A Review of Selected Presentations From DDW 2024
May 18-21, 2024 • Washington, DC
Extended Induction Response Over Time in Patients With Moderately to Severely Active Ulcerative Colitis Treated With Mirikizumab in the LUCENT-1 and -2 Trials
Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin 23 (IL-23) that is approved for the treatment of moderately to severely active ulcerative colitis (UC).1,2 The double-blind phase 3 LUCENT-1 and LUCENT-2 trials evaluated mirikizumab vs placebo as therapy for patients with moderately to severely active UC.3 In the LUCENT-1 trial, 1281 patients were randomized 3:1 to receive mirikizumab (300 mg) vs placebo administered every 4 weeks for 12 weeks. After the induction phase, 544 patients exhibited a response and 272 patients were nonresponders. In LUCENT-2, patients with a response to mirikizumab induction treatment were randomized 2:1 to receive mirikizumab (200 mg) vs placebo administered every 4 weeks for 40 weeks. In addition, the 272 patients who failed to respond to 3 doses of induction therapy entered the LUCENT-2 open-label extension study, in which patients received 3 additional doses of mirikizumab (300 mg) at weeks 12, 16, and 20.
Clinical response was defined as a decrease of at least 2 points and 30% in modified Mayo score vs baseline and either a decrease in rectal bleeding subscore of at least 1 point from baseline or a rectal bleeding subscore of 0. Symptomatic response was defined as a 30% decrease in the composite clinical endpoint comprising the stool frequency and rectal bleeding subscores. Symptomatic remission was defined as having a rectal bleeding subscore of 0 plus having either a stool frequency subscore of 0 or a stool frequency subscore of 1 with a 1-point or greater decrease vs baseline. The Urgency Numeric Rating Scale (NRS) was used to assess bowel urgency, and a lower score reflected a decrease in bowel urgency. Bowel urgency remission was defined by an Urgency NRS score of 0 or 1.
At baseline in LUCENT-1, the 272 patients who eventually entered the extension study had a median age of 44.0±14.2 years and 67% were male.4,5 The median duration of disease was 7.6±6.8 years, and 56.6% of patients had left-sided colitis while 42.6% had pancolitis. The mean modified Mayo score was 6.5±1.4, and over one-half of patients (56.6%) had a severe modified Mayo score of 7, 8, or 9. The mean Urgency NRS score was 6.2±2.2, and 72.4% of patients had a Mayo endoscopic subscore of 3, indicating severe disease in nearly two-thirds of patients. Over one-half of the patients (54.0%) had failed prior therapy with tofacitinib or a biologic agent. Corticosteroid use was noted in 43.4% of patients and immunomodulator use in 28.3%.
At week 24 of the extension study, after receiving a total of 6 doses of mirikizumab, 53.7% of patients demonstrated a clinical response (Table). At weeks 12, 16, 20, and 24, the rate of symptomatic response was 30.5%, 52.9%, 62.1%, and 72.4%, and the rate of symptomatic remission was 4.8%, 19.5%, 26.8%, and 37.1%, respectively, reflecting meaningful improvements in the population of patients who failed 12 weeks of induction treatment. Improvements were also observed across the 12 weeks of extended induction therapy in terms of bowel urgency change from baseline, which improved from -1.2±2.2 at week 12 to -2.5±2.7 at week 24. The proportion of patients experiencing bowel urgency remission improved from 7.0% at week 12 to 19.9% at week 24.
References
1. Choi D, Sheridan H, Bhat S. Mirikizumab: a new therapeutic option for the treatment of ulcerative colitis [published online February 12, 2024]. Ann Pharmacother. doi:10.1177/10600280241229742.
2. Omvoh [package insert]. Indianapolis, IN: Eli Lilly and Company; 2023.
3. D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2023;388(26):2444-2455.
4. D’Haens G, Afzali A, Filip R, et al. Extended induction response in patients treated with mirikizumab with moderately to severely active ulcerative colitis in the LUCENT trials [Abstract P554]. J Crohns Colitis. 2023;17(suppl 1):i682-i683.
