Highlights in Ulcerative Colitis From the American College of Gastroenterology 2023 Annual Scientific Meeting: Commentary

The American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting, held in Vancouver, Canada, in October 2023, provided valuable insights into the management of ulcerative colitis (UC). Data focused on the efficacy, safety, and utilization of treatment options among several single-agent therapies, such as guselkumab, ustekinumab, etrasimod, upadacitinib, risankizumab, mirikizumab, and ozanimod.

Guselkumab

When caring for patients with inflammatory bowel disease (IBD), it is important to keep in mind the patient’s disease activity and the presence or absence of extraintestinal manifestations. The severity of the disease is as important as the rapidity with which significant clinical response or remission needs to be reached while treating a patient. Therefore, what is deemed appropriate treatment depends on the patient’s clinical presentation. In general, it is preferred to use medications that are effective and have a rapid onset of efficacy. To do so, we are constantly trying to improve the way we deliver care to patients, particularly with novel therapeutics.

One such agent that was presented at the ACG meeting is guselkumab, a selective p19 inhibitor of interleukin-23 (IL-23).¹ At the ACG meeting, I presented data from the phase 3 QUASAR induction study on early symptomatic improvement with guselkumab induction in patients with moderately to severely active UC. The findings revealed that the use of guselkumab induction at 200 mg intravenously (IV) was effective in improving symptoms, starting as early as week 1 after the first dose. The symptomatic improvements increased through week 12, with the goal of therapy being rapid improvement. What we could not determine from the study is whether we could completely avoid the use of corticosteroids, given their well-known potential side effects. Given the potential adverse events that could arise with the use of corticosteroids in patients with IBD, I envision a future study looking at a prospective randomized controlled study evaluating patients’ ability to completely avoid the use of corticosteroids while being treated with placebo or active guselkumab therapy. We do have other agents that are effective and treat patients rapidly, including infliximab as salvage therapy in hospitals for patients with acute severe colitis. We also have preliminary data on the efficacy of tofacitinib with clinical response as early as day 3, and the efficacy of upadacitinib as early as day 1.^2-5 These data are exciting and potentially a game-changer for future medical therapeutic interventions.

Ustekinumab vs Upadacitinib

A multicenter, retrospective cohort study compared the effectiveness of ustekinumab, a monoclonal antibody directed against IL-12 and IL-23, with that of upadacitinib, a Janus kinase inhibitor, in patients with UC between weeks 8 to 16, evaluating endoscopic outcomes post-induction therapy.⁶ Conducted at 2 centers, the primary endpoint was clinical response between week 8 and week 16, with a secondary endpoint of corticosteroid-free clinical remission within that same timeframe as well as endoscopic response and remission within 1 year. This study showed significantly higher odds of clinical response, corticosteroid-free clinical remission at weeks 8 to 16, and endoscopic remission within 52 weeks for upadacitinib vs ustekinumab. However, the study’s limitations include its retrospective nature, incomplete data regarding certain disease severity markers, and a relatively short-term follow-up. Nonetheless, the study provides an initial insight into whether a signal exists, and further investigation is warranted. Recently, a network meta-analysis demonstrated that upadacitinib may prove to be more effective than ustekinumab for induction of response and remission in patients with UC.⁷

In the United States, gaining access to upadacitinib typically requires failing an antitumor necrosis factor agent, per the US Food and Drug Administration (FDA). Although upadacitinib has some issues, its efficacy is excellent and is considered a potent agent. Similarly, ustekinumab demonstrates significant effectiveness. Therefore a clinician must personally determine the most suitable approach for the clinical scenario and specific patient.

ABSTRACT SUMMARY A Nationwide Comparison of Ustekinumab, Vedolizumab, and Adalimumab on Infections, Vascular Disorders, and Neuromusculoskeletal Adverse Events in Ulcerative Colitis Patients: A Pharmacovigilance Investigation.

