Etrasimod offers orally delivered therapy option in UC
Etrasimod helped patients with moderate-to-severe ulcerative colitis achieve clinical and endoscopic improvements.
In the study, researchers randomly assigned patients to 12 weeks of therapy with 1 mg or 2 mg once-daily etrasimod (APD334, Arena Pharmaceuticals) or placebo. Patients had a modified Mayo score between 4 and 9, endoscopic subscores of at least 2 and rectal bleeding subscores of at least 1. The primary endpoint was an increase in the mean improvement in Mayo score from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement.
After 12 weeks of therapy, patients in the 2-mg etrasimod group had a greater increase in in mean improvement of modified Mayo score compared with placebo (difference from placebo, 0.99 point; 90% CI, 0.3–1.68), while patients in the 1-mg group had a mean improvement of 0.43 point better than placebo. A greater proportion of patients in the 2-mg group also experienced endoscopic improvement than the placebo group (41.8% vs. 17.8%, P = .003).
Healio Gastroenterology and Liver Disease talked with the study’s first author, William J. Sandborn, MD, director of the Inflammatory Bowel Disease Center at UC San Diego Health, about their research and the next steps for the development of etrasimod.
What is the drug’s mechanism?
It’s called a sphingosine 1-phosphate or S1P modulator. Basically, there’s a subset of lymphocytes that are destined to go through lymph nodes, and the sphingosine 1-phosphate receptor allows those lymphocytes to eventually leave the lymph nodes and go to the rest of the body and participate in the immune system. Sphingosine 1-phosphate modulators pause the receptor on the surface of lymphocytes to be internalized and then those lymphocytes are trapped in the lymph nodes and don’t go out to the rest of the body. That selectively reduces the immune system in that area.
How was the study designed, and what were the primary goals?
Sandborn: The study meant to recruit patients with moderate-to-severe UC and to give them a 12-week course of therapy to try to induce a clinical response, clinical remission, endoscopic improvement and histologic improvement. We tested all those goals.
What did the findings show?
Sandborn: Symptoms that are important to patients, like stool frequency and rectal bleeding, improved in a dose-dependent fashion with etrasimod. Some of the secondary outcomes, like the percentages of patients who achieved clinical response, clinical improvement, endoscopic improvement and full-on clinical remission on different doses of etrasimod relative to placebo, were greatest with the highest dose of etrasminod at 2 mg.
What were the significance of the findings, and how does this drug fit into clinical practice?
Sandborn: The response and remission rates were quite good. They were at least as good as what you would see in intravenous or subcutaneously administered biologic drugs, and this drug was given orally. It’s a convenient, once-a-day medication with the potency of biologics from an efficacy standpoint. It’s hard to fully assess safety in a 12-weeks trial compared with long-term studies in phase 3, but with the limitation of a phase 2 study sample size and 12-week duration, the safety looked quite good. What patients and practitioners are looking for are substantially effective and safe medicines that would eventually allow us to transition away from the heavy reliance on intravenous and parenteral biologics. This drug looks like it might fit nicely in that niche.
What are the next steps?
Sandborn: We are still in the clinical trial phase. For UC, the phase 3 trials are planned with the regulatory authorities. There is now recruiting underway around the world. We’re also heading into phase 2, and later, phase 3 studies in Crohn’s disease.