Highlights in Ulcerative Colitis From Digestive Disease Week 2023: Commentary

Presentations on ulcerative colitis (UC) at Digestive Disease Week (DDW) 2023 shed light on significant advances in the understanding, prevention, and treatment of this disease. Data were presented for existing and emerging agents, including ozanimod, tofacitinib, ustekinumab, infliximab, mirikizumab, guselkumab, etrasimod, thiopurine, and vedolizumab.

Ozanimod

Sphingosine-1-phosphate (S1P) modulators are a novel approach to the treatment of inflammatory bowel disease (IBD).¹ One of these modulators, ozanimod, was recently approved for the treatment of moderate to severe UC.² Initially, gastroenterologists were concerned about several potential risks associated with ozanimod, such as its effect on the atrioventricular node in the heart, causing bradycardia or alterations in heart rhythm.³ However, during induction and maintenance in the True North open-label extension study, these events were found to be very uncommon.⁴ Similarly, macular edema and worsening of sleep apnea were identified as potential risks, but they were not observed to a significant degree in the induction or 1-year maintenance population.

A study conducted by Dr Maria Abreu and colleagues at the University of Miami looked at the long-term extension of ozanimod treatment, spanning 3 years.⁵ The study did not identify any new safety signals or worsening of existing ones. This finding provides substantial reassurance regarding the long-term safety profile of ozanimod. Additionally, other abstracts on ozanimod emphasized not only its safety but also its sustained effectiveness, including clinical improvement over the 3-year period of the open-label extension.^6-8

Dr Abreu also presented a poster demonstrating the persistence of endoscopic improvement, histologic remission, and mucosal healing, the latter of which is a combination of endoscopic improvement and histologic improvement.⁹ It is interesting to note that 97% of the patients continued treatment in the open-label extension for up to 6 months, and this persistence rate remained at about 87% at the end of the year and at 72% after nearly 3 years of treatment. These data provide further reassurance regarding the safety and efficacy of ozanimod. A subsequent abstract from the University of Chicago, which examined the use of ozanimod at the University of Chicago Medical Center, aimed to correlate clinical response with absolute lymphocyte count. Ozanimod works by trapping lymphocytes in the lymph nodes, and treatment with this drug is expected to lead to an approximately 50% reduction in lymphocyte counts.¹⁰ Interestingly, in another abstract, presented at ACG 2022, ozanimod did not cause any increased risk of infection with lymphocyte counts as low as 50% below normal.¹¹ Unsurprisingly, in the University of Chicago experience, it was observed that efficacy was greater in patients who had a 75% reduction in their absolute lymphocyte count.¹⁰ Other S1P modulators that are currently in development may have greater potency in lowering lymphocyte counts by trapping lymphocytes in the lymph nodes. Further research is needed to determine their effectiveness in comparison with ozanimod.

Tofacitinib vs Ustekinumab

The TORUS study, presented by Dr Anthony Buisson, from France, aimed to compare the effectiveness of tofacitinib, an oral Janus kinase (JAK) inhibitor, with that of ustekinumab in patients with UC who had previously been exposed to at least one anti–tumor necrosis factor (anti-TNF) agent.¹² With various advanced agents, including ustekinumab, risankizumab, vedolizumab, tofacitinib, upadacitinib, and S1P modulators, an increased absolute response rate has been observed in bio-naïve populations. Several attempts have been made to conduct network meta-analyses specifically in patients with prior exposure to biologics, which are almost always TNF blockers.

In this multicenter, retrospective study, the researchers reviewed outcomes with either tofacitinib or ustekinumab in a series of patients who had prior inadequate responses to TNF blockers. The study included nearly 300 patients; 124 received tofacitinib and 165 received ustekinumab. The patients were all comparable in terms of demographic features, age, disease distribution, and severity. Additionally, the 2 groups were matched with propensity scores, ensuring that most of the patients were being compared with other patients similar in age and general demographics. The study examined several different endpoints, including corticosteroid-free remission at 4 months after the initiation of therapy. The rates of remission were comparable; approximately 38% of those in the tofacitinib group and 36% in the ustekinumab group achieved this important endpoint. Results for subsequent endpoints continued to be similar in the tofacitinib and ustekinumab groups as the patients were followed over time. It is important to note that this study is retrospective and therefore subject to potential bias.

Although head-to-head trials would be desirable, it is unfortunate that as the number of advanced therapies for IBD, UC, and Crohn’s disease continues to grow, conducting such trials becomes a challenge. Therefore, it is crucial to accumulate more real-world evidence to compare and eventually prioritize these treatments. Of note, patients with prior biologic exposure in UC demonstrated comparable responses. This means that patients have the option to choose among an oral agent, a JAK inhibitor such as tofacitinib, and a parenteral subcutaneous formulation such as ustekinumab.

