab per label, so there was no dose escalation. It included an early patient population that was bio-naive. Arguably, endoscopic activity was less than what we would usually see in a typical patient with moderate to severe Crohn disease. With that being said, powered for superiority, we didn’t see any difference in either the clinical or endoscopic outcomes. From each one of you, what is your overall take on it and how is it going to change your clinical practice? I’ll start with Jessica. Did you have any expectations going in?

Yes; I’m not surprised by the results. It shows what would potentially be considered a well-known first-line agent, adalimumab, in the treatment of Crohn disease; ustekinumab performed just as well, and this agent has a superior safety profile. I don’t think that’s arguable, and you give it less frequently: Dosing is every 8 weeks compared to 2 weeks. In that sense, when you see that data as a prescriber, you might say, “Why wouldn’t I go with the more convenient, safer choice if the efficacy is essentially equivalent?” That’s the takeaway for me from that study; all things—payers and whatnot—being considered, they’re both injectables, so you have that convenience factor, but there’s less dosing with ustekinumab. In the end, even though there wasn’t a superior result for ustekinumab, from an efficacy standpoint, that’s still a positive outcome.

 Yes; there were hints in there that, for most end points, they were the same. There were hints of some favorability of ustekinumab regarding safety. The number of people who discontinued the trial due to adverse events was almost twice as high in the adalimumab arms. It was 11% vs 6%. Then, among the week 16 responders, the percentage of patients who were doing well at week 52 was about 10 percentage points higher in the ustekinumab group. That fits with the sense that there is less drop-off. If you’re a responder, you tend to maintain your response with ustekinumab—there’s less loss of response. Those are the hints that those are some of the positive features of ustekinumab. I view it as a win-win because these are probably the 2 most common drugs I use in the treatment of Crohn disease, so they’re both good drugs. In an ideal world, if we didn’t have insurance barriers or cost access, sure, you would use the ustekinumab all the time. In the real world, it’s twice as expensive, so that plays a role. Anecdotally, I do feel that it has a bit of a target on its back lately. Since the first of the year, it seems like we have had much more pushback in issues related to either starting ustekinumab or changing the dose of ustekinumab, including right here. It is an issue, and it’s only going to get worse in 2 years when we get 6 biosimilars hanging out, waiting for activation.

I would like to press you on 2 things; I see it the same way you guys do. The only other thing is the issue around dose escalation. I’m helping the launch of this therapeutic drug monitoring [TDM] stuff. I feel like there’s an epidemic of dose escalation that’s not adding a lot of value. With ustekinumab, that adequacy of dosing is good for most patients. If you looked at the pharmacokinetic and pharmacodynamic paper that we published in 

, for both UC [ulcerative colitis]and Crohn, 75% of the patients plateau efficacy at about the 25th percentile of drug concentration for the labeled dose. Most patients have enough of the drug, and I don’t see much utility in empirically dose escalating for something that’s never been shown to work. You take an expensive drug and make it mega expensive, and we don’t know if it works. If you measure the drug level, you get off the hook for dose escalating 75% of the time. With adalimumab, there’s much more of it. Now we have the SERENE trials that show it doesn’t work well in terms of more intensive dosing, but it’s an inconvenient fact in the way that we’ve built our practice guidelines and come to practice now. I feel less pressure to dose escalate with ustekinumab, which I like. I don’t know how you guys see all that.

It is interesting; we do a lot of dose escalating up here [Brigham and Women’s Hospital] and we have looked at this. One of our fellows, Rahul S. Dalal, MD, published a few things on this at DDW [Digestive Disease Week] this year. Essentially, what we found is if you’re a primary nonresponder to ustekinumab, there’s absolutely 0 utility in dose escalating. However, there does seem to be some recapture in the patients who had an initial response and then lost response. We saw about 50% recapturing clinical response. There seemed to be no difference between Q6 and Q4, so how people decide the level that they’re escalating to is provider dependent. There are no data that suggests that one is better than the other, but we saw some recapture and we’re studying this prospectively now, so we shall see. There might be some utility in some of those secondary nonresponders, but I don’t know how to use TDM for ustekinumab in my practice. I don’t routinely check levels. I don’t know what to do with them. If the patient does lose response, I’m almost reflexively dose escalating to try to recapture response with a low threshold to move on if it doesn’t work.

Do you think the results of some of these new trials are going to influence how we prescribe biologics in bio-naive patients? Is the SEAVUE trial going to change anything?

