Gastroenterology & Hepatology

July 2024 - Volume 20, Issue 7, Supplement 5

Highlights in Crohn’s Disease From Digestive Disease Week 2024

Expert Comments by:
Millie D. Long, MD, MPH
Professor of Medicine
Department of Medicine, Division of Gastroenterology and Hepatology
UNC School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

A Review of Selected Presentations From DDW 2024
May 18-21, 2024    Washington, DC

Upadacitinib Treatment Is Associated With Improved Clinical and Quality of Life Outcomes in Patients With Crohn’s Disease: Results From the U-ENDURE Long-Term Extension

The oral selective Janus kinase inhibitor upadacitinib received US Food and Drug Administration (FDA) approval for the treatment of adults with moderately to severely active Crohn’s disease (CD) who had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) blockers based on 2 placebo-controlled phase 3 induction trials (U-EXCEL and U-EXCEED) and a maintenance trial (U-ENDURE).1,2 In those trials, upadacitinib was significantly more effective than placebo in patients with moderate-to-severe CD as assessed by clinical remission rate and endoscopic response rate. 

In U-ENDURE, upadacitinib maintenance therapy at 15 mg or 30 mg once daily was associated with improvements in clinical response/remission, health-related quality of life (HRQOL), and reductions in fatigue compared with maintenance placebo in patients responding to upadacitinib induction.2 Patients who completed the 52-week maintenance period in U-ENDURE could continue treatment in a long-term extension (LTE) study. 

At DDW 2024, a long-term analysis of the efficacy and safety of upadacitinib versus placebo was reported.3 The analysis included randomized responders (patients from week 0 of the maintenance substudy 1) and patients in the ongoing U-ENDURE LTE study.3 Efficacy and health-related outcomes were assessed in patients in the LTE who were receiving upadacitinib 15 mg (n=107), upadacitinib 30 mg (n=173), or placebo (n=89) once daily. 

The LTE showed sustained improvements in clinical remission rates and HRQOL outcomes with upadacitinib versus placebo (Figure 1). Week 48 stool frequency/abdominal pain score (SF/APS) clinical remission rates were 76.7% with upadacitinib 30 mg, 82.1% with upadacitinib 15 mg, and 70.2% with placebo, and week 48 Crohn’s Disease Activity Index (CDAI) clinical remission rates were 84.3%, 82.3%, and 75.4%, respectively. Regarding HRQOL, week 48 IBD Questionnaire (IBDQ) response rates were 94.0% with upadacitinib 30 mg, 88.2% with upadacitinib 15 mg, and 78.8% with placebo, and changes in Functional Assessment of Chronic Illness Therapy–Fatigue from induction were also greater with upadacitinib versus placebo. 

Researchers noted that comparable clinical and QOL outcomes were observed in patients from cohort 1 and in patients meeting the criteria for moderately to severely active CD, defined as a CDAI ≥200 at induction baseline and clinical response at week 12 with upadacitinib.

A safety analysis was conducted that included the LTE and randomized responders, with patients having received upadacitinib 30 mg for a median of 96.0 weeks, upadacitinib 15 mg for a median of 51.6 weeks, or placebo for a median of 20 weeks. Rates of some adverse events (AEs) were numerically higher with upadacitinib, including herpes zoster, adjudicated gastrointestinal perforations, neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders. However, no new safety outcomes were observed during the LTE.

References

1.U.S. Food & Drug Administration. FDA approves first oral treatment for moderately to severely active Crohn’s disease. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-oral-treatment-moderately-severely-active-crohns-disease. Accessed June 14, 2024. 

2.Loftus Jr. EV, Panés J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2023;388(21):1966-1980.

3.Rubin DT, Louis E, Panes J, et al. Upadacitinib treatment is associated with improved clinical and quality of life outcomes in patients with Crohn’s disease: results from the U-ENDURE long-term extension. Abstract Su1798. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

Risankizumab Versus Ustekinumab for the Achievement of Clinical Remission and Reduction in Inflammatory Biomarkers in Patients With Moderate-to-Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial

The open-label, multicenter, randomized, phase 3b SEQUENCE trial compared the selective interleukin (IL)-23 p19 inhibitor risankizumab against the IL-12/IL-23 p40 inhibitor ustekinumab in patients with moderate-to-severe CD refractory to anti-TNF therapy. A total of 520 patients received either risankizumab 600 mg intravenous (IV) induction at baseline, week 4, and week 8, followed by 360 mg subcutaneous (SC) maintenance dosing every 8 weeks starting at week 12 (n=255), or ustekinumab administered via a single IV weight-based dose followed by ustekinumab 90 mg SC maintenance dosing every 8 weeks starting at week 8 (n=265). A corticosteroid taper was started at week 2. Patients were stratified based on number of anti-TNF therapies failed and steroid use at baseline.