Infliximab

Regarding the treatment of UC with intravenous biologic agents like infliximab, several important observations have been made. Traditionally, therapeutic drug monitoring has focused on reactive measures—specifically, trough levels of biologic agents taken right before a scheduled intravenous or subcutaneous administration. These measurements have been helpful to determine how to approach patients with an initial response that was later lost. For patients with low drug levels, treatments are often escalated to higher doses or shorter intervals, and those with antidrug antibodies are switched to another therapy within the same class. Patients who have good drug levels at trough but whose condition does not improve may be switched to a drug with a different mechanism of action.

In the past 5 to 10 years, proactive therapeutic drug monitoring has been the subject of much debate. Although 2 trials from Europe, TAXIS and TAILORx, failed to demonstrate benefits, an underlying theme is that we can improve treatment outcomes, as in many cases responses are lost or inadequate because of initial dosing.^13,14 This problem has been particularly evident in patients with severe UC; researchers in Amsterdam measured infliximab levels in their stool samples. These measurements indicated increased clearance, which refers to the rate at which a drug is eliminated from the body. Consequently, we are learning that several factors contribute to faster clearance, and that more intensive dosing or shorter intervals are necessary for patients with rapid clearing from the start.

ABSTRACT SUMMARY Efficacy and Safety Outcomes in Patients With Moderate to Severe Ulcerative Colitis Stratified by Ethnicity and Race: A Pooled Analysis of Data From GEMINI 1, VARSITY, and VISIBLE 1.

The phase 3/3b GEMINI, VARSIT Y, and VISIBLE 1 trials investigated vedolizumab vs adalimumab or placebo in patients with moderately to severely active UC (Abstract 1741). A post hoc study suggested that outcomes in non-White patients were worse than outcomes in patients of White ethnicity. However, robust conclusions could not be drawn because of the small proportion of patients representing minority ethnic groups (10.9% Asian, 1.0% Black, and 1.8% Other). Clinical trials could be improved by recruiting a diverse population that represents patients treated in a real-world setting.

In their study, Rosen and colleagues, from Stanford University, evaluated infliximab clearance in relation to disease activity during induction and maintenance therapy in a pediatric population with acute severe UC, both in the hospital and in the ambulatory setting.¹⁵ The study demonstrated that in comparison with adults, pediatric patients with severe UC have higher clearance rates, which correlate with increased severity of clinical disease; this finding supports the need for higher dosing. In our hospitalized patients with severe UC, we adjust dosing on the basis of clearance, using albumin as a clearance marker. Patients with low albumin levels have a high clearance rate and are initially dosed with 10 mg/kg. Then, we monitor the C-reactive protein (CRP) level. If it drops as expected and then starts to rise, we initiate re-treatment within days of the initial dose.

A practical challenge is measuring clearance accurately and adjusting dosing more rapidly. Currently, because of the relatively slow turnover in drug levels (which may take 5-7 days), estimating clearance may be necessary. It has been proved that albumin is the best marker for increased clearance in these patients.

Mirikizumab

Mirikizumab is a monoclonal antibody that targets the p19 subunit of interleukin-23 (IL-23). It is currently being investigated and approaching approval for the treatment of moderate to severe UC in adults.¹⁶ It is also likely to be evaluated and found effective in moderate to severe Crohn’s disease, as we have seen positive results from treatment with other agents that target IL-23, such as ustekinumab and risankizumab.^17,18

Kaplan and colleagues conducted the SHINE study, which evaluated the pharmacokinetics, efficacy, and safety of mirikizumab as induction therapy in pediatric patients with moderately to severely active UC.¹⁹ Similar to what we saw in adult patients with UC, mirikizumab demonstrated pharmacokinetics similar to those reported in the LUCENT study, as well as similar initial efficacy and safety.²⁰

Over the past several years, it has been recognized that this class of IL-23 blockers, including p40 in the setting of ustekinumab and the p19 subunit with risankizumab, mirikizumab, and guselkumab, show great efficacy and remarkable safety in Crohn’s disease and UC.²¹ IL-23 is a prominent cytokine in the skin of patients with psoriasis and in the indices of patients with psoriatic arthritis. However, unlike blocking TNF, targeting IL-23 does not have the same systemic effect on infection risk. IL-23 inhibition is becoming an acceptable and promising approach in terms of both efficacy and safety for the treatment of Crohn’s disease.

