David Rubin, MD, on Using Combination Therapy for IBD

At AIBD 2023, Dr Rubin reviewed the history of combination therapy for inflammatory bowel disease and explored the potential of combining newer biologic and small molecule therapies to address the understand the immunological basis of IBD and in time, break the therapeutic ceiling.

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

TRANSCRIPT:

Hi. It's Dr David Rubin from the University of Chicago. I'm at the Advances in IBD meeting in Orlando, Florida, and it's 2023. I delivered a keynote lecture at this meeting on combining therapies in IBD. And while people were expecting me to talk primarily about some of our dual-targeted, immune-based therapies, I actually reminded the audience that we've been combining therapies in IBD for as long as we've been treating IBD.

For example, we've known for many years that combining oral and rectal mesalamine is more effective than either option alone for induction, and actually, for maintenance of remission in ulcerative colitis. The other example, of course, is that we've used corticosteroids in combination with many other therapies either as an induction strategy, bridging to something like thiopurines, or as an induction strategy while we simultaneously start other drugs like our advanced therapies.

But then I spent a lot of time in this lecture discussing the evolving approach to combining immune-based strategies. Now on the surface, the idea of combining targets and thinking about more than one immune target makes sense. Just like we might treat a polymicrobial infection with multiple antibiotics, the idea of an inflammatory bowel disease with multiple immune-based strategies has some rationale. For the most part, though, our experience doing so has been in either one of two situations. It's either been because we had nothing else to offer, and we were just throwing multiple drugs together in individual patients as a salvage strategy, or it was what I call convenience combo therapy, which is really based on the idea that the patient has either extraintestinal manifestations or a comorbid or coexistent other immune condition where we're using 2 drugs with different mechanisms to treat 2 conditions, but, by the way, they happen to also both treat the bowel. That's what I call convenience dosing. It's also how you get them paid for.

But what I moved into and talked a little bit more was more rational and scientifically based strategies of combining therapies. For example, we've started to learn more about the clinical immunology strategy of thinking about IL 23 inhibition with anti-TNF. That has demonstrated both in mice and in a proof-of-concept study in humans with ulcerative colitis that it works better than the monotherapy with each of those strategies. And we've also started to learn a little bit more about how we might combine small molecule strategies for induction, especially with an inflamed bowel that might be leaking protein, bridging it into or combining it with a monoclonal antibody strategy to then maintain the patient subsequently, once that bowel is healed and there's less of a pharmacodynamic challenge of the monoclonal antibody. I also then spoke a little bit about some novel combination strategies that are certainly worth exploring further, like partial enteral nutrition or dietary strategies as an adjuvant therapy along with anticytokine therapies or emerging approaches of therapies that might heal the bowel or promote healing of the bowel along with anti-inflammatory strategies. And so, certainly, one of the ways we can move our field forward and think about breaking the therapeutic ceiling is to think more carefully about when we can combine therapies, what the appropriate safety considerations of such approaches might be, and then, of course, how do we know whether we continue both therapies indefinitely, or whether we might sequence these therapies and pull one off or even pulse one of the therapies intermittently while having an underlying strategy of that patient in terms of their ongoing care.

So in all, I think that we've been using combo therapy for a long time, but it's time for us as a field to really be much more thoughtful about how we can do this and make our patients better, and certainly understand the immunological basis of this disease as well as understand how we can incorporate very important things like the diet and increasing understanding of the microbiome as part of all of this.

Thank you very much.