5. Rubin DT, Charabaty A, Jairath V, et al. Extended induction response over time in patients with moderately to severely active ulcerative colitis treated with mirikizumab in the LUCENT-1 and -2 trials [DDW abstract Su1802]. Gastroenterology. 2024;166(6)(suppl 1).
The Efficacy and Safety of Guselkumab as Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Maintenance Study
Guselkumab is a fully human monoclonal antibody that binds to the p19 subunit of IL-23, preventing binding to and activation of the IL-23 receptor and release of proinflammatory cytokines. The phase 3 QUASAR maintenance study evaluated the safety and efficacy of guselkumab subcutaneous (SC) maintenance treatment in patients with moderately to severely active UC who responded to induction treatment with intravenous (IV) guselkumab.1-3 Patients who had demonstrated a response in the phase 2b or phase 3 QUASAR induction study were enrolled.1,3 Prior to entering the QUASAR induction study, eligible patients had a baseline modified Mayo score of 5 to 9, with a rectal bleeding subscore of 1 or greater, and a Mayo endoscopic subscore of at least 2 based on central review. The phase 2b induction study randomized 313 patients evenly across 3 arms to receive guselkumab 400 mg IV, guselkumab 200 mg IV, or placebo, administered every 4 weeks for a total of 3 doses. The phase 3 QUASAR induction study enrolled 701 patients who were randomized 3:2 to receive IV guselkumab (200 mg, every 4 weeks) vs placebo at weeks 0, 4, and 8.
Patients who responded to guselkumab induction therapy and entered the QUASAR maintenance study were evenly randomized into 3 arms. Patients in Arm 1 received guselkumab SC (200 mg, every 4 weeks); patients in Arm 2 received guselkumab SC (100 mg, every 8 weeks); and patients in Arm 3 received placebo. Patients in Arm 3 experienced guselkumab withdrawal. The study continued through week 44. Tapering of corticosteroid therapy was mandatory during the maintenance portion of the study.
The QUASAR maintenance study enrolled 568 patients. Characteristics at induction baseline were well balanced across the 3 arms in the maintenance study.2 The median age was 40.7±13.75 years, and 55% of patients were male. Sixty-four percent of patients had a modified Mayo score of 7, 8, or 9, and 66% had a Mayo endoscopic subscore of 3, reflecting severe disease in the majority of patients prior to induction therapy. The median level of C-reactive protein (CRP) was 3.9 mg/L (interquartile range [IQR], 1.5-9.2 mg/L), and the median level of fecal calprotectin was 1605.0 mg/kg (IQR, 669.0-3337.0 mg/kg). Forty percent of patients were using corticosteroids, and 42% of patients had a history of inadequate response or intolerance to biologic and/or Janus kinase (JAK) inhibitor therapy.
Prior to entering the QUASAR maintenance study, 34% of the 568 patients were in clinical remission, 39% exhibited endoscopic improvement, and 22% were in endoscopic remission. The mean modified Mayo score was 2.5±1.53. Levels of inflammatory markers had decreased from the induction baseline: the mean level of CRP was 1.5 mg/L (IQR, 0.6-3.8 mg/L), and the mean level of fecal calprotectin was 303.5 mg/kg (IQR, 79.5-1194.0 mg/kg). Through week 44, the rate of discontinuation was low, at 12.0% (range, 10.6%-13.7%). The majority of patients who discontinued study therapy did so owing to an adverse event (AE; 5.1%).
The QUASAR maintenance study met its primary endpoint, demonstrating clinical remission rates at week 44 of 50.0% with the higher dose of guselkumab (P<.001 vs placebo), 45.2% with the lower dose of guselkumab (P<.001 vs placebo), and 18.9% with placebo (Figure 1). Sixty-nine percent of patients in Arm 1 or Arm 2 were also in endoscopic remission. The study also met its major secondary endpoints with statistical significance at week 44 for both Arm 1 and Arm 2 vs Arm 3, including corticosteroid-free clinical remission (P<.001 for both), maintenance of clinical remission (P<.005 for both), maintenance of clinical response (P<.001 for both), and symptomatic remission (P<.001 for both). The trial met its secondary endoscopic and histologic endpoints, including endoscopic improvement, histologic-endoscopic mucosal improvement, and endoscopic remission (P<.001 for each comparison of Arm 1 or Arm 2 vs Arm 3). Patient-reported endpoints were also significantly improved with maintenance guselkumab compared with placebo. Guselkumab treatment was generally well tolerated, with no new safety signals.