I do think these head-to-head trials are important. When the VARSITY trial was published, it was a pivotal moment in this space. We have been asking for these head-to-head trials to try to understand positioning and we’re finally starting to get them, and we are going to get more. Having data like these and seeing the results can influence practice patterns. I appreciate having data with these head-to-heads to understand how I’m going to position therapies in my own practice. These things matter. We have been guessing at positioning and using things like network meta-analyses to try to understand. Until we have actual biomarkers or actual tests where we can test patients up front and say, “This is the therapy you need to be on first,” this is the type of data that we need to help inform our practices.

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Details of the head-to-head SEAVUE study of ustekinumab vs adalimumab for induction and maintenance therapy in patients with moderate to severe Crohn disease.

SEAVUE: Ustekinumab vs Adalimumab in Crohn Disease

Let’s get into some of the newer data that were presented at DDW [Digestive Disease Week]. Ed, you mentioned this subgroup analysis of the GEMINI [2] trial and symptomatic improvement. Do you want to summarize what [the abstract of] Marla C. Dubinsky’s, MD, demonstrated and how it may influence your practice?

: It showed the patient with that moderate disease where the CDAI [Crohn's Disease Activity Index] is elevated, but below 330, as opposed to severe, where it’s above 330—those patients had bigger improvements on vedolizumab. They had bigger improvements in their abdominal pain scores and stool frequency scores compared with patients who had higher CDAI levels. Similarly, when they broke out anti-TNF [tumor necrosis factor] exposure, anti-TNF-naive patients had bigger reductions in abdominal pain scores and stool frequency scores than the patients who were bio-exposed. It fits with what we’ve been talking about, that there may be a window of opportunity for the patient with moderate Crohn who is bio-naive. It gives you another treatment option, where you’re not necessarily, say, relegated to adalimumab or ustekinumab, for example.

People who are listening may think about using vedolizumab more as a first-line treatment for Crohn disease. We had more data, Bill, that you presented as far as the long-term safety for ustekinumab. We’re always looking for more data when it comes to safety. Can you summarize what that showed?

Over 5 years,it showed that there’s a robust safety signal for ustekinumab. That fits with more than 10 years of data in the psoriasis setting with some of the registries that occurred there. There are no real signals for infection, malignancy, or major cardiovascular events. All those things that we worry about, to some degree, with JAK [Janus kinase] inhibitors and TNF blockers, we just don’t see.

The data set is very robust. I still get questions from some of our colleagues: “Well, why is that the case?” Why do you think it looks so clean? Not only as an IL-12/23 blocker, but even the anti-P19s look clean. Is it that we should accept the data, or do people need to understand why we think there isn’t a lot of toxicity with blocking these pathways? Because if we would’ve gone back to—let’s think the CERTIFY trial going into the [IM]-UNITI trial—a lot of us thought there might be a toxicity penalty, especially with higher doses, but we’ve never seen that. Do you have an opinion on that?

Yes; I’m a huge fan of basic science for identifying mechanisms, pathways, and new drugs, but to predict what is going to be safe from an infection standpoint, you have to go to the clinic. We have this huge amount of observed data, both observational registry data and randomized clinical trials relative to placebo, that show that IL-12/23 blockade and IL-23 blockade look like background disease. There seems to be no increase over the placebo for a given patient population adjusted for age and other factors. Conversely, that is not the case with JAK inhibitors and TNF blockers. With both of those classes of drugs, you see a higher risk of infection. With JAK inhibitors, you see a higher risk of nonmelanoma skin cancer. For a long time, we said that you needed azathioprine or 6-MP [mercaptopurine] to get the non-Hodgkin lymphoma signal with TNF blockers. Then we had that huge study out of Denmark that showed that it’s not true. There’s about a 3-fold increased risk of lymphoma with monotherapy or with TNF blockers. If you go to combination therapy, the risk goes up to 6-fold or 7-fold. I don’t think it’s chance. I don’t think it’s under study. There’s a huge amount of experience now, and they’re just different. Do I feel we have a robust scientific explanation for why anti-TNFs in the inflammation state causes infection and some forms of malignancy and [IL]-12/23 blockade does not? I don’t know, but I feel confident with this huge, amassed clinical experience with the drugs. There are differences, and I’m not waiting for another shoe to drop. We know the toxicity profile of the drug is not going to change.

Edward Loftus Jr, MD, and William Sandborn, MD, review the 5-year remission data from the IM-UNITI trial for ustekinumab and post hoc analysis from the GEMINI 2 trial for vedolizumab in patients with Crohn disease.

Edward Loftus Jr., MD

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