Dr Rubin discusses his address from DIgestive Disease Week 2023 in which he looks to the future of inflammatory disease therapy and advances in the field that include combination therapy, head-to-head drug trials, new therapies and more that will help advance the field of IBD care.

David Rubin, MD, is the Joseph B Kirsner Professor In Medicine, chief of Gastroenterology, Hepatology and Nutrition, and director of the Digestive Diseases Center at the University of Chicago School of Medicine.

TRANSCRIPT:

Hi, it's David Rubin from the University of Chicago. And I'm in my beautiful city of Chicago for DDW 2023.

Yesterday I spoke in a session related to DDW on how to advance our therapies and advance our field in taking care of people who have Crohn's disease and ulcerative colitis.

In the session, my job was to cover a number of difficult and important topics. One was to explore how we might use head-to-head trials and comparative studies to understand our treatments more effectively. The second was how we might combine therapies to achieve better results. The third was how we might subsequently deintensify or deescalate our therapies. And lastly, how we can be smart about new mechanisms and how they may be added to what we're doing or where they'll fit in the future.

When I tackled this topic, what I explained to the audience is first, the rationale for needing head-to-head studies or comparative effectiveness studies. That may sound obvious, but the reality is that there remains an unmet need in our field to improve our treatments for people with IBD. And in order to do so, we also want to know which therapies should we use first and which therapies might we sequence and use later.

We also want to better understand what's the timing for treatments. Do patients really need to earn their way to advanced therapies or are we really in a place now where a patient with a specific presentation or prognosis is already someone who should be on one of our advanced therapies tied to an early assessment of response. In 2023, it is time for us to assess patients in some objective manner to know if a treatment we start for their Crohn's or colitis is doing what it's supposed to be doing within weeks, not months. And we should know whether that treatment can be optimized in other ways. That was covered in a separate lecture during the same session by Severine Vermeer in a beautiful way to help us understand optimization.

But the comparative studies we have fall into several flavors. There are the real world observational studies where patients have arrived on specific therapies for many different reasons, some of which are the clinician's preference or recommendations, some of which of course are the patient's choices. And of course, in many parts of the world, including here in the United States, it is related to the availability of therapies from insurance companies.

But then there are the prospective and randomized comparative studies which go back all the way to the early days of our field where sulfasalazine was compared to mesalamine and other analogs of 5-ASAs to the National Cooperative Crohn's Disease Study where sulfasalazine, prednisone, and azathioprine were compared with placebo to the more modern approaches to all of this where we look at head-to-head studies that are designed to demonstrate superiority, like our study of VARSITY comparing adalimumab to vedolizumab, and our study of SEAVUE, which was looking at ustekinumab compared with adalimumab, to studies of non-inferiority, which is the regulatory pathway that the FDA created and other groups have used to demonstrate that a biosimilar is not inferior or superior to an originator drug.

So there's lots of different types of comparative studies. So what can we learn about these? Well, one message that we've learned is that our presumption about whether one agent is better than another based on observational data or on network meta-analysis may be completely wrong when you compare the therapies side by side in a prospective trial. Examples of that might be based on what we thought would happen with novel in emerging agents like a drug called etrolizumab, where we expected it might be better than anti-TNF. But in studies against infliximab and adalimumab in ulcerative colitis, it was not. A different example is the presumption that one therapy might be safer than another, although long-term safety studies are always important, it's important to acknowledge that in both SEAVUE, looking at ustekinumab and adalimumab, and in VARSITY, looking at vedolizumab and adalimumab, at the end result the safety of those therapies were essentially the same despite the presumption that vedo or ustekinumab might be safer than the anti-TNF agent in those studies.

I also discussed some ongoing studies that were comparing drugs one to another, and then I moved into the understanding of how we might combine therapies. Combining therapies is something that everyone asks about, and of course it starts with the idea that we've used steroids combined with many therapies, but I'll emphasize to the opposite. Most of our pivotal trials have at least half the patients not on steroids when they get novel agents. And I continue to believe we're overutilizing steroids when we know we're going to start a new agent. This is especially true with our rapidly acting new advanced therapies, including the small molecules, but I didn't talk about those in this particular lecture.

Now getting to this issue of doing combination therapies, there are what I call the convenience combination therapies where we use one drug to treat the IBD, and because the patient has some other immune condition may be involving skin or joints, we add a second agent to cover that, but we end up with some benefit in the bowel disease because you now have two agents on board.

But then there are the more rationally designed combination studies where we're exploring whether combined mechanisms, potential synergy between therapies, and other strategies might make more sense. The way I summarized it in my presentation was based on the intensity of the therapy matching the burden of inflammation. And the concept that when you're inducing remission for many of our patients, we need a more intense therapy upfront. But when we get into the maintenance phase, we're talking more about prevention of relapse, prevention of progression, we might be able to deintensify or deescalate. And I made the distinction between those two terms from deescalation, meaning you worked your way up to a more intensive therapy strategy, so you're going to deescalate, and the deintensification where you start in intensely like a top down strategy or someone who needs a lot of therapy upfront, and then you deintensify later. I think using the right terms as we explore this from a clinical trial point of view, but frankly in clinical practice as well, makes good sense.