References
1. Peyrin-Biroulet L, Allegretti JR, Rubin DT, et al. Guselkumab in patients with moderately to severely active ulcerative colitis: QUASAR phase 2b induction study. Gastroenterology. 2023;165(6):1443-1457.
2. Rubin DT, Allegretti JR, Panés J, et al. The efficacy and safety of guselkumab as maintenance therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 QUASAR maintenance study [DDW abstract 759]. Gastroenterology. 2024;166(6)(suppl 1).
3. Allegretti JR, Peyrin-Biroulet L, Feagan BG, et al. The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active ulcerative colitis: results from the phase 3 QUASAR induction study [DDW abstract 913b]. Gastroenterology. 2023;164(6)(suppl):S-1572.
Clinical Relevance of Baseline and Change in Urgency Numeric Rating Scale Score for Mirikizumab Treatment for Ulcerative Colitis
In the phase 3 LUCENT-1 induction and LUCENT-2 maintenance trials, mirikizumab demonstrated efficacy and safety vs placebo in patients with moderately to severely active UC.1,2 Patients in LUCENT-1 were randomized 3:1 to receive mirikizumab (300 mg) vs placebo every 4 weeks for a total of 3 doses. Patients with a response in LUCENT-1 were enrolled into LUCENT-2 and were randomized 2:1 to receive mirikizumab (200 mg) vs placebo every 4 weeks through week 40, for a total of 52 weeks of study therapy. A study was conducted to evaluate efficacy endpoints among patients in the LUCENT-1 and -2 trials based on bowel urgency severity at induction baseline.3 Bowel urgency was characterized by the Urgency NRS score, with patients grouped into categories based on scores of 0 to 3 (low), 4 to 6 (moderate), and 7 to 10 (severe).
The analysis included 1162 patients from LUCENT-1 and 544 from LUCENT-2. At baseline, the LUCENT-1 population included 149 patients with a low Urgency NRS score, 437 patients with a moderate score, and 576 with a severe score, whereas the LUCENT-2 population included 70 patients with a low score, 215 with a moderate score, and 259 with a severe score. In general, mirikizumab yielded superior results compared with placebo, regardless of baseline bowel urgency status. At week 12, a greater proportion of patients showed a clinical response with mirikizumab vs placebo in the low, moderate, and severe cohorts (P<.001; Figure 2). Also at week 12, mirikizumab was superior to placebo in terms of endoscopic remission (low, P<.001; moderate, P<.01; severe, P<.05), clinical remission (low, P<.01; moderate, P<.05; severe, P<.05), and symptomatic remission (low, P<.05; moderate, P<.01; severe, P<.001).
At week 52, the rate of clinical response was significantly improved with mirikizumab compared with placebo (low, P<.01; moderate, P<.001; severe, P<.001), as was the rate of endoscopic remission (low, P<.05; moderate, P<.01; severe, P<.001) and the rate of symptomatic remission (low, P<.01; moderate, P<.001; severe, P<.001). The rate of clinical remission was not significantly different between mirikizumab and placebo among patients in the low cohort at week 52; however, the rate of clinical remission was superior with mirikizumab vs placebo among patients in the moderate (P<.01) and severe (P<.001) cohorts.
In general, Urgency NRS scores were more likely to improve among patients treated with mirikizumab vs placebo at weeks 12 and 52; however, improvement in NRS score was less likely among patients who did not achieve the clinical endpoints. Individual Urgency NRS scores were also analyzed. Among patients who had a baseline NRS score of 6 and who achieved remission at week 52, the NRS score at week 52 had shifted to a lower value from baseline in most patients, with nearly one-half of patients (47.6%) achieving an Urgency NRS score of 0. Greater improvements in Urgency NRS score were observed with mirikizumab compared with placebo among patients who did achieve the clinical endpoints as well as in patients who did not achieve the clinical endpoints.