As presented at the United European Gastroenterology Week 2023, the trial met its 2 primary endpoints, demonstrating noninferiority in week 24 clinical remission rate (CDAI <150) with risankizumab versus ustekinumab in approximately one-half of planned subjects (58.6% vs 39.5%) and significantly superior endoscopic remission rate, defined as a Simple Endoscopic Score for CD (SES-CD) less than or equal to 4 at week 48 with risankizumab versus ustekinumab (31.8% vs 16.2%; P<.0001).1

At DDW 2024, an update was presented from SEQUENCE reporting on changes in biomarkers including C-reactive protein (CRP) and fecal calprotectin (FCP), clinical responses, clinical remissions, and biologic remissions (Figure 2).2 The CDAI clinical response rate, defined as a reduction of CDAI by at least 100 points from baseline, was significantly higher with risankizumab versus ustekinumab starting at week 8 (60.9% vs 51.3%; P≤.05) (a post hoc analysis) and continuing through week 48 (67.5% vs 46.8%; P≤.001) (a prespecified analysis). 

The clinical remission rate (CDAI <150) was also significantly higher with risankizumab versus ustekinumab starting at week 24 (59.6% vs 42.6%; P≤.001) and continuing through week 48 (60.8% vs 40.8%; P≤.001). Clinical remission rates assessed by SF/APS were also significantly higher at weeks 24 and 48 in the risankizumab arm. 

Endoscopic remission rates with risankizumab were nearly twice those with ustekinumab, as previously reported (31.8% vs 16.2%; P<.001). Mucosal healing, defined as an SES-CD ulcerated surface subscore of 0 in patients with a subscore of at least 1 at baseline, was attained in 30.2% of patients receiving risankizumab and 12.1% of patients receiving ustekinumab (P≤.001). 

Regarding biomarkers, risankizumab was associated with significantly greater reductions from baseline over ustekinumab in high-sensitivity CRP starting at week 8 and in FCP starting at week 24, with sustained reductions through week 48.

Finally, rates of biologic remission, defined as normalization of FCP (≤250 mg/kg) or high-sensitivity CRP (≤5 mg/L) and clinical remission, were also significantly superior with risankizumab versus ustekinumab at week 24 (17.5% difference between arms; P≤.001) and at week 48 (18.5% difference between arms; P≤.001).

The authors concluded that, in this randomized trial of patients with CD for whom prior anti-TNF therapy had failed, risankizumab was associated with significant benefits over ustekinumab related to the short-term and long-term treatment goals of symptomatic and endoscopic improvement as recommended by the STRIDE-II,3 as well as in the intermediate goal of inflammatory biomarker reduction and in the composite endpoint of biologic remission. 

References

1. Peyrin-Biroulet L, Chapman JC, Colombel JF, et al. Risankizumab versus ustekinumab for patients with moderate to severe Crohn’s disease: results from the phase 3b SEQUENCE study. Abstract LBA-1. Presented at: UEGW 2023; October 14-17, 2023; Copenhagen, Denmark. 

2. Dubinsky MC, Ferrante M, Atreya R, et al. Risankizumab versus ustekinumab for the achievement of clinical remission and reduction in inflammatory biomarkers in patients with moderate-to-severe Crohn’s disease: results from the phase 3b SEQUENCE trial. Abstract 763. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

3. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD)—determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570-1583.

Real-World Clinical Effectiveness and Safety of Vedolizumab and Ustekinumab in Biologic-Naive Patients With Crohn’s Disease by Disease Location: Results From the EVOLVE Expansion Study

Two biologics currently approved for the treatment of patients with moderately to severely active CD are the α4β7 integrin antibody vedolizumab and the IL-12/IL-23 p40 inhibitor ustekinumab.1,2 The real-world retrospective, observational, multicenter EVOLVE expansion trial used patient charts to compare safety and efficacy outcomes in patients with CD receiving vedolizumab or ustekinumab.3 The study enrolled patients with CD in Australia, Belgium, and Switzerland who were biologic-naive, had initiated treatment with vedolizumab or ustekinumab, and had at least 6 months of follow-up. 