A nationwide cohort of patients with UC were evaluated in a study by Miranda and colleagues, in which the safety profiles of 3 biologic agents were examined (ustekinumab, vedolizumab, and adalimumab) (Poster 2191). The US Food and Drug Administration’s Adverse Event Reports System was queried for each drug, resulting in a dataset of 34,418 reported adverse event cases among patients with UC. Patients with UC were significantly more likely to develop an infection while on ustekinumab therapy compared with adalimumab therapy (relative risk [RR], 1.20; 95% CI, 1.06-1.35; P<.05); a similar outcome was observed with vedolizumab (RR, 1.22; 95% CI, 1.16-1.28; P<.001). Significantly fewer patients treated with ustekinumab vs adalimumab experienced vascular complications (RR, 0.51; 95% CI, 0.35-0.74; P<.001) and musculoskeletal complications (RR, 0.52; 95% CI, 0.41-0.65; P<.001). Compared with adalimumab, nervous system complications were significantly reduced for ustekinumab (RR, 0.76; 95% CI, 0.63-0.91; P<.001) and vedolizumab (RR, 0.83; 95% CI, 0.78-0.89; P<.001)

Ustekinumab Monotherapy

A presentation by Dr Sands examined the use of ustekinumab monotherapy for patients with UC from the UNIFI study, which focused on the association between efficacy and long-term outcomes.⁸ In the study, patients were randomized to receive IV ustekinumab or placebo. Following the IV induction, they received subcutaneous ustekinumab at 90 mg every 12 or 8 weeks or placebo, and were then enrolled in the maintenance trial. Notably, the FDA-approved dose in the United States is the 8-week regimen, not the 12-week regimen. Observing the 4-year results, the patients who experienced the best outcomes were those who had disease clearance. This group exhibited histologic-endoscopic mucosal improvement (HEMI) and symptomatic remission shortly after induction. Patients who attained disease clearance 8 weeks after the IV induction showed greater long-term symptomatic remission outcomes and experienced a longer time before treatment failure compared with patients who achieved symptomatic remission without HEMI, or patients who had neither symptomatic remission nor HEMI after induction. Early positive responses across all factors led to more durable responses, which, although expected, is valuable to articulate and present in the literature. The beauty of the IL-23 antagonist ustekinumab lies in its exceptional and durable responses. Patients who initially respond to treatment tend to maintain that response. This is something we have seen with other IL-23 selective antagonists, including guselkumab and mirikizumab. Notably, mirikizumab recently gained regulatory approval for the treatment of UC. Patients who respond to therapy with mirikizumab within a short time can be assured of maintaining their favorable clinical state.

ABSTRACT SUMMARY Cumulative Response to Guselkumab Through Week 24 of Induction in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Induction Study.

The phase 3 QUASAR induction study assessed the efficacy and safety of the IL-23 p19 subunit antagonist guselkumab among patients with moderately to severely active UC who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, and/ or advanced therapies. In a poster presented by Rubin and colleagues, the cumulative response and safety results of continued treatment with guselkumab for up to 24 weeks was reported (Poster 0726). Among patients who were treated with guselkumab who did not achieve a response at week 12, more than one-half (55%) achieved a clinical response at week 24 with continued guselkumab treatment. Continued treatment with guselkumab provided a clinical benefit to patients regardless of prior exposure to advanced therapies. No new safety signals were reported in this long-term follow-up compared with the first 12 weeks of guselkumab treatment.

Ustekinumab vs Adalimumab

Evaluating therapeutic persistence in real-world scenarios is crucial to understanding the duration of drug usage after treatment begins. Presented at the ACG meeting, a study by Zhdanava and colleagues assessed the effectiveness and real-world treatment persistence among bio-naive patients with UC who were initiated with ustekinumab or adalimumab treatment.⁹ The study was a retrospective analysis of the IQVIA PharMetrics Plus database, encompassing an overall assessment of 371 patients in the ustekinumab cohort and 1726 in the adalimumab cohort. The patients receiving ustekinumab were more likely to be persistent on medication, including persistence while corticosteroid free and also while on monotherapy ustekinumab, compared with patients treated with adalimumab. This durable and sustained treatment is a desirable outcome when initiating a medication. This outcome is also not surprising, considering the characteristics of the IL-12/23 inhibitors, which are known for their ability to sustain durable responses. After a patient enters a state of response or remission, they tend to maintain it over time.

