Dr Targownik reviews the potential applications of combined therapies for inflammatory bowel disease that target different pathways to provide better outcomes.

Laura Targownik, MD, is an associate professor and the division director of gastroenterology and hepatology at the Temerty Faculty of Medicine of the University of Toronto. 

TRANSCRIPT:

Hello, my name is Dr. Laura Targownik, and I'm an associate professor of medicine at the University of Toronto based at Mount Sinai Hospital in Toronto, Ontario, Canada. I recently spoke at Crohn's and Colitis Congress 2023 in Denver, Colorado, on the topic of dual-targeted therapy for patients with inflammatory bowel disease. The issue about dual targeted therapy arises from the fact that despite having made major advances in the care of inflammatory bowel disease over the last 20 years, starting in the early 2000s with the introduction of anti-TNF agents, there still remains a significant number of patients we are not able to bring into complete remission despite optimized therapy with single agents. We already use combination therapy to some extent combining often targeted therapies like anti-TNFs, anti-integrins, IL-12 and 23 antagonists, and more recently JAK inhibitors and S1P inhibitors with traditional medications like immunomodulators, such as azathioprine or methotrexate, as well as with corticosteroids like prednisone.

However, even with this, we still recognize there are significant treatment gaps, mostly due once again to patients not obtaining complete remission, as well as dealing with the side effect profiles of many of our traditional medications. Therefore, one of the methodologies that has been proposed to close this gap has been to try to use targeted therapies in combination. So there's a number of different situations where this potentially can arise. One situation may be in patients who identify as having exceptionally severe disease, we know tend to be more poorly responsive to single agent therapy, or people who have high-risk presentations such as those who feel if they're left untreated or undertreated may be at risk of developing long-term complications. We also have a group of patients who we have on a single agent who are doing somewhat better, but maybe they're not completely better, and there's a gap between how they're feeling and how they optimally could be feeling.

Now, in some of these patients, we may wish to switch to another single agent, but often these patients are feeling 50, 75, 80% better on that agent and are afraid of giving up the gains that they may have made. In addition, we recognize that a lot of patients want to get better very quickly. While a lot of our agents work, they may take time for patients to feel a clinical response. And it's possible that using certain agents in combination may lead to more rapid remission or bringing disease under control. And then the other thing is recognizing that as we move into an era of increased personalization, then we may find there are patients in whom their pattern of inflammation or what is driving their inflammation may be best targeted by 2 agents. So there clearly are a number of patients who could potentially benefit from this approach, but there are also going to be some drawbacks.

And the major drawback we have is that any time we combine therapies, we're also leaving open the possibility that we're combining risks as well. So different agents may have different side-effect profiles, and it's possible that adding them together may augment those concerns about side effects or safety concerns. The major issue with combination therapy probably still is cost. These drugs are still very much more expensive than traditional therapies, and many insurers or governmental agencies are very apprehensive about covering patients for 2 medications when, as far as they're concerned, a different one may do just as well.

So what I'm hoping to do today is to go through at least some of the data that we do have where combo therapy has been evaluated, so at least we can make the best informed decisions about when these therapies may be most effective. At this time, the best level of evidence comes from a recently published paper called the VEGA trial, and the VEGA trial was a study performed in ulcerative colitis where they sought to combine 2 different agents. One agent is a traditional anti-TNF, golimumab, which is subcutaneously delivered, generally given at a dose of 200 milligrams for the first dose, and then 100 milligrams 2 weeks later and 6 weeks later. And it was combined in this case with a new agent called guselkumab, which is an IL-23 inhibitor given at onset, and then given 4 weeks and 8 weeks later also subcutaneously. And this was compared to single agent therapy with either golimumab or guselkumab alone.

So for the maintenance phase, patients who received golimumab during induction went on to receive golimumab every 4 weeks. Patients who received guselkumab during induction went on to receive guselkumab 8 eight weeks. And patients who received the combination of guselkumab with golimumab went on to receive guselkumab monotherapy for another 8 weeks for the duration of the maintenance therapy.

Now, when they looked at the induction outcomes, looking at clinical remission and endoscopic response, there was a clear benefit in favor of combination therapy over either agent alone. About 22% of the patients went into clinical remission who received either golimumab or guselkumab. However, when they were used in combination, the clinical remission rate at 12 weeks was 36%. Similarly, endoscopic improvement was about 25% for golimumab, 30% for guselkumab. But when they were used in combination, the rate of endoscopic improvement at 12 weeks reached almost 50%. If we extend it out to the maintenance phase where patients received either continuing monotherapy with the agent they started with, or in the case where patients were started on dual combination therapy, they received just maintenance guselkumab. Clinical remission was obtained in 22% of golimumab users, 31% of guselkumab users, and 44% of patients who received guselkumab monotherapy following combination therapy induction.

And when we looked at rates of endoscopic normalization, the rates for golimumab were 7%, guselkumab 15%, and combination therapy 25%, once again, showing a clear sustained benefit in favor of patients who received guselkumab early. What the study failed to answer is the long-term benefits of combination therapy. It may be that if patients received dual therapy for even longer, they would have even a higher clinical remission and normalization rates at 38 weeks.

Another scenario where they've been recently evaluated was in the EXPLORER CD trial. What this trial sought to do was identify an exceptionally high-risk cohort. So these were people, people who had Crohn's disease who were early in the course of therapy, had highly active disease. It was an open-label trial where they received triple therapy combining vedolizumab, which is an anti-integrin, adalimumab, an anti-TNF, and methotrexate as an immunomodulator. And what they started to do was, looking this open label trial, how the patients were doing at the week 34 mark.What they found is that at week 34, half their patients had gone into clinical remission, and a third of the patients had gone into endoscopic remission. And there were significant improvements both in the SES-CD score, a marker of endoscopic activity, and the CDAI score, a marker of symptomatic activity. So this once again showed in a high-risk cohort, the combination therapy is highly effective. Unfortunately, there was no control arm so we really don't know how these patients would've done if they were treated using traditional therapies.

Now, in terms of safety, these studies were both small. None of them showed any distinct safety signal that would caution someone against using combination therapy. Now, we do have some data to inform this from open label trials. So there is a lot of clinical experience that is accruing from patients, particularly those who have been highly unresponsive to therapies who are getting combination therapies in real practice.

And there was a recent meta-analysis performed which sought to pool clinical experiences from multiple small reports. And particularly when they were looking at safety, they found no matter what the combination therapies used, whether it was an anti-TNF with an anti-integrin, an anti-TNF with an IL-23, and anti-TNF with the JAK inhibitors or various other combinations of the above medications, that rates of serious complications were always in the single digits. And it's worth remembering that these are patients who are recalcitrant to most therapies who may have a baseline higher risk of developing complications.

However, we still don't know really, and there's still a lot of knowledge gaps in terms of dual therapy. First of all, we have very little long-term evidence. So we don't know whether using long-term therapy leads to higher rates of sustained responses over time. We also don't know how effective it is in certain treatment groups. So the patients in whom I wish to use combination therapy, maybe that second group who I talked about earlier—the patients who are doing somewhat better but not completely better—where we want to use a second therapy to augment the response. We don't really have a lot of data yet to inform how we should manage these patients. And then we still have a lot of those same barriers, which are convincing payers and governmental agencies about the benefits to using these therapies, particularly in those who haven't responded very well to monotherapy. So I hope you've enjoyed this presentation, and feel free to reach out if you have any other questions.