A Review of Selected Presentations From the ACG 2023 Annual Scientific Meeting
• October 20-25, 2023 • Vancouver, Canada
Analysis of Upadacitinib in IBD: Evaluating Safety and Efficacy Across Phase 3 Trials in Patients With Crohn’s Disease or Ulcerative Colitis
Current research into new therapeutics for inflammatory bowel disease (IBD) focuses on targeted biologics and small molecules to attack specific molecular pathways that promote IBD pathologies. Upadacitinib is an oral, reversible inhibitor of Janus kinase (JAK) that is approved as induction or maintenance therapy for patients with moderately to severely active Crohn’s disease (CD) or ulcerative colitis (UC) who have had an inadequate response to 1 or more tumor necrosis factor (TNF) inhibitors.1,2 U-ACHIEVE and U-ENDURE, both phase 3 trials, demonstrated the superiority of upadacitinib (15 or 30 mg, daily) in comparison with placebo as maintenance therapy in patients with moderately to severely active UC or CD.3,4 To evaluate long-term safety outcomes, investigators conducted a post hoc analysis of patient data from the 2 trials.5 Treatment-emergent adverse events (AEs) were pooled from patients in both studies who responded to upadacitinib induction and then received placebo or upadacitinib as maintenance therapy.
The analysis included 746 patients from U-ACHIEVE and 673 from U-ENDURE. In a comparison of the placebo vs the upadacitinib cohorts, the rates of serious and severe treatment-emergent AEs were higher with placebo than with upadacitinib in both patients with UC and those with CD. The most frequently reported infections were nasopharyngitis (exposure-adjusted event rate [EAER], 11.6-14.2), upper respiratory infection (EAER, 6.8-7.3), and COVID19 (EAER, 6.9-7.6). Rates of serious infections were similar across treatment groups; however, herpes zoster was more common among patients treated with upadacitinib. In each upadacitinib treatment group (15 or 30 mg; 0.3/100 patient-years), 1 gastrointestinal perforation was observed, whereas 2 perforations were observed in the placebo group. Rates of venous thromboembolism were higher with 15 mg of upadacitinib (EAER, 1.0) or 30 mg of upadacitinib (EAER, 0.9) than with placebo (EAER, 0), all in patients with UC. The EAERs for malignancies excluding non-melanoma skin cancer were as follows: 0.6 in the group that received 15 mg of upadacitinib, 1.0 in the group that received 30 mg of upadacitinib, and 0.4 in the placebo group.
Another post hoc study evaluated outcomes from patients who had a CD activity index (CDAI) of at least 220 at baseline in the phase 3 U-EXCEED and U-EXCEL induction trials (n=857) or who achieved a clinical response (at least a 100-point reduction in the CDAI from baseline [CR-100]) in the phase 3 U-ENDURE maintenance trial of upadacitinib vs placebo (n=343).6 Among patients with a CDAI of at least 220 at baseline, higher rates of CDAI clinical remission (46.2% vs 22.5% in U-EXCEL; 35.9% vs 17.8% in U-EXCEED; P<.0001 for both) and of endoscopic response (45.5% vs 12.6% in U-EXCEL; 34.1% vs 3.4% in U-EXCEED; P<.0001 for both) were observed with upadacitinib induction than with placebo (Figure 1). Analysis of key secondary endpoints, including stool frequency/abdominal pain score clinical remission, CR-100, steroid-free clinical remission, and endoscopic remission, also showed significantly superior outcomes with upadacitinib vs placebo in this patient subgroup. No new safety signals emerged.
Patients from U-ENDURE who were included in the analysis had achieved a CR-100 with upadacitinib induction therapy. At week 52 of maintenance therapy, the rates of CDAI clinical remission were 54.6% with upadacitinib (30 mg), 41.6% with upadacitinib (15 mg), and 14.4% with placebo (P<.0001), and the rates of endoscopic response were 41.2%, 27.8%, and 7.2%, respectively (P<.0001) (Figure 2). A higher proportion of patients treated with upadacitinib than with placebo achieved key secondary endpoints, including corticosteroid-free CDAI clinical remission, endoscopic remission, stool frequency/abdominal pain score clinical remission, and others.
References
1. Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne). 2023;10:1089099.
2. Rinvoq (upadacitinib) prescribing information. AbbVie Biotechnology Ltd; 2023. www.accessdata.fda.gov/drugsatfda_docs/label/2022/211675s004lbl.pdf. Accessed November 15, 2023.
3. 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.
