Key Tips for Integrating New Ulcerative Colitis Therapies

This transcript has been edited for clarity. 
I’m Jordan Axelrad, and I’m an associate professor of medicine at NYU Grossman School of Medicine and co-director of the Inflammatory Bowel Disease Center at NYU Langone Health. Today I’m going to be reviewing practical considerations for incorporating some of our novel non–anti-TNF-targeted advanced therapies in clinical inflammatory bowel disease (IBD) practice, with a focus on ulcerative colitis. 
First, let’s start with the JAK inhibitors. JAK inhibitors are small molecules that inhibit a variety of proinflammatory cytokines. We have tofacitinib, which was approved by the US Food and Drug Administration (FDA) to treat ulcerative colitis in 2018, which primarily inhibits JAK1 and JAK3, and more recently, upadacitinib, which was FDA-approved to treat ulcerative colitis in 2022, which primarily inhibits JAK1. 
The efficacy and safety of JAK inhibitors are dose dependent. I’m going to focus on upadacitinib as one of our novel JAK inhibitors, which has primarily been the preferred agent. I’ll review some of the data. 
Upadacitinib induction for outpatients with moderate to severe ulcerative colitis is 45 mg for 8 weeks, followed by 15 or 30 mg in maintenance. Of course, the guidance is to use the lowest dose that achieves and maintains remission. 
This drug works very fast. A substantial proportion of patients do see clinical improvement within days, and that’s much faster than some of our other advanced therapies. Typically, in practice, we’re using the 30 mg dose for maintenance in most patients, although 15 mg should be considered for patients at high risk for adverse events of JAK inhibitors. 
In real-world studies, patients with ulcerative colitis who receive upadacitinib do fairly well, and in some cohorts, up to 80% are achieving meaningful remission despite having a multidrug-refractory background.
The reason that this is the preferred JAK inhibitor is because many real-world studies have also demonstrated that it is more effective than tofacitinib. Based on these data, we’re really using upadacitinib as our preferred JAK inhibitor for new starts of therapy. 
From a safety standpoint, this drug does have an FDA black box warning about increased risk for mortality, major adverse cardiovascular events, venous thromboembolism, malignancies, and serious infections. Most of these data came from a study of patients on tofacitinib with rheumatoid arthritis who were over the age of 50 and had at least one cardiovascular risk factor. However, we do not actually see an increased risk for cardiovascular events, venous thromboembolism, or malignancy in patients with IBD treated with JAK inhibitors.
One common side effect of upadacitinib that may be slightly underappreciated in clinical practice is that a significant proportion of patients report acne; it can be higher than 20% in some studies. Also, of note, JAK inhibitors do cross the placenta. We don’t yet have data in pregnancy, so this ought to be avoided in pregnancy. 
A few special considerations: There are emerging data that upadacitinib may be effective for acute severe ulcerative colitis as a co-therapy, and that it’s particularly good for patients who have extraintestinal manifestations such as arthropathy or psoriasis, which are common comorbid extraintestinal manifestations of IBD. 
Turning now to other agents, the interleukin-23 (IL-23) antagonists, another class of drugs where we’re seeing increasing number of agents in the field. These are monoclonal antibodies that target the p19 subunit of IL-23. We have risankizumab for moderate to severe Crohn’s disease and ulcerative colitis and mirikizumab for moderate to severe ulcerative colitis. [Editor’s note: Guselkumab was approved for moderate to severe ulcerative colitis treatment after this video was recorded.] 
These are similar but distinct from ustekinumab. Ustekinumab blocks IL-12/23 via inhibition of the p40 subunit, and the IL-23 antagonists alone inhibit the p19 subunit. 
Risankizumab, which was approved for moderate to severe Crohn’s disease in 2022, was based on the ADVANCE, MOTIVATE, and FORTIFY trials; and for ulcerative colitis, for which we had approval this year, based on the INSPIRE and COMMAND trials. 
The doses between Crohn’s and ulcerative colitis are a bit different. In Crohn’s disease, it’s 600 mg IV for 3 months, followed by subcutaneous dosing of 180 or 360 mg every 8 weeks. In ulcerative colitis, it’s 1200 mg IV a month for 3 months, followed by subcutaneous dosing of 180 or 360 mg every 8 weeks. The rates of achieving clinical and endoscopic endpoints were notably higher in those who were biologic naive.