Guselkumab

Like mirikizumab, guselkumab is an anti–IL-23 antibody that targets the p19 subunit. It is currently being evaluated in both Crohn’s disease and UC. Jessica Allegretti, from the Brigham and Women’s Hospital, and colleagues presented results from the QUASAR phase 3 study.²² This randomized, double-blind, placebo-controlled, multicenter study evaluated the safety and efficacy of guselkumab in adults with moderate to severe UC. As anticipated, given the positive outcomes observed with other therapies targeting IL-23 in UC and Crohn’s disease, the researchers found that 3 intravenous 200-mg doses of guselkumab, given 1 month apart, were both safe and effective in treating patients with moderate to severe UC.

Etrasimod

Etrasimod is an oral S1P modulator that is currently being evaluated in moderate to severe UC.²³ Initial results of its efficacy were presented at the European Crohn’s and Colitis Organisation (ECCO) Congress and the United European Gastroenterology Week. Severine Vermiere, from Leuven, Belgium, and colleagues also looked at its safety in 2.5 years of global clinical trials in UC.²⁴ Like ozanimod, etrasimod demonstrated persistent safety, with no new safety signals identified during the 2.5 years following the initial induction studies. The most common side effects were serious infections, including herpes zoster. Surprisingly, these infections were more common in placebo-treated patients. It is worth noting that in other settings, S1P and other advanced agents have been associated with a slightly increased risk of herpes zoster. As a result, it has become routine practice to recommend age-appropriate vaccines, including pneumococcal and shingles vaccines, as soon as possible before therapy with advanced agents is initiated to mitigate the increased risk. It is interesting to note that etrasimod was not associated with an elevated risk of herpes zoster during the extension phase.

Thiopurine and Vedolizumab

Historically, when newer biologic agents like vedolizumab, ustekinumab, risankizumab, and guselkumab are evaluated, patients participating in clinical trials may or may not have been on immunomodulators. None of these studies have been able to demonstrate that concomitant therapy with an immunomodulator is superior. This lack of benefit from combining immunomodulators with biologics was first shown in the ACCENT study of infliximab in Crohn’s disease 20 years ago.²⁵ These studies, including current ones, were not designed with sufficient statistical power to establish a difference between the outcomes of patients on immunomodulators and those of patients not on immunomodulators. Also, patients were not randomized according to their use of immunomodulators. The subsequent SONIC study, which prospectively randomized patients to infliximab alone, azathioprine alone, or combination therapy, found that the combination was better.²⁶ However, similar investigations have not yet been conducted with other biologic therapies.

In a trial by Pudipeddi and colleagues, the focus was on evaluating the potential risks and benefits of withdrawing immunomodulator therapy from patients who were already receiving it.²⁷ This trial aimed to determine whether discontinuing immunomodulator therapy would have any significant benefit. Previous studies, such as the STORI study with infliximab, have shown that patients who were on combination therapy and from whom azathioprine was withdrawn could continue to do well if they were in clinical, endoscopic, and histologic remission.²⁸ Therefore, in the retrospective study by Pudipeddi and colleagues, it was observed that when azathioprine was withdrawn from patients who were not in a state of clinical, endoscopic, and histologic remission, they did not do as well as patients who had continued the combination therapy.²⁷

ABSTRACT SUMMARY Safety of Upadacitinib in Ulcerative Colitis: Long-Term Data From the Phase 3 Open-Label Extension Study (U-ACTIVATE).

In the open-label extension study of the phase 3 U-ACTIVATE trial, longterm safety with upadacitinib (15 or 30 mg, daily) was similar to that in prior data from the 52-week U-ACHIEVE maintenance study in patients with moderately to severely active UC (Abstract Tu1732). In 1308 patients representing 2350 patient-years of exposure to upadacitinib, rates of treatment-emergent AEs, AEs of special interest, and malignancies were consistent with prior safety results in patients with UC.

I believe this finding is consistent with the messaging we have regarding individuals who request to withdraw from combination therapy. We have found that withdrawing the immunomodulator is generally acceptable if the patients are in a clinical, endoscopic, and as deep a remission as possible, whether in the context of UC or Crohn’s disease. It is also reassuring to assess the drug level of the biologic and ensure that it is adequate at the time of the assessment. For instance, if no drug level is detectable, I would discontinue the biologic and continue with the immunomodulator. In summary, although both the immunomodulator or the other agent can be withdrawn, it is generally considered safer to withdraw the immunomodulator than the biologic, especially if the patients are in deep remission.