There are several different agents that are currently under investigation related to sphingosine 1-phosphate (S1P) receptor agonism.
S1P agonism induces receptor internalization, and the lymphocytes lose response to the S1P gradient, and consequently become trapped in the lymph nodes causing peripheral lymphopenia. This action sequesters lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation. Upon withdrawal of the drugs in this class, receptor expression is restored, the lymphocytes leave the node and it reverses the lymphopenia.
Fingolimod was the first S1P agonist agent that was approved (FDA approved in 2010) for multiple sclerosis, and it’s commercially available (Gilenya, Novartis). It’s an orally administered medication, nonspecific (inhibiting receptors 1, 3, 4, 5), and there’s been no observed increase in serious infections or malignancies. This is very attractive, given the other alternative agents’ profiles we use to treat patients with IBD. There is, however, a first dose cardiac effect with this particular agent, including heart rate reduction, cardiac conduction abnormalities, in addition to macular edema and also liver function testing abnormalities that have been reported.
Because of these shortcomings, the next generation of S1P agonist, ozanimod (RPC1063, Receptos/Celgene) came to fruition and this was selective for S1P receptors 1 and 5. This agent has better tissue penetration and faster clearance. In the phase 2 TOUCHSTONE trials, it demonstrated benefits for patients with moderate-to-severe ulcerative colitis, there was no macular edema, abnormal liver function test, and there was no report of symptomatic bradycardia seen directly. As a consequence this agent looks very promising.
The most recent agent that has been evaluated is etrasimod (APD334, Arena Pharmaceuticals), the next generation S1P agent, which has an increased selectivity of the 1, 4 and 5 receptors. The OASIS trial was a 12-week trial, phase 2 study of patients with UC, which was just completed in December. The data show there was a statistically significant improvement in Mayo scores with the 2-mg dose at week 12. In the 1-mg group there was no benefit, but the 2-mg group had greater endoscopic improvement compared with placebo (41.8% vs. 17.8%; P = .003). Remission was achieved by 33% of the 2-mg group vs. 8% of the placebo group (P = .001), and the four-component total Mayo clinical score remission was achieved by 24.5% vs. 6% (P = .004).
The beauty was it was well-tolerated and resulted in fewer severe adverse events (0% in the 2-mg group vs. 5.8% in the 1-mg group and 11% in the placebo group). So, heart rate and AV conduction defects were low throughout the study with no medication stopped from bradycardia or AV block, no liver test abnormalities compared with placebo, and no macular edema. With this agent there was no observed pulmonary function test abnormalities as had been described with fingolimod.
The results thus far look promising; however, I await the results of the phase 3 studies. This agent has the potential to add another option to our medical arsenal for the treatment of patients with IBD. Thus far, the beauty of this agent is that there is no observed malignancy and no infection. This agent will have significant potential if shown to be efficacious in phase 3 given its safety profile.
Gary R. Lichtenstein, MD
Professor of Medicine
Director, Center for Inflammatory Bowel Disease
University of Pennsylvania Health System, Philadelphia, PA
Disclosures: Lichtenstein reports no relationship with Arena Pharmaceuticals and was not involved with the study, but does report a consulting relationship with Celgene regarding ozanimod. He also reports financial relationships with AbbVie, Actavis, Alaven Corporation, Ferring, Hospira, Janssen Ortho Biotech, Luitpold/American Reagent, Pfizer, Prometheus Laboratories, Salix Pharmaceuticals, Santarus, Shire, Takeda and UCB.