Etrasimod

Dr Dubinsky presented a study showcasing symptomatic improvement within 2 days on etrasimod induction from the ELEVATE UC 52 and the ELEVATE UC 12 studies evaluating patients with UC.¹⁰ This study underscored the desire for our medical therapies to have rapid responses from specific agents, aiming to potentially reduce corticosteroid exposure, improve patients’ quality of life, and facilitate a faster recovery. Conducted as a post hoc analysis of phase 3 trials, the findings revealed early improvement among patients receiving etrasimod vs placebo, with noticeable differences starting only 2 days after treatment initiation, suggesting a rapid onset of efficacy. But what proportion of patients responded positively to this treatment within the 2-day timeframe? Answering this question will be crucial, because if most patients do not respond, the advantage of using this treatment may be limited. Further insights are eagerly awaited.

Upadacitinib

Dr Panaccione presented data on the safety profile of upadacitinib in IBD through a pooled analysis of 2 phase 3 maintenance studies: U-ACHIEVE and U-ENDURE.¹¹ These studies included patients who had either UC or Crohn’s disease (CD). Although combining data from UC and CD directly is unusual, when assessing safety, combining this data becomes important because of the rarity of safety events. The study’s safety profiles were acceptable, showing no identification of new safety signals that would suggest an increased likelihood of adverse events. Infectious complications, such as herpes zoster, were higher in active treatment vs placebo. There was 1 patient in the upadacitinib cohort and 2 in the placebo cohort who experienced gastrointestinal perforation, making it challenging to establish a clear relation. Cardiovascular events occurred in 1 patient under active therapy and 1 patient taking placebo, and 2 patients had venous thromboembolic disease under active therapy. In terms of malignancies, there were 4 cases in the higher-dose group (2 cases with 15 mg, and 4 cases with 30 mg) and 1 case in the placebo group. Importantly, there were no reported cases of tuberculosis, lymphoma, or death.

ABSTRACT SUMMARY Endoscopic and Histologic Remission After 2 Years Treatment With Mirikizumab in Patients With Moderately-to-Severely Active Ulcerative Colitis.

Magro and colleagues provided results of endoscopic and histologic remission following 2 years of treatment with mirikizumab in patients with moderately to severely active UC treated in the long-term, open-label extension trial LUCENT-3 (Poster 2204). The study authors found that several histologic and endoscopic outcomes were sustained after 2 years of mirikizumab treatment, including histologic improvement (59.4%), histologic remission (51.9%), endoscopic remission (65.3%), HEMI (53.1%), HEMR (47.7%), endoscopic normalization (28.9%), and alternate HEMR (24.7%). These outcomes were sustained regardless of prior biologic or tofacitinib failure.

Dr Dubinsky presented a study focusing on the time to relapse during treatment with upadacitinib in patients with UC who have responded to induction therapy.¹² This study evaluated 2 approved maintenance doses of upadacitinib 15 mg and 30 mg and found that the probability of relapse during maintenance was lower with low-dose upadacitinib. However, this raises the question of the safety advantages of maintaining a lower dose over a higher one. In general, when using immunosuppression, the principle of lower is better often applies. One notable advantage of upadacitinib is its lack of immunogenicity, allowing for the initial use of a lower dose while observing patient response. If a patient responds well to a lower dose, it is a positive outcome. Conversely, if they do not respond, the dose may be escalated directly to 30 mg or an intermediate approach may be attempted, starting at 15 mg and moving up to 30 mg. However, the study did not directly address this potential dosing strategy. Nonetheless, this nuanced approach to dosing may emerge as a clinical practice pattern, given the safety profile of upadacitinib.

Risankizumab

Dr Loftus presented data on the phase 3 INSPIRE study, which evaluated risankizumab—a monoclonal antibody targeting the p13 component of IL-23—induction in patients with moderate to severely active UC.¹³ The findings revealed that treatment with risankizumab was superior to placebo as an inductive therapy for achieving clinical remission. Additionally, the study showcased positive outcomes across secondary endpoints, including an endoscopic-histologic improvement while maintaining a well-tolerated profile with no new safety concerns. These data are promising, as they introduce a potentially favorable and durable treatment option for UC patients, especially considering the need for more agents with favorable safety profiles. Although risankizumab is not yet FDA approved for UC, its efficacy and safety in this study could make it a valuable addition to our treatment options in the near future.

ABSTRACT SUMMARY Real-World Clinical, Endoscopic, and Safety Outcomes After Upadacitinib Induction for Ulcerative Colitis: A Multicenter Retrospective Cohort Study.

