CHICAGO — A new agent under consideration for approval by the US Food and Drug Administration (FDA) to treat moderately to severely active ulcerative colitis (UC) has an “acceptable” safety profile, new evidence reveals.
Etrasimod (Arena Pharma/Pfizer) is an oral sphingosine-1-phosphate (S1P) receptor that binds with high affinity to receptors 1, 4, and 5. If approved by the FDA, etrasimod could become the second agent in the S1P class approved for ulcerative colitis in the United States. The other agent, ozanimod (Zeposia), received FDA approval for treating moderately to severely active UC in May 2021.
The updated safety profile of etrasimod, presented at Digestive Disease Week (DDW) 2023, is based on data from multiple clinical trials, including OASIS phase 2 and the ELEVATE phase 3 placebo-controlled trials, as well as an ongoing, open-label extension study.
“Etrasimod was well tolerated in patients with moderately to severely active UC and had an acceptable safety profile that did not appear to change with longer-term treatment up to 2.5 years,” said OASIS lead author Séverine Vermeire, MD, PhD, an expert on translational research in gastrointestinal disorders and professor of medicine at KU Leuven in Leuven, Belgium, while presenting the findings at DDW.
Vermeire noted that data show an elevated risk for atrioventricular (AV) block or bradycardia in a minority of people treated with the agent during this time period. However, most of the heart-related risk was during induction, and the risks could be minimized by ordering an electrocardiogram (ECG) before prescribing, she said.
Cumulative Safety Data
Researchers separated the trial participants into two cohorts. The all-UC cohort consisted of 956 patients who took at least one dose of etrasimod. The placebo-controlled cohort consisted of 629 patients taking etrasimod and 314 patients who took a placebo. Some patients participated in more than one study, the researchers note.
In both cohorts, mean duration of disease was about 7 years, about 42% of all participants were female, and mean age was about 41 years.
Investigators looked at the frequency of adverse events and exposure-adjusted incidence rates from the OASIS phase 2 and the ELEVATE phase 3 placebo-controlled trials, as well as an ongoing, open-label extension study. They also assessed safety in placebo and 1 mg or 2 mg etrasimod in the phase 2 NCT02447302 or two phase 3 trials, NCT03945188 and NCT03996369, reported up until January 31, 2022.
There were 770 patient years of etrasimod exposure in the all-UC cohort, while exposure in the placebo-controlled cohort was 288 patient years in the etrasimod group and 115 patient years in the placebo group. Mean exposure to etrasimod was 42 weeks in the all-UC cohort. Mean exposure in the placebo-controlled cohort was 24 weeks in the etrasimod group and 19 weeks in the placebo group.
Because of the mechanism of action of etrasimod, Vermeire and colleagues focused on cardiovascular events, macular edema, severe or opportunistic infections, herpes zoster infections, and malignancies.
Eleven patients (1.8%) treated with etrasimod reported bradycardia or sinus bradycardia in the placebo-controlled research, and 9 of 11 were asymptomatic. No bradycardia was associated with taking a placebo. In the all-UC cohort, bradycardia or sinus bradycardia was reported in 14 patients (1.5%).
“Bradycardia is something you need to tell patients may occur,” Vermeire said. “Most of the bradycardia occurred on day one or day two, mostly on day one.”
Four people taking etrasimod in the placebo-controlled cohort and 7 people in the all-UC cohort had AV block of the first or second degree. No reports of AV block occurred in the placebo group.
“Other adverse events of special interest, including hypertension and macular edema, were all rare and similar between the treatment arms,” Vermeire said.
Herpes zoster infections were reported in two patients taking etrasimod and two taking placebo in the placebo-controlled cohort. Seven cases were reported in the all-UC cohort. Vermeire said she advocates vaccinating patients against herpes zoster soon after UC diagnosis, if possible.
In the placebo-controlled cohort, 11 patients taking etrasimod and two patients taking placebo experienced elevated alanine aminotransferase (ALT). This was fewer than 2% of patients. One patient taking etrasimod and one receiving placebo discontinued the study for this reason. In the all-UC cohort, 27 people experienced elevated ALT.
In the placebo-controlled cohort, 13 people treated with etrasimod and two taking placebo developed elevated gamma glutamyl transferase. This adverse event was reported in 32 patients in the all-UC cohort.
There were no deaths reported in the placebo-controlled cohort of patients. One patient in the all-UC cohort developed a neuroendocrine tumor and died. The person received etrasimod 2 mg daily for about 6 months before the event’s onset. “This was assessed as unlikely related to the study treatment as judged by investigators,” Vermeire said.
Limitations of the study include a relatively short average duration of exposure to etrasimod.
“As the study continues, we will continue collecting and reporting the safety data,” Vermeire said.
A Well-Tolerated Therapy
“The important take-home message is that patients tolerated therapy very well,” said session co-moderator Jordan E. Axelrad, MD, MPH, when asked to comment.
There were very few adverse events, and of these, they were mostly minor, with patients being able to continue on therapy in large part, added Axelrad, a gastroenterologist at the Inflammatory Bowel Disease Center at NYU Langone Health in New York City.
Physicians will “need to get comfortable” with ordering an ECG to screen patients before prescribing etrasimod, he noted.
“Once we can get past that hurdle [of ordering an ECG], we should be integrating it into our practice,” Axelrad said.
The study was funded by Arena Pharmaceuticals, which was acquired by Pfizer; Pfizer completed the acquisition in March 2022. Vermeire reports receiving consulting and speaking fees from Arena Pharmaceuticals and grant and research support from Pfizer. Axelrad reports no relevant financial relationships.
Digestive Disease Week (DDW) 2023. Abstract 948. Presented May 9, 2023.
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and critical care. Follow Damian on Twitter: @MedReporter.
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