Thanks to the recent approval of multiple new small molecules for treatment of ulcerative colitis (UC), the treatment landscape has changed, Millie Long, MD, explained at Digestive Disease Week 2022 on May 21.

With these recent advancements and more upcoming, it’s important to be aware of the efficacy and safety of all treatment options, which are unique depending upon the mechanism of action, she said.

Dr Long is a professor of medicine in the Division of Gastroenterology and Hepatology at the University of North Carolina, as well as the Director of the Gastroenterology and Hepatology Fellowship Program.

Dr Long tracked the development of therapies for UC, from sulfasalazine in the 1970s, thiopurines in the 1980s, and then "an explosion of options" with the run of biologics since 2000 (infliximab, adalimumab, vedolizumab, ustekinumab, and more). The last 4 years or so have seen approvals in the small molecule class for UC with tofacitinib (2018), ozanimod (2021), and upadacitinib (2022).

Dr Long explained that ozanimod, a sphingosine-1-phosphate (S1P) receptor modulator, works by internalizing S1P receptors in lymphocytes and preventing them from mobilizing to inflammatory sites. This small molecule binds "with very high-affinity to S1P subtypes 1 and 5" and the selectivity of this agent "really helps with safety," Dr Long stated. In the TRUE NORTH phase 3 trial for patients with UC, the rates of clinical remission and response, endoscopic improvement, and mucosal healing at week 10 were higher among those patients treated with ozanimod for induction than among those receiving placebo. In maintenance, ozanimod showed better clinical remission and response, endoscopic improvement, and mucosal healing, and had better rates of maintenance remission, glucocorticoid-free remission, and durable remission at week 52 than placebo.

When considering positioning, Dr Long stated that without prior exposure to anti-TNF therapies who were treated with ozanimod had better response at week 10 than those patients who had previously been exposed. However, she said that at week 52, all patients had good results no matter their pre-exposure to anti-TNFs.

Safety considerations for ozanimod include a risk of bradycardia, serious or opportunistic infections, macular edema, and elevated liver enzymes. Additionally, in TRUE NORTH, absolute lymphocyte count decreased by a mean of 54% from baseline to week 10, although severe lymphopenia was not seen. Bradycardia was more common among those patients treated with ozanimod than with placebo during induction therapy but not during maintenance. Elevated liver aminotransferase levels were more common with ozanimod therapy than placebo, patients did not experience drug-induced liver injury.

There is also a contraindication for patients with Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block except, with a functioning pacemaker.

Tofacitinib is a JAK inhibitor with pan-JAK activity (with a higher affinity for JAK1 and JAK3 than JAK2 and TYK2) that was approved in 2018 for treatment of adults with moderate to severe UC. Since that approval, however, tofacitinib has been positioned after TNF therapies, due to safety concerns surrounding venous thromboembolic events seen in rheumatoid arthritis trials. In OCTAVE 1 and OCTAVE 2 (induction trials), and OCTAVE sustain (maintenance trial), patients receiving 10mg of tofacitinib did better in remission, mucosal healing, Mayo Stool Frequency Subscore, and Mayo Rectal Bleeding Subscore than those receiving placebo.

Upadacitinib is a selective JAK1 inhibitor, currently in phase 3 trials for both CD and UC. According to the U-ACCOMPLISH and U-ACHIEVE induction studies, patients with UC treated with upadacitinib had a higher rate of remission at week 8 than those in the placebo group. In the U-ACHIEVE maintenance trial, both dosing arms of upadacitinib outperformed placebo on remission at week 52. Secondary endpoints of U-ACHIEVE maintenance also found that upadacitinib was better than placebo in endoscopic remission, corticosteroid-free remission, and maintenance of clinical response.

According to a subgroup analysis, patients who had previously had an inadequate response, loss of response, or intolerance to biologic therapies, had much the same robust response to upadacitnib as patients who had positive response to a biologics. Dr Long explained that upadacitinib does not appear to have the loss of effectiveness in a post-TNF position.

Dr Long added that when it came to upadacitinib and safety, there was still uncertainty. Though she noted that because it is a selective JAK inhibitor, "I think that hopefully we'll find this to be reassuring." The current safety profile for upadacitinib includes risks for herpes zoster, acne, and opportunistic infections.

—Allison Casey

Reference:
Long, MD. Choosing the right therapy for your patient: ulcerative colitis. Presented at: Digestive Disease Week 2022; May 21, 2022. San Diego, CA