References
1. D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2023;388(26):2444-2455.
2. Omvoh [package insert]. Indianapolis, IN: Eli Lilly and Company; 2023.
3. Clemow D, Dubinsky M, Baygani S, et al. Clinical relevance of baseline and change in urgency numeric rating scale score for mirikizumab treatment for ulcerative colitis [DDW abstract Su1814]. Gastroenterology. 2024;166(6)(suppl 1).
Risankizumab in Patients With Moderately to Severely Active Ulcerative Colitis in the Phase 3 INSPIRE and COMMAND Studies
Risankizumab is a humanized monoclonal antibody directed at the p19 subunit of IL-23.1 The phase 3 INSPIRE study investigated the safety and efficacy of 12 weeks of risankizumab vs placebo as induction therapy in patients with moderately to severely active UC.2 Patients were randomized 2:1 to receive risankizumab (1200 mg, IV) vs placebo at weeks 0, 4, 8, and 12. The double-blind study yielded a significant improvement with risankizumab vs placebo in the primary endpoint of clinical remission at week 12 (20.3% vs 6.2%; P<.00001). Risankizumab therapy was superior to placebo for all secondary endpoints and was generally well tolerated.
Patients with a response at week 12 in the INSPIRE study were eligible for enrollment in the COMMAND maintenance study.3 Patients in this study were evenly randomized to receive risankizumab (360 mg, SC; n=195), risankizumab (180 mg, SC; n=193), or placebo (n=196) every 8 weeks. The primary endpoint was the rate of clinical remission based on the adapted Mayo score at week 52. Baseline characteristics were well balanced across the 3 arms. The mean disease duration ranged from 7.1 to 7.4 years, and the proportion of patients with an adapted Mayo score of greater than 7 ranged from 41.4% to 49.7%. One-fourth of patients had no prior failure to advanced therapies, whereas approximately 22% (range, 19.7%-25.3%) had failed more than 2 prior advanced therapies. The proportion of patients in clinical remission at baseline based on the adapted Mayo score ranged from 21.6% to 29.3%.
The COMMAND study met its primary endpoint. The rate of clinical remission at week 52 was 37.6% with the higher dose of risankizumab (P≤.01) and was 40.2% with the lower dose (P≤.001) vs 25.1% with placebo (Figure 3). Among patients who had shown an inadequate response to prior therapies such as aminosalicylates, corticosteroids, and immunomodulators, the rate of clinical remission at week 52 was 61.7% with the higher dose of risankizumab (P≤.01) and was 50.9% with the lower dose (P>.05) vs 31.1% with placebo. Among patients with an inadequate response to advanced therapies, the rate of clinical remission at week 52 was significantly improved with the lower dose of risankizumab (36.6% vs 23.2%; P≤.05) but the difference did not reach significance with the higher dose. Both dose levels of risankizumab were significantly better vs placebo based on endoscopic improvement, histologic-endoscopic mucosal improvement, and endoscopic remission, as well as maintenance of clinical remission and corticosteroid-free clinical remission. Patient-reported outcomes were also superior with risankizumab compared with placebo. Maintenance treatment with SC risankizumab was generally well tolerated, and no new safety concerns were raised.
Patients with an inadequate response to 12 weeks of induction therapy in the INSPIRE study were enrolled in the extended treatment period.4 These patients were evenly randomized to receive risankizumab (1200 mg or 1800 mg, IV), risankizumab (360 mg, SC), or risankizumab (180 mg, SC), administered every 8 weeks. Patients in a fourth arm received placebo. After 12 weeks of additional treatment with risankizumab, the rate of clinical response ranged from 50.0% to 57.1% and the rate of clinical remission ranged from 8.8% to 15.7% across the 3 arms. Among patients who demonstrated a response to 12 additional weeks of risankizumab SC induction therapy, the proportion of patients with a clinical response at week 52 ranged from 45.3% to 46.4% and the proportion of patients who achieved clinical remission ranged from 17.9% to 22.8%. No new safety signals arose.