An analysis from EVOLVE presented at DDW 2024 reported on the real-world clinical effectiveness and safety of vedolizumab and ustekinumab based on disease location. The analysis included 293 patients with ileal CD (158 receiving vedolizumab and 135 receiving ustekinumab), 185 patients with ileocolonic CD (91 receiving vedolizumab and 94 receiving ustekinumab), and 121 patients with colonic CD (84 receiving vedolizumab and 37 receiving ustekinumab). Significant differences in some baseline characteristics were noted between the vedolizumab and ustekinumab groups. Although the differences that reached significance varied by disease location subgroup, factors that were significantly different in at least 1 subgroup included age, country, year of treatment initiation, corticosteroid dependency status, and biochemical index. 

After an inverse probability of treatment weighting method was used to adjust for differences in baseline characteristics between groups, demographic and baseline clinical characteristics were similar between treatment groups across disease location subgroups. 

During 36 months of treatment, there was no significant difference in the cumulative rate of clinical response with vedolizumab versus ustekinumab in patients with ileal CD (79.2% vs 85.8%; P=.67), ileocolonic CD (85.7% vs 90.8%; P=.94), and colonic CD (88.0% vs 68.0%; P=.22). Similarly, there were no significant differences between treatment groups in the cumulative rate of clinical remission, mucosal health, and treatment persistence. 

The incidence of serious AEs (SAEs) was similar in the vedolizumab and ustekinumab groups in patients with ileal CD (5.2 vs 4.6 events per 100 patient-years [PY]; P=.83) and ileocolonic CD (3.6 vs 5.7 events per 100 PY; P=.37), and higher in the vedolizumab group versus the ustekinumab group in patients with colonic CD (8.4 vs 8.1 events per 100 PY; P=.04). 

Serious infections occurred at a similar rate in the vedolizumab and ustekinumab groups in patients with ileal CD (1.4 vs 0.4 events per 100 PY; P=.36) and were more frequent with vedolizumab versus ustekinumab in patients with ileocolonic CD (1.2 vs 0 events per 100 PY; P value not estimable) and in patients with colonic CD (1.8 vs 1.5 events per 100 PY; P=.03). Both SAEs and serious infections occurred at similar rates across disease location subgroups.

Rates of CD exacerbations were similar between treatment groups in all disease location subgroups and were also similar across disease location subgroups (Figure 3). Among patients with ileal CD, rates of CD-related surgeries were higher in the vedolizumab group than in the ustekinumab group (4.3 vs 1.3 events per 100 PY; hazard ratio, 5.53; P=.02). However, only 12 of 158 patients with ileal CD receiving vedolizumab (7.6%) and 3 of 135 patients receiving ustekinumab (2.2%) required surgery, indicating that surgery rates were low in both groups. No other differences in CD-related surgery rates were noted. Finally, there were no significant differences between treatment groups or disease location cohorts in rates of CD-related hospitalizations. 

Overall, these outcomes indicate no significant differences in cumulative rates of clinical response, clinical remission, mucosal healing, or treatment persistence with first-line vedolizumab or ustekinumab regardless of baseline disease location.

References

1. Entyvio (vedolizumab) [package insert]. Lexington, MA: Takeda Pharmaceuticals U.S.A.; April 2024. 

2. Stelara (ustekinumab) [package insert]. Horsham, PA: Janssen Biotech, Inc.; March 2024. 

3. Scharl M, Christensen B, Bressler B, et al. Real-world clinical effectiveness and safety of vedolizumab and ustekinumab in biologic-naive patients with Crohn’s disease by disease location: results from the EVOLVE expansion study. Abstract Tu1821. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

Super-Responders in Patients With Moderate-to-Severe Crohn’s Disease Treated With Subcutaneous Infliximab Maintenance Therapy: A Post Hoc Analysis of the LIBERTY-CD Study

An SC formulation of infliximab is available for the maintenance treatment of moderate-to-severe ulcerative colitis (UC) or moderate-to-severe CD following an IV infliximab product.1 The approval was based on results of the randomized, phase 3 LIBERTY-CD trial, which demonstrated the superiority of SC infliximab over placebo as maintenance therapy after IV infliximab induction in patients with CD.2

At DDW 2024, a post hoc analysis from LIBERTY-CD was presented that grouped patients into response trajectories based on level of responses to SC infliximab therapy.3 The analysis included 231 patients from the SC infliximab arm of LIBERTY-CD. Group-based trajectory modeling was used to develop response trajectories based on longitudinal patient-reported outcomes of abdominal pain and stool frequency. 