Dalal and colleagues reported real-world outcomes from a retrospective cohort study of 76 patients with UC who had initiated treatment with upadacitinib induction therapy between March 2022 and February 2023 at 2 large academic institutions (Poster 3556). Corticosteroid-free clinical remission, the primary outcome, was achieved in 64.0% of the cohort at a follow-up visit between 8 to 16 weeks after upadacitinib induction. Clinical response was achieved in 84.2% of patients, biochemical remission in 88.2% of patients, and improvement in arthralgia in 62.5% of patients, all of which were assessed at a follow-up visit between 8 to 16 weeks after upadacitinib induction. Endoscopic response and endoscopic remission, both assessed at a median of 34.1 weeks of follow-up, was achieved in 61.5% and 34.6% of patients, respectively. Adverse events were recorded in 14.5% of patients, and a total of 11.8% of patients discontinued treatment during the follow-up period.

Mirikizumab

Dr Panaccione presented 2-year efficacy and safety data on mirikizumab after 104 weeks of continuous treatment in the LUCENT-3 trial, an open-label extension study.¹⁴ Mirikizumab was recently FDA approved for UC treatment. The study focused on the sustained benefits of mirikizumab in patients, including those who previously failed biologic therapy. The study demonstrated sustained long-term benefits through week 104. Notably, patients who had experienced biologic therapy failure showed significant improvement with mirikizumab, unlike with some other agents in the IL-23 class, which might have reduced efficacy after prior biologic use. Understanding treatment response after a failed biologic is crucial in guiding future treatment choices. These findings reiterate the potential of mirikizumab as a valuable treatment option, especially for patients who have not responded to previous biologic therapies.

Ozanimod

Dr Afzali presented findings from the True North study, specifically examining the long-term outcomes of patients with UC treated with ozanimod, a selective sphingosine 1-phosphate receptor modulator, who sustained clinical remission for over 3 years (week 52) in the open-label extension.¹⁵ Ozanimod has been approved for the treatment of moderate to severely active UC, initially based on the 52-week efficacy data. This post hoc analysis assessed patients who demonstrated clinical response at week 52 and then continued treatment in the open-label extension. The analysis revealed that most patients who had clinical remission after 1 year demonstrated sustained efficacy for an additional 2 years during continuous treatment. This finding aligns with observations in other trials, highlighting that patients who achieve positive outcomes after 1 year tend to maintain a durable response.

ABSTRACT SUMMARY Efficacy and Safety of Etrasimod in Patients With and Without Concomitant Corticosteroid Treatment in the Phase 3 ELEVATE UC 52 And ELEVATE UC 12 Trials.

The efficacy and safety of the oral, once-daily, selective S1P receptor modulator etrasimod was evaluated for the treatment of moderately to severely active UC in the ELEVATE UC trial (Poster 2200). Among patients with corticosteroid use at baseline, this study demonstrated that patients randomized to treatment with etrasimod were more likely to achieve corticosteroid-free clinical remission at week 52 compared with placebo. Among patients with corticosteroid use at baseline, 31.2% in the etrasimod arm and 9.5% in the placebo arm achieved clinical remission at week 52. In patients with no corticosteroid use at baseline, 33.2% in the etrasimod arm and 6.9% in the placebo arm achieved clinical remission at week 52. The clinical and endoscopic benefits observed with etrasimod were similar regardless of corticosteroid use at baseline. Additionally, safety outcomes remained consistent with etrasimod regardless of baseline corticosteroid use, with no change in the incidence of infections according to baseline corticosteroids.

Dr Abreu conducted a study analyzing the durability of symptomatic and clinical outcomes in patients receiving ozanimod treatment in the open-label extension phase of the True North study.¹⁶ The ongoing open-label study collected data over 3 years and focused on symptomatic, clinical, and mucosal endpoints in patients who were clinical responders at week 52. This highlights that patients exhibited durable symptomatic responses and sustained clinical outcomes up to week 94 with continuous treatment, emphasizing the lasting benefits of the medication. Of note, these outcomes were not influenced by achieving more objective measures of responsiveness at week 52. This suggests that patients who initially respond well to treatment tend to maintain their positive status over the long term. These promising findings offer reassurance to patients that maintaining a state of well-being over an extended period is a strong likelihood.