4. Loftus EV, Jr., Panés J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2023;388(21):1966-1980.
5. Panaccione R, Panes J, Peyrin-Biroulet L, et al. Safety of upadacitinib in IBD: pooled analysis of phase 3 maintenance studies, U-ACHIEVE and U-ENDURE, in patients with moderately to severely active ulcerative colitis or Crohn’s disease. Abstract P3631. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
6. Rubin DT, Loftus EV, Regueiro M, et al. Efficacy of upadacitinib in patients with Crohn’s disease activity index-based eligibility criteria: post hoc analysis of U-EXCEL, U-EXCEED, and U-ENDURE phase 3 trials. Abstract P0732. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
Safety and Efficacy of Risankizumab in Crohn’s Disease: Prospective Real-World Experience and Systematic Literature Review
Risankizumab is a selective inhibitor of interleukin-23 (IL-23) that is approved for the treatment of adults with moderately to severely active CD.1,2 A prospective study evaluated real-world outcomes in 145 patients with CD who were followed for 12 weeks after the initiation of treatment with risankizumab.3 Of these patients, 81 were treated for active luminal disease and were included in the efficacy analysis, 45 of whom (56%) had received prior treatment with ustekinumab. In the efficacy cohort of 81 patients, the median age was 44 years (interquartile range [IQR], 35-58 years), and the median duration of disease was 15 years (IQR, 9-27 years). More than half of the patients had ileocolonic disease (53%). The most common disease phenotype was stricturing (44%), followed by perianal (31%) and penetrating (20%). In the efficacy cohort, 48% of the patients had received 3 or more prior advanced therapies, and 60% had a history that included bowel resection. By week 12, 70% of patients achieved clinical remission, with 63% achieving corticosteroid-free clinical remission. Most of the patients who achieved clinical remission did so by week 4. Among the patients who were ustekinumab-naive vs those who were ustekinumab-experienced at baseline, the rates of clinical remission were 78% vs 64% (P=.222), and the rates of corticosteroid-free clinical remission were 75% vs 52% (P=.041) (Figure 3); however, in multivariate analysis, prior therapy with ustekinumab was not associated with a lower rate of corticosteroid-free clinical remission at week 12.
A systematic review of literature was conducted to evaluate dosing practices and outcomes in patients who had CD treated with risankizumab.4 The study included 5 papers: 1 cohort study, 1 phase 2 randomized controlled clinical trial, 1 phase 2 open-label extension trial, and 2 phase 3 randomized controlled clinical trials. Risankizumab was administered intravenously at doses of 200, 600, and 1200 mg and was administered subcutaneously at a dose of 180 mg. The rate of clinical remission, based on a CDAI of less than 150, was 37% (15/41 patients) with 200 mg of risankizumab in the phase 2 open-label trial; the rates of clinical remission were higher in the 2 phase 3 trials, in which risankizumab was administered at either 600 or 1200 mg (42% vs 40% and 45% vs 42%, respectively). Rates of endoscopic remission in the phase 2 and phase 3 trials ranged from 19% to 24% with 600 mg of risankizumab and from 20% to 24% with 1200 mg of risankizumab. In the phase 3 trials, rates of AEs ranged from 51% to 59% with 1200 mg of risankizumab and from 48% to 56% with 600 mg of risankizumab; in the phase 2 open-label trial, 600 mg of risankizumab was associated with a higher rate of AEs (76%). In the real-world GETAID cohort study, 600 mg of risankizumab was associated with a 20% rate of AEs and a 7% rate of serious AEs.
References
1. Skyrizi (risankizumab) prescribing information. Abbvie Biotechnology, Ltd; 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761105s014lbl.pdf. Accessed November 15, 2023.
2. Horst S, Cross RK. Clinical evaluation of risankizumab in the treatment of adults with moderately to severely active Crohn’s disease: patient selection and reported outcomes. Drug Des Devel Ther. 2023;17:273-282.
