Gil Melmed, MD, on the Future of IBD Management: What's In Store?
Gil Melmed, MD, provides an overview of his talk on the future of IBD management which he presented at the virtual Advances in Inflammatory Bowel Disease 2020 regional meeting August 22.
Additional Resources:
For more information about AIBD 2020 Regionals and to register for upcoming sessions, visit https://www.aibdregionals.com.
Gil Melmed, MD, is codirector of the Inflammatory Bowel Disease Center at Cedars-Sinai in Los Angeles, California.
TRANSCRIPT:
Dr. Gil Melmed: I'm Dr. Gil Melmed. I'm the director of the Adult IBD Program at Cedars Sinai Medical Center. I want to give you a brief overview of what we've discussed at our advances in IBD meeting today regarding the future of IBD therapies.
We have some really exciting novel therapeutics that are going to be building on some of the new classes that have recently come out with potentially enhanced efficacy and safety profiles that will have a potential significant impact on how we treat IBD going forward.
One of the more significant advances in the last few years has been in the realm of anti‑IL‑12/23 therapies. We heard earlier from Millie Long and from Mike Chiorean about the utility of using ustekinumab for both Crohn's disease and ulcerative colitis. Ustekinumab, by way of mechanism, blocks both the IL‑12 and the IL‑23 receptors because it targets a subunit that is common to both receptors.
Its efficacy presumably relates to its blockade of both but perhaps selectively more so the IL‑23 pathway. Novel therapeutics currently in development are capitalizing on the ability to selectively target just that IL‑23 pathway without the IL‑12. By doing so, we may actually see enhanced efficacy or potentially even more favorable safety profiles of upcoming therapeutics.
One such drug, risankizumab, is in advanced late‑phase testing for Crohn's disease and also being tested currently in clinical trials for ulcerative colitis.
We've learned with comparative head‑to‑head data from another disease state, from psoriasis, that when a selective IL‑23 like risankizumab is compared directly against a IL‑23 compound, ustekinumab, that there is actually a significant superiority of efficacy in that disease state.
We don't know whether that will actually hold out to be true in Crohn's disease and ulcerative colitis, but the concept of being able to even more selectively target a specific pro‑inflammatory pathway gives us some very exciting possibilities for new drugs that will be coming out.
In addition to the IL‑23 pathways, we also have recently seen approval of a JAK inhibitor, tofacitinib, the first JAK inhibitor approved for inflammatory bowel disease. Tofacitinib is approved for ulcerative colitis, as we heard earlier by Mike Chiorean. Its mechanism of blockade of the JAK receptors also relates to how it particularly blocks some of the subunits within that receptor.
Newer compounds currently in development capitalize on this conceptual idea that the JAK inhibitor family may allow for additional selectivity when targeting JAK receptors. We know that the JAK family of receptors actually are created from dimers or are three potential subunits and the mixing and matching of different subunits, JAK1, JAK2, JAK3, TYK2.
Different mixing and matching of dimerization of those subunits may lead to different kinds of JAK receptors, different kinds of JAK signaling, and also, therefore, the ability to modify the immune response through selective targeting of some of those subunits or some of those receptors.
That may lead to different downstream effects of this kind of JAK signaling, such that newer JAK inhibitors currently in development may even have more effective and better safety profiles than currently available therapeutics.
These are two of the most exciting areas; I think that in the imminent future, the next two to three years or so, we will be seeing results from these late‑phase trials and potentially regulatory approvals for both of these compounds.
Another class that is a new class of drug which we haven't yet seen in inflammatory bowel disease are the S1P inhibitors (the sphingosine‑phosphate inhibitors). These have a mechanism that is somewhat akin to the antitrafficking mechanism that we've already learned about from vedolizumab and natalizumab.
However, instead of blocking the activated lymphocytes from entering the gut mucosa, these S1P inhibitors block the lymphocytes from entering the gut by creating a barrier from them exiting the lymph nodes. By keeping them sequestering these lymphocytes within the lymph nodes, they are then unable to get to the gut.
These S1P inhibitors have been approved already in other disease states, and we're eager to see results of late-phase trials of S1P inhibitors for inflammatory bowel disease. Both ulcerative colitis and Crohn's disease are being investigated.
S1P inhibitors, like JAK inhibitors, are oral. This is also another exciting area for us to be evolving into as we think about the future of IBD therapies, including effective safe oral alternatives for our patients.
With all of these new and exciting compounds under development and hopefully seeing regulatory approval in the next few years, we're going to be increasingly faced with questions about how do we choose which drug to give which patient and at which time?
In addition to the robust clinical trial development of multiple different drugs, we also have a lot of research going on into the appropriate ways of positioning therapies, one against the other.
Unfortunately there's still quite a lack of head‑to‑head trials in inflammatory bowel disease, but more head‑to‑head trials are currently ongoing, as well as comparative effectiveness research, which will allow us to see clues as to how to best position therapies one against the other.
We're already learning and seeing that certain classes of drugs may be more effective when used early on or before other classes of medications. We talked about some of these advances in some of our advanced understanding.
Finally, to leave you off with the concept of the paradigm of treatment, which has evolved into one of what we call a treat‑to‑target approach. This treat‑to‑target approach really reflects, no matter which medication we're using for our patients, to always have that target in mind.
Because if we are able to identify the target, and then measure whether that target has been achieved in our patients, we will then be able to appropriately optimize or switch therapies in order to get the patients on the more effective, more safe option for them, regardless of which treatment we start out with.
With the exciting developments in clinical trials, as well as the very interesting and ongoing active comparative effectiveness research that is ongoing, the future of IBD treatment over the next few years is likely to be very different than the landscape we currently have available to us today, and the future is bright.
