David Hudesman, MD, on Newer and Emerging Therapies for IBD
In this video, David Hudesman, MD, of NYU-Langone Health, recaps his presentation on new and emerging therapeutic targets in IBD.
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David Hudesman, MD, is codirector of the Inflammatory Bowel Disease Center at NYU-Langone Health in New York City.
David Hudesman: I'm Dr. David Hudesman, codirector of the Inflammatory Bowel Disease Center and associate professor of medicine at NYU Langone Health. I'm going to give a brief overview on my lecture on newer and emerging therapeutic targets that was given at the AIBD Regionals at UNC‑Chapel Hill.
Before I go into the new targets, I want to set the stage on why it's important we have newer options for our patients. I think it's been a pretty exciting time for managing our patients with inflammatory bowel disease, with newer therapies and more therapeutic options for our patients over the past five or six years.
However, primary non‑response, secondary loss of response, whether it's antibody development to a biologic or shifting in the molecular pathway, cost of medications, adverse events, route of administration--these are all reasons why we need more options for our patients. Even with our best data for some of our current agents still, we only get about a 60% to 70% response rate and 30%, 40% remission rate. I touched on a variety of different therapeutic targets.
The first one I touched on was the IL‑23 pathway. So currently, ustekinumab is FDA-approved for both Crohn's and ulcerative colitis, and that blocks the p40 subunit for both IL‑12 and IL‑23. Now we have newer agents, and over four different agents that are selective IL‑23 inhibitors, this blocks something called the p19 subunit.
When you're selectively blocking IL‑23, you're just focusing on the Th17 pathway rather than the Th1 pathway. Why this theoretically could be more beneficial is this is more targeted for the intestine. Could this possibly be more efficacious or have less side effects than ustekinumab?
However, we don't have that data yet, but this is the theory behind this selective pathway. I presented some data on mirikizumab, as well as risankizumab for UC and Crohn's disease, respectively, in their phase 2 trials and their phase 2 programs. They showed improvement both clinically and endoscopically.
These are some of the agents among other IL‑23s that we're currently enrolling in phase 3. Risankizumab finished enrolling in their phase 3 and hopefully in the next few years these are going to be other agents we could use for both Crohn's disease and ulcerative colitis.
Just talking about safety briefly with ustekinumab. That ustekinumab has been on the market for psoriasis since 2008. Then one of the registries, the PSOLAR Registry, really showed this pathway is a very safe pathway and compared to other biologic agents did not have any increased risk of serious infection or malignancy.
The next group of agents I spoke about were JAK inhibitors, one of our oral small molecules. Our current JAK inhibitor that we have FDA‑approved for ulcerative colitis is tofacitinib, and we have safety concerns with that medication with herpes zoster. However, we now have the Shingrix vaccine or the shingles vaccine, which is a killed vaccine that can minimize that risk. As all of you know, or many of you know, that the FDA guidance given the increased risk shown for both pulmonary embolism and mortality in the RA literature in patients that were over the age of 50 with cardiac risks.
The JAK inhibitors I touched on both filgotnib and upadacitinib. These are more selective JAK inhibitors. There are four different JAK proteins, and tofacitinib is nonselective and touches on two of them, JAK1 and JAK3.
Whereas both upadacitinib and filgotnib are more selective, they're selective JAK1 inhibitors. The hope is that, again, we're going to see the efficacy that we've seen with tofacitinib, but hopefully less side effects. We need more clinical data and real‑world data.
But most recently, at the selection study, which was filgotnib and ulcerative colitis, the data was just released, showing both improvement clinically and endoscopically, both in induction and in maintenance. Hopefully, this will be one of our newer agents coming to market within the next year.
The next group of agents I spoke about are sphingosine 1‑phosphate receptor modulators. This is an oral small molecule, and this is under the umbrella of antitrafficking agent.
The way these medications work are your inflammatory cells or T cells that leave the lymph node. They leave the lymph node and go to their target through these S1P receptors. So if we modulate them, we prevent these cells from leaving the lymph node and getting to the area of the intestine to prevent damage.
A little bit similar but a little bit different to vedolizumab, which is an anti‑integrin, which is blocking the receptors on your white blood cells from binding to the blood vessels. This is a little bit a step higher.
We have two agents I touched on. One was Ozanimod. Their phase II data for ulcerative colitis was published in the New England Journal back in 2016. We just had a recent press release in June showing that they hit their primary endpoints, both induction and maintenance for their phase 3 data. We don't have the full data just of yet, but that's exciting that we hopefully will have another oral small‑molecule, new mechanism of action for our IBD patients. I also touch on some recent data with the etrasimod that showed both mucosal improvement and histologic improvement with this receptor modulator.
The last agent I touched on with etrolizumab. This is another anti‑integrin similar to vedolizumab. However, unfortunately, etrolizumab had a very ambitious clinical trials program and had 7 clinical trials ongoing for both induction maintenance, past TNF-exposure naive. Unfortunately, there was a press release, we don't have the full data, but in the press release, they were mixed results with the induction trial. Some trials showed benefit with etrolizumab and ulcerative colitis, other trials did not, and all of their maintenance trials did not reach their primary endpoint. Again, we need to take a deeper dive into this.
This again is a very exciting time. We have more agents than we've ever had, and over the next 3 to 5 years or 1 to 5 years, we're going to have even more agents with newer mechanisms of action. Hopefully, FDA‑approved, and the next steps are going to be, how do we position these therapies?
Which one should come first? Can we personalize these therapies? Whether it's genetic blood markers, whether it's biopsies or stools. Can we personalize these agents? Should we be combining these agents really to improve our efficacy?
These are all very interesting topics, and looking forward to seeing some data on this over the next few years. Thank you very much for your time.