3. Zinger A, Choi D, Choi N, et al. Effectiveness and safety of risankizumab induction therapy in Crohn’s disease: prospective real-world experience in a large tertiary center. Abstract P3532. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
4. Pulakurthi YS, Kogilathota Jagirdhar GS, Sadum N, et al. Risankizumab for the treatment of moderate to severe Crohn’s disease: a systematic review of literature. Abstract P0741. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
Ustekinumab Reintroduction: Week 16 Results and Baseline Response Analysis From the POWER Study in Patients With Crohn’s Disease
Following successful induction with ustekinumab, a secondary loss of response to ustekinumab maintenance therapy administered every 8 weeks develops in some patients with CD.1-3 The double-blind, multicenter, phase 3b POWER study evaluated the safety and efficacy of a single intravenous dose of ustekinumab vs continuous maintenance with the subcutaneous administration of ustekinumab in patients who had CD with a secondary loss of response to ustekinumab maintenance therapy.4 The 36-week study enrolled patients with moderately to severely active CD who initially responded to induction therapy with ustekinumab administered intravenously and who experienced a secondary loss of response to maintenance therapy with ustekinumab (90 mg, every 8 weeks) administered subcutaneously. Loss of response was defined as a CDAI higher than 220 to 450 plus either elevated C-reactive protein (CRP), elevated fecal calprotectin, or endoscopic evidence of active CD. Following randomization, 108 patients in arm 1 received reinduction therapy with intravenous ustekinumab (6 mg/kg) plus a subcutaneous placebo, and 107 patients in arm 2 received an intravenous placebo plus continued maintenance therapy with subcutaneous ustekinumab (90 mg, every 8 weeks).
A post hoc analysis was conducted to evaluate pharmacokinetics, pharmacodynamics, and immunogenicity in patients from the POWER trial.3 Baseline characteristics were well balanced between the 2 arms. The patients had a median age of approximately 41 years and a mean CDAI of 289. Most of the patients (~90%) had previously been exposed to anti-TNF therapy, with or without vedolizumab. Endoscopy in a subset of patients (~60% in each arm) showed relatively mild disease. Most of the patients in each arm (86%-93%) completed treatment at week 16. The serum concentration of ustekinumab reached a median level of 105.62 μg/mL among the patients who received a single intravenous reinduction dose of ustekinumab vs 1.47 μg/mL among the patients who received the intravenous placebo, and it was also higher after intravenous reinduction at week 16. The change in CDAI was evaluated in patients on the basis of the ustekinumab trough concentration at baseline, and the CDAI reduction was superior for ustekinumab reinduction vs intravenous placebo in all groups. At week 16, the proportions of patients in clinical response were similar in the 2 arms among the patients with a trough concentration of ustekinumab at week 16 of at least 1.3 μg/mL (Figure 4). Among the patients with a ustekinumab serum trough concentration of at least 1.3 μg/mL, a greater proportion of those in arm 1 than in arm 2 achieved endoscopic remission (23.8% vs 8.3%). Immunogenicity was not a concern.
A related study investigated baseline characteristics that correlated with a clinical response to reinduction with ustekinumab.5 Parameters associated with an increased likelihood of achieving a clinical response at week 16 with ustekinumab vs placebo included duration of disease of less than 5 years (P=.029), both ileal and colonic involvement (P=.002), elevated baseline level of CRP (P=.029) or fecal calprotectin (P=.045), no more than 1 prior failure with a biologic therapy (P=.042), and prior perianal CD-related surgery (P=.013).
References
1. Feagan BG, Sandborn WJ, Gasink C, et al; UNITI-IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960.
2. Sandborn WJ, Rebuck R, Wang Y, et al. Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4.
3. Feagan B, Lee S, van der Woude CJ, et al. Pharmacokinetics, exposure-response relationships, and immunogenicity in Crohn’s disease patients with Ustekinumab secondary loss of response following Ustekinumab iv reintroduction: week 16 results from the POWER study. Abstract 32. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
4. Schreiber SW, Lee S, van der Woude CJ, et al. Efficacy and safety of intravenous ustekinumab re-induction therapy in Crohn’s disease patients with secondary loss of response to ustekinumab maintenance therapy: week 16 results from the POWER trial (ECCO abstract P436). J Crohns Colitis. 2023;17(suppl 1).
5. Wolf D, Lee S, Schreiber S, et al. Analysis of baseline characteristics associated with clinical response to ustekinumab iv re-induction strategy in patients with Crohn’s disease in the POWER trial. Abstract P2174. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
Efficacy and Safety of Guselkumab in Crohn’s Disease: Results From the GALAXI 1 Study
Guselkumab is a selective IL-23 antagonist that binds to p19.1 The double-blind phase 2 GALAXI 1 study evaluated 3 doses of guselkumab vs ustekinumab or placebo in patients with moderately to severely active CD.2,3 During the 12-week induction period, patients randomized to the guselkumab arm received 200, 600, or 1200 mg of guselkumab at weeks 0, 4, and 8. For the maintenance and long-term extension (LTE) studies, 100 or 200 mg of guselkumab was administered every 4 or 8 weeks. At week 12 of induction, 34% of the patients treated with guselkumab (63/185) and approximately 33% of those treated with ustekinumab (21/63) had failed to achieve a CDAI response. Compared with the 185 patients who received guselkumab at any dose, those who failed to achieve a response to induction therapy with guselkumab tended to have a longer duration of CD (11.1 vs 9.3 years), and a greater proportion of them had failed treatment with a biologic therapy (60.3% vs 54.6%). By week 48 of maintenance in the subgroup of induction nonresponders, 58.7% of the patients receiving guselkumab and 47.6% of those receiving ustekinumab had achieved a clinical response (Figure 5), and the rate of clinical remission was 41.3% with guselkumab vs 33.3% with ustekinumab. Among the induction nonresponders in the combined guselkumab subgroups vs the ustekinumab subgroup, the rates of remission based on patient-reported outcomes (PROs) were 42.9% vs 23.8%, and the rates of endoscopic response were 31.7% vs 23.8%.
