S1P Receptor Modulators for Ulcerative Colitis

Andres Yarur, MD: There are several novel compounds, with different mechanisms of action, that are being investigated for the treatment of ulcerative colitis [UC]. A very important group is the sphingosine-1-phosphate receptor modulators, or S1Ps. We have several S1Ps that have been developed. The original S1P modulators were nonselective. An example of this is fingolimod [Gilenya], which has been approved for multiple sclerosis. However, newer generations of selective S1Ps are being developed to targets that we really want to block. Ozanimod [Zeposia] already has reported phase 3 results for an ulcerative colitis trial. Etrasimod is currently under a phase 3 trial. Etrasimod specifically targets S1P1, 4, and 5. The goal is to offer high efficacy, but also have a good safety profile. So far we haven’t seen any major adverse events or signals with selective S1P agonists.

Timothy Ritter, MD: These are very exciting medications. It’s a whole new pathway for us to explore. The S1P modulators work by blocking the receptor on activated lymphocytes which allow lymphocytes to follow the gradient of S1P from the lymph node to the site of inflammation. When you have inflammation occur in the colon, it generates S1P and then the pathway of these lymphocytes follow. The S1P receptors block the ability of the lymphocytes to follow that pathway. The receptors internalize so that the T cells can’t get to where they need to go. This lymphocyte tracking prevents the inflammation from occurring at the colon and traps lymphocytes high in the lymph nodes. There are several S1P modulators out there. The S1P receptor is like the JAK [Janus kinase] receptor because there are several different specific receptors. We’re very excited and looking forward to using ozanimod, which has just come on the market and, I believe, blocks the S1P1 and 5 receptor. Some of the newer ones, such as etrasimod, also block the S1P4, so we expect there will be some differences in how they work. The differences may not be great, but they may be as well. It’ll take some time to sort those out. Certainly, as we get multiple new generations of these medications, we’re hopefully going to see a refined approach to treatment with better results and better safety.

Andres Yarur, MD: The ELEVATE UC 52 trial is a 52-week treat-through study. The main outcomes are clinical remission at week 12 and week 52. Patients are included if they have moderate to severe active ulcerative colitis. About 50% of the patients may have been exposed to a biologic or JAK inhibitor, while the rest of the 50% are naïve to these drugs. The trial is looking at clinical outcomes and endoscopic outcomes, which as we know, is a very important goal of treatment.

Timothy Ritter, MD: I think we will be looking at these things as potential first-line agents. They have a very nice efficacy and safety profile. They’re oral, which patients are going to prefer. They have very few adverse effects. I think, in the end, there will be a significant drive of both patients and physicians to use these medications very early on in the disease course. Oral medications have many advantages. One advantage is that you often have samples in the office, so you can get a patient started right away and circumvent some of the delays we face in getting medications approved by insurance companies. That’s always a benefit for oral medication. A lot of it is going to come down to coverage. Certainly, we can’t use the medications if we can’t get them covered by insurance. But hopefully that’s something that’s going to be worked out. Aside from the financial aspect of it, I think these are potentially first-line agents.

Transcript Edited for Clarity