References
1. Singh S, Kroe-Barrett RR, Canada KA, et al. Selective targeting of the IL23 pathway: generation and characterization of a novel high-affinity humanized anti-IL23A antibody. MAbs. 2015;7(4):778-791.
2. Risankizumab induction therapy in patients with moderately to severely active ulcerative colitis: efficacy and safety in the randomized phase 3 INSPIRE study. Gastroenterol Hepatol (N Y). 2023;19(12)(suppl 9):9-10.
3. Schreiber S, Panaccione R, Parkes G, et al. Risankizumab maintenance therapy in patients with moderately to severely active ulcerative colitis: efficacy and safety in the randomized phase 3 COMMAND study [DDW abstract 984]. Gastroenterology. 2024;166(6)(suppl 1).
4. Panaccione R, Melmed GY, Drobne D, et al. Additional risankizumab therapy is effective in patients with moderately to severely active ulcerative colitis who did not achieve clinical response to initial 12-week induction therapy: an analysis of phase 3 INSPIRE and COMMAND studies [DDW abstract 904]. Gastroenterology. 2024;166(6)(suppl 1).
Effect of Mirikizumab on Clinical and Endoscopic Outcomes After 1 Anti-TNF Failure in Patients With Moderately to Severely Active Ulcerative Colitis
The phase 3 LUCENT-1 induction and LUCENT-2 maintenance trials enrolled patients who had received prior therapy for their moderately to severely active UC.1 Among the 1281 patients enrolled in LUCENT-1, 41% had experienced failure to a biologic or tofacitinib at baseline, and 36.3% had experienced at least 1 failure to an anti–tumor necrosis factor (TNF) agent. A post hoc analysis investigated the clinical efficacy of mirikizumab vs placebo as induction or maintenance therapy, as well as the efficacy of mirikizumab in extended induction, among patients who had failed a single anti-TNF therapy at baseline.2 Of the 190 included patients, 146 received mirikizumab and 44 received placebo as induction therapy in LUCENT-1. P values were determined using the Cochran-Mantel-Haenszel test. Adjustments included baseline corticosteroid use, baseline disease activity, and region for LUCENT-1, and corticosteroid use, region, and clinical remission status at week 12 for LUCENT-2.
Mirikizumab was numerically superior to placebo based on most clinical endpoints in this patient subgroup; however, the number of patients in most groups was small, precluding robust analysis of statistical significance. At week 12, with mirikizumab vs placebo, the rate of clinical response was 64.4% vs 34.1% (P<.01), the rate of clinical remission was 18.5% vs 13.6%, the rate of symptomatic remission was 43.8% vs 27.3%, and the rate of endoscopic remission was 30.1% vs 15.9%, respectively (Figure 4). At week 52, with mirikizumab vs placebo, the rate of clinical response was 67.2% vs 44.8% (P<.05), the rate of clinical remission was 44.3% vs 17.2% (P<.05), and the rate of symptomatic remission was 63.9% vs 34.5% (P<.01), respectively. Mirikizumab was superior to placebo for other endpoints examined, but the comparison did not reach statistical significance, including for endoscopic remission (47.5% vs 27.6%), corticosteroid-free remission (37.7% vs 17.2%), and histologic-endoscopic mucosal remission (32.8% vs 17.2%).
Among 46 patients who had failed a single prior anti-TNF therapy and entered the extended induction portion of the LUCENT-2 trial, response rates to mirikizumab (300 mg, every 4 weeks) at week 24 were 45.7% for clinical response, 4.3% for clinical remission, 28.3% for symptomatic remission, and 10.9% for endoscopic remission. In the same subgroup of 46 patients, outcomes at week 52 were promising, based on rates of clinical response (75.0%), clinical remission (30.0%), symptomatic remission (55.0%), endoscopic remission (40.0%), corticosteroid-free remission (30.0%), and histologic-endoscopic mucosal remission (30.0%).
References
1. D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2023;
388(26):2444-2455.
2. Hart A, Martin-Arranz MD, Laharie D, et al. Effect of mirikizumab on clinical and endoscopic outcomes after 1 anti-TNF failure in patients with moderately to severely active ulcerative colitis [DDW abstract Su1818]. Gastroenterology. 2024;166(6)(suppl 1).