To that end, I looked at a few of the available trials that have now combined therapies. One of them was a study called EXPLORER that looked at what was termed high risk Crohn's disease, and you may have a sense of who some of those patients are in your practice, and they received methotrexate, vedolizumab, and adalimumab, triple therapy as part of their reduction strategy with withdrawal of one or the other therapies as the patients went on. So they didn't continue all three therapies. And it demonstrated very nicely without a comparator arm of placebo, but just generally proof of principle, that number one this was safe, and number two you had a good rate of clinical remission and endoscopic healing as high as 34% with this high risk group of patients. So that was one.

The other one was the more recently presented VEGA study, which was based on some animal model and observations that IL-23 inhibition plus TNF inhibition was actually potentially better or at least synergistically additive in some ways to either drug alone. And in VEGA we looked at combo therapy with a P19 IL-23 drug guselkumab with an anti-TNF drug golimumab. And an induction using those two at week 12 was better than either drug alone. And then there's a subsequent follow on where the patients got either golimumab or guselkumab, not the combo. And it's of great interest to us. It makes some sense from the science and animal data. And we'd like to understand better. And very importantly, it was safe. IL-23 tends to be a safe strategy. And adding anti-TNF in this situation was okay. There are two ongoing and enrolling studies called DUET Crohn's and DUET ulcerative colitis that are now looking at the combination of those two drugs, guselkumab and golimumab, and continuing that arm out into maintenance phase as well versus one of the drugs or the other in the maintenance phase as well. And we're anxiously awaiting what that might show us.

Moving into the understanding of deintensification and deescalation, I presented the results from a study called SPARE where patients who were on combo therapy of infliximab with an immunomodulator were randomized to either continue both drugs, or stop the immunomodulator, or stop the infliximab. And even though the three arms of this study were balanced in terms of the number who had already failed immunomodulators before they got on both drugs, it's of interest to note that the group that had the greatest relapse rate was when you withdrew the infliximab. In other words, withdrawing the immunomodulator or continuing both drugs seem to be a better strategy. So it's of interest to us to learn a little bit more about that.

But I summarized for the clinician that when you're considering deintensification or deescalation, first of all, you have to understand what's the risk to the patient, that they're going to have a relapse and that this might not be worth it after all, especially if it took a while to get them well. The second of course, is to understand that they're in deep remission before you do anything. You don't want to do it when they're still inflamed because you can predict what's going to happen there and there are multiple studies to support that. And then the third issue is you must have a monitoring strategy. Whether you're withdrawing a simple therapy like an aminosalicylate when you're on advanced treatment or whether you're pulling off an immunomodulator in the face of combo therapy with an anti-TNF, make sure you know how you're going to monitor that patient for preclinical relapse before they get sick again. And lastly, what's your rescue strategy? What will you do if this fails? And how will you get the patient well again? Are you going to go back to what you pulled off or are you going to use this as a reason to move on to something newer that might be better for that patient?

The final topic I covered during this presentation was how do we think about new therapies and where should we go. I spoke briefly about the explosion of options and also explosion of new therapies that are under investigation. Our huge challenge, as many of you understand, is recruitment into trials. The rate of recruitment now has been estimated to be 0.1 patient per month, per site. So you can imagine a single site doing a clinical trial for IBD is estimated to recruit one patient in a year into a large trial.

So with all these studies of combo therapy, head-to-head trials, new agents, we need to think much more thoughtfully, and creatively, and ethically about how to design trials so patients can be enrolled and we can learn together and move the field forward. That includes designing trials that minimize placebo exposure and understand rational ways to use science so that we can advance treatments in meaningful ways, including some companion diagnostics or therapeutic biomarkers that are emerging, and I gave some examples in my presentation, as well as understanding platform designs and adaptive study designs that will enable us to think more carefully about how to move patients through options and expose people to therapies that make sense, as well as endpoints that are going to be measurable early so we don't spend too much time on therapies that are not doing what they need to do.

I urge my colleagues to think carefully about how we can move the field, and for those who are in the room and who are listening to this video in industry, I also urge them to be more thoughtful about working together so that we can actually do this in a meaningful way and continue to advance the therapies and then move our field forward.

I will end by saying that what we have already is quite effective for most patients. It has to do with using the treatments early, assessing response early enough to know if the drug is doing what we need or the strategy's doing what we need, being thoughtful and incorporating comorbid illnesses or extraintestinal manifestations, talking more about diet and considering that as an adjunctive treatment strategy, especially in some patients during induction phase for Crohn's for example, and in others maybe thinking about how to understand that in a maintenance phase, and finally being much more proactive in the way we've design future trials so that we can advance our field.

So I hope that you found this helpful. It is an exciting time in IBD, but we have work to do in order to maximize the potential of all that's happening. And if you weren't at DDW, I hope that I'll get to see you at a live meeting in the near future. Thank you.