The GALAXI 1 trial included an LTE study to assess clinical, endoscopic, and safety outcomes.4 The LTE study included 151 patients treated with guselkumab and 48 treated with ustekinumab. Nonresponder imputation was used to account for missing patient data. At week 144, the rate of clinical remission with guselkumab was 95.4% among patients in the LTE observed population and 54.1% in the overall study population; the rate of clinical remission with ustekinumab was 83.8% among patients in the LTE study and 46.0% among all randomized patients. At week 144, rates of endoscopic response were generally maintained with guselkumab (73.5% among observed LTE patients, 34.7% among all randomized patients) and with ustekinumab (41.4% among observed LTE patients, 19.4% among all randomized patients). Rates of endoscopic remission at week 144 with guselkumab were 49.4% in the observed LTE population and 23.3% among all randomized patients; with ustekinumab, the rates were 27.6% in the observed LTE population and 12.9% among all randomized patients. Rates of PRO-2 remission were 89.8% in the observed LTE population and 51.4% among all randomized patients with guselkumab and were 75.7% in the observed LTE population and 39.7% among all randomized patients with ustekinumab. No new safety signals arose. Most infections were not serious; rates of discontinuation, serious AEs, and serious infections were generally low throughout the LTE.
References
1. Verstockt B, Salas A, Sands BE, et al; Alimentiv Translational Research Consortium (ATRC). IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2023;20(7):433-446.
2. Panaccione R, Afzali A, D’Haens GR, et al. Efficacy of guselkumab in patients with moderately to severely active Crohn’s disease not in clinical response at week 12: results from the GALAXI 1 study. Abstract 69. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
3. Sandborn WJ, D’Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn’s disease: induction results from the phase 2 GALAXI-1 study. Gastroenterol. 2022;162(6):1650-1664.e1658.
4. Afzali A, Danese S, Panaccione R, et al. Efficacy and safety of guselkumab for Crohn’s disease through 3 years: GALAXI-1 long-term extension. Abstract P0674. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
Real-World Clinical Effectiveness and Safety of Vedolizumab and Ustekinumab in Bio-naive Patients With Complex or Noncomplex Crohn’s Disease: Results From the EVOLVE Expansion Study
Real-world outcomes in patients with CD treated with vedolizumab or ustekinumab were evaluated in 2 retrospective, multicenter, observational studies that assessed patient chart data from the EVOLVE Expansion trial.1-3 The retrospective analyses included patients with either complex or noncomplex CD.4,5 The Evolve Expansion trial enrolled biologic-naive patients with previously diagnosed CD in whom treatment with ustekinumab or vedolizumab was initiated during the eligibility period in Australia, Belgium, or Switzerland. Complex CD was defined as the presence of 1 or more of the following conditions: active fistula at treatment initiation, any prior CD-related surgery since diagnosis, and any CD-related hospitalization within 12 months before the initiation of treatment. The main study endpoints were clinical outcomes, treatment persistence, and safety. A series of hierarchical algorithms was used to assess clinical outcomes, including clinical response, clinical remission, and mucosal healing.6
The patients with complex CD whose data were analyzed included 97 treated with ustekinumab and 99 treated with vedolizumab.4 After adjustment by inverse probability to treatment weighting, no significant differences in baseline characteristics were found between the 2 treatment cohorts. In the 2 cohorts, the median duration of disease was 9.2 to 9.7 months, and 51% to 52% of the patients had ileal disease without upper tract disease. Disease behavior at baseline was nonstricturing and nonpenetrating in 47% to 49% of patients and was stricturing in 29% to 35% of patients. Most of the patients had moderate disease (68%-70%); severe disease was noted in 16% to 17%. Characteristics of complex CD included fistula before the initiation of treatment (27%-28%), CD-related surgeries since diagnosis (67%-72%), and CD-related hospitalizations in the 12 months before the initiation of treatment (53%).
