Dr Hanauer discusses the results of the True North trial of ozanimod, the first sphingosine-1-phosphate receptor agonist approved for the treatment of ulcerative colitis, which he spoke about at the ACG Postgraduate Course on October 24.

Stephen B. Hanauer, MD, FACG, is the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

TRANSCRIPT

Dr. Stephen Hanauer:  Hi, I'm Dr. Steve Hanauer from Northwestern University in Chicago, and I'm here at this year's American College of Gastroenterology meeting where I've just given a lecture for the product theater on ozanimod for moderate to severe ulcerative colitis.

Ozanimod is one of the newer what are known as sphingosine-1-phosphate modulators, which is becoming an important mechanism in the treatment of several inflammatory diseases, including multiple sclerosis and now ulcerative colitis, and will be evaluated in other disorders.

Sphingosine-1-phosphate is ubiquitous in the body, and there are several different receptors in different cell types that affect physiologic functioning in the body.

Within the heart conduction is also managed partially by sphingosine-1-phosphate, but within the lymph nodes and within lymphocytes, sphingosine attaches to a receptor on lymphocytes that allows it to follow a gradient out of the lymph nodes into the lymphoid vessels and then into the circulation where there's an even higher gradient of sphingosine-1-phosphate.

Ozanimod is a small molecule inhibitor of the sphingosine-1-phosphate receptor. What happens is ozanimod binds to the receptor. The receptor is then internalized within the lymphocytes, and it blinds the lymphocytes. They can't find their way out through this sphingosine-1-phosphate gradient. They're essentially trapped within the lymphocytes, can't get into the lymph vessels or into the circulation.

An expected effect of ozanimod is going to be a decrease in lymphocyte counts, but not significant clinical lymphopenia.

Ozanimod has been found to be effective for the treatment of several forms of multiple sclerosis and was approved by the FDA in 2020 for multiple sclerosis and relapsing forms.

Most recently, several months ago, ozanimod was approved for the treatment of moderate to severe ulcerative colitis based on the True North studies. These studies compared ozanimod to placebo for patients with moderate to severe ulcerative colitis, with the endpoint of clinical remission after 10 weeks as well as clinical remission at the end of 52 weeks in a maintenance study.

Patients who improved initially with ozanimod at 10 weeks were allowed to go into the maintenance study where they were re-randomized to ozanimod 0.92 milligrams, essentially the 1 milligram dose, which was maintained for an additional 42 weeks with the primary endpoint of clinical remission at the end of 52 weeks.

Additional endpoints at the end of 52 weeks or clinical improvement, endoscopic improvement, and a combination of endoscopic and histologic improvement, all of which were superior with ozanimod compared to placebo.

As far as safety is concerned, there was only one patient in this large trial that developed bradycardia. While common infections were common in both the ozanimod and the placebo group, there was no increased risk of serious infections with ozanimod compared to patients treated with placebo in the maintenance phase.

Liver enzyme abnormality was seen in approximately 5% of patients through the study. Most of this was mild. Most of these resolved over the ensuing several weeks, but increasing aminotransferase or elevation in bilirubin would lead to discontinuation.

There were some cases of herpes zoster infection greater than placebo in approximately 2% of patients in the induction and then the maintenance study. It is recommended that patients who have never been exposed to varicella, never had a varicella, meaning a chickenpox, vaccine, should get primary immunization.

Then in patients who have had varicella infections, it's not recommended, but should be considered that those individuals get the Shingrix vaccine to prevent or reduce the risk of herpes zoster.

What we saw in these trials was a new mechanism of action that worked quickly. There were clinical effects within the first 2 weeks, induction benefits by 10 weeks that continued to accrue over an additional 42 weeks.

We also saw steroid-free remissions and endoscopic and histologic improvement in the patients treated with ozanimod compared to placebo. Common infections were common. Serious infections were not seeing in greater proportion of patients. Thank you.