Four categories of response trajectory were identified based on response rates, level of response, and outcomes. Super-responders (n=61) had a rapid and sustained improvement, fast responders (n=56) had a slightly lesser improvement that was sustained, slow responders (n=63) showed a gradual and sustained improvement, and limited responders (n=51) had a partial improvement in the maintenance phase. These distinct response trajectories were evident and stabilized around weeks 10 to 14.

Compared with other subgroups, patients in the super-responder subgroup tended to have a lower baseline body weight, lower body mass index, and a higher CDAI score. In a multivariate analysis, factors significantly associated with the super-responder subgroup included baseline body mass index (odds ratio [OR], 0.91; P=.020) and week 10 infliximab serum level of at least 14 μg/mL (OR, 2.78; P=.003). However, researchers noted that there are limitations to predicting super-response status. 

There was a trend toward higher predose infliximab serum levels in super-responders versus other response trajectories throughout the maintenance phase starting at week 10, with the difference reaching statistical significance at week 30.

Clinical outcomes at week 54 were most favorable in super-responders than in the other trajectories (Table). Clinical remission rates (CDAI <150) were 73.8% in super-responders, 53.6% in fast responders, 73.0% in slow responders, and 45.1% in limited responders (P=.002048). Endoscopic response rates (50% decrease in SES-CD) were 63.9%, 37.5%, 58.7%, and 41.2%, respectively (P=.008708). Corticosteroid-free remission rates were 63.6%, 33.3%, 52.2%, and 18.5%, respectively (P=.006773), and endoscopic remission rates were 42.6%, 25.0%, 41.3%, and 27.5%, respectively (P=.093548). 

Safety profiles with SC infliximab were similar across response trajectory groups, as were rates of treatment-emergent SAEs and injection site reactions.

Researchers concluded that additional studies evaluating the association between super-response status and long-term outcomes are needed.

References

1. Zymfentra (infliximab-dyyb) [package insert]. Jersey City, New Jersey: CELLTRION, Inc.; February 2024. 

2. Colombel JF, Hanauer SB, Sandborn W, et al. Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn’s disease: a phase 3, randomised, placebo-controlled study (LIBERTY-CD). Abstract DOP86. Presented at: ECCO 2023; March 1-3, 2023; Copenhagen, Denmark. 

3. Schreiber S, Sands BE, Hanauer SB, et al. Super-responders in patients with moderate-to-severe Crohn’s disease treated with subcutaneous infliximab maintenance therapy: a post hoc analysis of the LIBERTY-CD study. Abstract Su1767. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

Risankizumab Effectiveness in Ustekinumab-Naive and Ustekinumab-Experienced Patients With Crohn’s Disease: Real-World Data From a Large Tertiary Center

The efficacy of risankizumab in patients with prior failure of ustekinumab has not been well described. Thus, a real-world analysis was undertaken to evaluate the effectiveness of risankizumab based on prior treatment with ustekinumab.1 This prospective, observational study included 143 patients with active CD, defined as a Harvey-Bradshaw Index (HBI) of 5 or greater, FCP greater than 250 μg/g, or evidence of active disease per ileocolonoscopy or imaging. Patients with ostomy, J-pouch, or surgery within 6 months of starting treatment were excluded. 

Researchers prospectively monitored HBI at weeks 2, 4, 8, 12, 26, and 52, and monitored FCP at weeks 12, 26, and 52. Key outcomes included clinical remission, defined as a modified HBI less than 5, steroid-free clinical remission, treatment persistence, and change in FCP over time.

The cohort included 67 ustekinumab-naive patients and 76 ustekinumab-experienced patients. Ustekinumab-experienced patients were older than ustekinumab-naive patients (median age, 45 vs 36 years), were more likely to have received at least 2 advanced therapies (92.1% vs 32.8%), and were more likely to have undergone bowel resection (68% vs 47.7%).

Clinical remission rates were numerically higher among ustekinumab-naive patients compared with ustekinumab-experienced patients throughout the follow-up period, but this trend reached statistical significance for steroid-free clinical remission only at week 12 (74% vs 54%; P=.03) (Figure 4). At week 52, rates of clinical remission in the ustekinumab-naive and ustekinumab-experienced patients were 66% and 54%, respectively (P=.46), and rates of steroid-free clinical remission were 63% and 45%, respectively (P=.22).

In a multivariate analysis, no factors were significantly associated with likelihood of steroid-free clinical remission at 1 year, including prior ustekinumab exposure, lack of response to prior ustekinumab, disease duration, history of bowel resection, number of previous therapies for advanced disease, and HBI at baseline.