Turning to mirikizumab, this was approved for moderate to severe ulcerative colitis in 2023 based on the LUCENT trials. Also, we had the VIVID trial in Crohn’s disease, which showed that it, too, was superior to placebo and noninferior to ustekinumab. This drug is dosed a little differently. For ulcerative colitis, it’s 300 mg IV monthly for 3 months, followed by subcutaneous dosing, two 100 mg injections every 4 weeks. It’s a little different as far as the maintenance dosing of injections compared with risankizumab. 
These drugs work relatively quickly. Although we have limited safety data, there was a very limited number of adverse events in the clinical trials, which largely mirrored those of ustekinumab. There is no-to-low risk for immunogenicity with IL-23 agents, again differing from our anti-TNF agents. Although we have no published data on pregnancy and IL-23 for IBD, data from ustekinumab suggest that this is very safe.
The last class we’re going to review is the sphingosine 1-phosphate (S1P) receptor modulators. We have etrasimod and ozanimod, which are two oral S1P receptor modulators currently approved for moderate to severe ulcerative colitis. 
These are hypothesized to work by binding S1P receptors on immune cells and preventing them from sensing an S1P gradient that drives immune cells to sites of inflammation. Basically, this drug works by keeping immune cells in lymphoid organs, such as lymph nodes, and then fewer cells are trafficked to sites of inflammation, such as the gut in ulcerative colitis or the brain in multiple sclerosis, for which ozanimod is also indicated. 
Turning specifically to ozanimod, this is an S1P receptor modulator that targets S1P1 and S1P5. There are several S1P receptors. It’s been approved for ulcerative colitis since 2021, based on the True North clinical trials. There is a first-week dose titration due to concerns of bradycardia, which we’ll review in a moment. Then it’s followed by a dosing of 0.92 mg daily in maintenance after that first-week dose titration. 
While we still have limited real-world data, this drug seems to be fairly effective in patients who are advanced therapy naive, and real-world data show that about 50% of patients do achieve clinical remission by week 10. This drug also has a long half-life. 
Turning to etrasimod, this is another S1P receptor modulator that targets S1P1, -4, and -5. It’s been approved for moderate to severe ulcerative colitis since 2023, based on the ELEVATE UC 12 and UC 52 studies. This has no dose titration. It’s prescribed orally, 2 mg daily, through induction and maintenance. Uniquely, it was also studied in patients with proctitis. Again, we see notably higher rates of response in biologic-naive patients compared with advanced therapy exposed. This notably also has a shorter half-life than ozanimod. 
This class of drugs is unique in that there’s a bit of work required prior to prescribing. Patients require a baseline ECG to demonstrate that there are no conduction abnormalities, specifically heart block, as this can cause symptomatic bradycardia. Patients are also required to have a fundoscopic exam — in particular, patients with a history of diabetes, uveitis, or macular edema. Patients are required to have annual skin cancer screening and should have that prior or shortly after treatment initiation. 
From a safety standpoint, as this drug targets lymphocyte trafficking, we can expect reductions in the peripheral lymphocyte count. This has not been tied directly to infection risk. We also see increased rates of shingles and occasionally bradycardia, but symptomatic bradycardia is not common.
Pulling this all together and reviewing some practical tips, when thinking about positioning some of these new therapies in the management of IBD, there are really four important characteristics. You need to consider efficacy, safety, individual patient characteristics, and individual disease characteristics. 
First, you should always start highly effective therapy early based on symptoms, inflammatory burden, and risk factors for severe disease. Waiting longer to initiate some of our advanced therapies increases patients’ risks of developing complications and more treatment-refractory disease. 
Second, for patients who are more moderate with less severe symptoms or inflammatory burden, use the anti-integrins, IL-23 antagonists, such as risankizumab, [guselkumab], and mirikizumab, or our S1P receptor modulators, such as ozanimod and etrasimod, for first line. This should depend on patient preferences and background. For patients who are more risk averse, such as those who are elderly or have comorbidities, consider safety. Utilize the anti-integrins or IL-23 antagonists as first line. 
Finally, for patients who have more severe symptoms, prioritize efficacy. Use anti-TNF agents followed by JAK inhibitors, such as upadacitinib, for better efficacy. 
Thank you for listening.