One-Year Comparative Effectiveness of Upadacitinib Versus Tofacitinib for Ulcerative Colitis: A Multicenter Cohort Study
Two JAK inhibitors are approved for the treatment of patients with UC.1-4 Upadacitinib selectively inhibits JAK1, whereas tofacitinib inhibits both JAK1 and JAK3. The 2 JAK inhibitors have not been directly compared in a clinical trial setting, and comparative real-world outcomes have not been well described. To address this gap, a retrospective real-world cohort study was conducted to evaluate efficacy and safety outcomes in patients with UC after 52 weeks of therapy with upadacitinib vs tofacitinib.5 The study included patients from 2 sites who initiated treatment with tofacitinib or upadacitinib for UC between January 1, 2020 and February 1, 2023. The primary outcome was corticosteroid-free clinical remission at 52±4 weeks. In addition to no corticosteroid use, corticosteroid-free clinical remission was defined by 3 criteria, based on data availability: (1) A Simple Clinical Colitis Activity Index score of 2 points or less; (2) a partial Mayo score of 2 points or less; and (3) the physician global assessment of clinical remission.
Included in the comparative analysis were 74 patients treated with tofacitinib (58% female) and 81 treated with upadacitinib (47% female). The median age at initiation of treatment was 39 to 40 years, and the median disease duration was 7 to 9 years. Eighty-eight percent of patients in each cohort were White. The median body mass index ranged from 24.2 to 25.0. Patients in both cohorts had received similar numbers of prior lines of anti-TNF therapy (P=.69). However, more patients in the upadacitinib cohort had received prior vedolizumab (74% vs 59%; P=.05) or prior ustekinumab (31% vs 8%; P<.01). In the upadacitinib cohort, 30% of patients had received prior tofacitinib. Over one-half of patients (53%-56%) were using prednisone or budesonide at baseline. Measures of disease activity were similar in the 2 cohorts at baseline.
After 12 weeks of therapy, a greater proportion of patients treated with upadacitinib experienced corticosteroid-free clinical remission (61% vs 47%), but the difference was not significant (Figure 5). However, a significant difference was observed at 52 weeks, with 72% of patients treated with upadacitinib achieving corticosteroid-free clinical remission vs 48% of patients treated with tofacitinib (P<.05). Treatment persistence at 52 weeks was also superior with upadacitinib compared with tofacitinib (86% vs 64%; P<.05). Other comparisons at 52 weeks that did not reach significance included endoscopic response (70% vs 73%) and endoscopic remission (52% vs 34%) with upadacitinib vs tofacitinib, respectively.
Covariates were successfully balanced to adjust for confounding. Upadacitinib was associated with a superior likelihood of achieving corticosteroid-free clinical remission at both 12 weeks (odds ratio, 2.28; 95% CI, 1.13-4.59) and at 52 weeks (odds ratio, 3.01; 95% CI, 1.39-6.55). A sensitivity analysis showed that upadacitinib was still superior to tofacitinib in achieving corticosteroid-free clinical remission at both 12 and 52 weeks when patients with prior exposure to tofacitinib in the upadacitinib cohort were excluded. With upadacitinib vs tofacitinib, the most common reasons for discontinuation were a lack of response (64% vs 89%), AEs (18% vs 7%), colectomy for dysplasia (9% vs 0%), and adherence or cost (9% vs 4%). AEs with both JAK inhibitors were consistent with descriptions in published reports.
References
1. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113-2128.
2. Rinvoq [package insert]. North Chicago, IL: AbbVie Biotechnology Ltd; 2024.
3. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.
4. Xeljanz [package insert]. New York, NY: Pfizer, Inc; 2022.
5. Dalal RS, Kallumkal G, Cabral HJ, Barnes EL, Allegretti JR. One-year comparative effectiveness of upadacitinib versus tofacitinib for ulcerative colitis: a multicenter cohort study [DDW abstract 247]. Gastroenterology. 2024;166(6)(suppl 1).