No significant differences were observed between the ustekinumab-naive and ustekinumab-experienced patients in regard to the proportion of patients remaining on risankizumab to week 52 (69% vs 80%; P=.30) and the proportion of steroid-free clinical remissions that were maintained from week 12 through week 52 (76% vs 75%; P>.99).

FCP levels declined to a similar extent in both ustekinumab-
naive and ustekinumab-experienced patients, with at least 80% of evaluable patients in each group attaining FCP less than 250 μg/g by week 52. 

Researchers concluded that clinical responses to risankizumab were generally comparable regardless of ustekinumab exposure but appeared to be less robust in ustekinumab-experienced patients. They suggested that the nonsignificant differences noted between arms could indicate that ustekinumab-
experienced patients are a more difficult-to-treat population and could reflect a higher HBI at baseline in those patients. They added that these findings support risankizumab as an option for patients with CD regardless of prior ustekinumab exposure.

Reference

1. Zinger A, Choi D, Choi NK, et al. Risankizumab effectiveness in ustekinumab-naive and ustekinumab- experienced patients with Crohn’s disease: real-world data from a large tertiary center. Abstract 1177. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

Improvement in Inflammatory Bowel Disease Questionnaire Items: Fatigue, Depression, Anxiety, and Bowel Urgency in Patients With Crohn’s Disease Treated With Upadacitinib in Phase 3 Trials

Another presentation at DDW 2024 on upadacitinib in CD focused on specific HRQOL outcomes as measured by the IBDQ.1 HRQOL outcomes in clinical trials of CD therapies are important, as CD is associated with substantial mental and physical effects that negatively affect HRQOL. After adjusting for other factors, individuals with IBD report a higher incidence of psychiatric
disorders.2 The relapsing and remitting disease course, uncomfortable symptoms, and side effects of treatment also negatively affect QOL.3 

As reported in the U-EXCEL, U-EXCEED, and U-ENDURE trials, upadacitinib is associated with improvements in HRQOL over placebo as assessed by the IBDQ, which is a well-validated measure of HRQOL in patients with IBD.4 To better understand changes in HRQOL associated with upadacitinib treatment, an analysis was conducted to investigate changes in specific IBDQ items in patients enrolled across the U-EXCEL, U-EXCEED, and U-ENDURE trials.1 

The tool includes 32 items, with each assessed on a 7-point scale ranging from 7 (the symptom occurs none of the time) to 1 (the symptom occurs all of the time). The current analysis focused on fatigue, depression, anxiety, and bowel urgency to elucidate how IBD symptoms and severity change with treatment. 

In the phase 3 upadacitinib trials, IBDQ outcomes were assessed at baseline, week 4, week 12, and week 52. This analysis grouped responses for each item into 2 categories: one for patients reporting the symptom “all,” “most,” “a good bit,” or “some” of the time, and the other for patients reporting the symptom “a little,” “hardly,” or “none” of the time.

During the induction treatment period, the proportion of patients reporting having symptoms “all” to “some” of the time was significantly lower in week 12 in the upadacitinib arm than in the placebo arm for fatigue (52.1% vs 78.4%; P<.0001), depression (35.5% vs 53.9%; P<.0001), anxiety (37.2% vs 59.6%; P<.0001), and bowel urgency (31.9% vs 55.6%; P<.0001). 

These trends were sustained through the 52-week maintenance phase, with significant reductions in fatigue, depression, anxiety, and bowel urgency reported with either upadacitinib maintenance dose (15 mg or 30 mg once daily) versus placebo (Figure 5). 

References

1. Loftus Jr. EV, Rubin DT, Louis E, et al. Improvement in inflammatory bowel disease questionnaire items: fatigue, depression, anxiety, and bowel urgency in patients with Crohn’s disease treated with upadacitinib in phase 3 trials. Abstract Su1863. Presented at: DDW 2024; May 18-21, 2024; Washington, DC.

2. Bernstein CN, Hitchon CA, Walld R, et al. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflamm Bowel Dis. 2019;25(2):360-368.

3. Mitropoulou MA, Fradelos EC, Lee KY, et al. Quality of life in patients with inflammatory bowel disease: importance of psychological symptoms. Cureus. 2022;14(8):e28502.

4. Chen XL, Zhong LH, Wen Y, et al. Inflammatory bowel disease-specific health-related quality of life instruments: a systematic review of measurement properties. Health Qual Life Outcomes. 2017;15(1):177.

 

 

 

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