The analysis generally showed no significant differences between the outcomes of patients with complex CD treated with ustekinumab vs vedolizumab. After 36 months of treatment, the weighted cumulative rate of response was 79.4% with ustekinumab or vedolizumab (P=.78), and the weighted cumulative rate of clinical remission was 82.9% to 83.1% (P=.58). The rate of weighted cumulative mucosal healing was 78.7% with ustekinumab vs 90.1% with vedolizumab (P=.12), and the rate of weighted cumulative treatment persistence was 70.9% with ustekinumab vs 73.9% with vedolizumab (P=.83). Similarly, after 12 or 24 months of follow-up, no significant differences in clinical outcomes were observed. During 36 months of follow-up, rates of serious infections were low (incidence rate of first occurrence per 100 patient-years [IRFO100], 0.0 with ustekinumab vs 1.3 with vedolizumab; hazard ratio [HR], not estimable). With ustekinumab vs vedolizumab, the IRFO100 was 7.7 vs 5.7 for serious AEs (HR, 0.72; 95% CI, 0.32-1.64; P=.44), 14.2 vs 11.5 for CD exacerbations (HR, 0.89; 95% CI, 0.47-1.67; P=.71), 2.3 vs 6.2 for CD-related surgeries (HR, 3.20; 95% CI, 0.91-11.28; P=.07), and 13.0 vs 9.0 for CD-related hospitalizations (HR, 0.83; 95% CI, 0.43-1.59; P=.57) (Figure 6).
A related study retrospectively examined real-world data from patients with noncomplex CD in the EVOLVE study.5 Patients with noncomplex CD were those who did not have active fistula at baseline, had no prior CD-related surgery since diagnosis, and had no CD-related hospitalization before baseline. This study also used the hierarchical algorithms for clinical assessment, and inverse probability of treatment weighting was used to adjust patient data at baseline. The study included 218 patients treated with ustekinumab and 209 treated with vedolizumab. Patient baseline characteristics were similar in the 2 treatment cohorts. Among the patients with noncomplex CD, after 36 months of follow-up, ustekinumab and vedolizumab yielded rates of clinical and safety endpoints that did not differ significantly on the basis of clinical response, clinical remission, mucosal healing, treatment persistence, serious AEs, serious infections, CD exacerbations, CD-related surgeries, and CD-related hospitalizations (P>.05 for each).
References
1. Feagan BG, Sandborn WJ, Gasink C, et al; UNITI-IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960.
2. Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721.
3. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(3):618-627.e3.
4. Ferrante M, Christensen B, Bressler B, et al. Real-world clinical effectiveness and safety of Vedolizumab and Ustekinumab in bio-naive patient with complex Crohn’s disease: results from the EVOLVE expansion study. Abstract 71. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
5. Ferrante M, Christensen B, Bressler B, et al. Real-world clinical effectiveness and safety of vedolizumab and ustekinumab in bio-naïve patients with non-complicated Crohn’s disease: results from the EVOLVE expansion study. Abstract P3560. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
6. Bressler B, Yarur A, Silverberg MS, et al. Vedolizumab and anti-tumour necrosis factor a real-world outcomes in biologic-naïve inflammatory bowel disease patients: results from the EVOLVE study. J Crohns Colitis. 2021;15(10):1694-1706.
Insights on Filgotinib in Crohn’s Disease From the DIVERSITY1 and SELECTION Studies
Filgotinib is a JAK inhibitor approved by the European Medicines Agency for the treatment of patients with moderately to severely active UC.1 The double-blind, phase 3 DIVERSITY1 study investigated filgotinib vs placebo as induction and maintenance therapy in patients with moderately to severely active CD.2 Patients were evenly randomized to receive 100 or 200 mg of filgotinib daily or placebo for 10 weeks during induction or through week 58 for maintenance therapy. Induction study A included patients with or without prior biologic exposure, and study B included only patients who were biologic-experienced. After the induction period, patients with a response to filgotinib were randomized in a 2:1 ratio to continue with filgotinib at the induction dose or to receive placebo. The study had 2 primary endpoints: clinical remission, defined as a CDAI of less than 150, and endoscopic response, defined as a reduction of at least 50% in the Simple Endoscopic Score for Crohn’s Disease (SES-CD) from baseline or clinical remission on the basis of a 2-item PRO.
The DIVERSITY1 study enrolled 1363 patients into 6 arms. After 10 weeks of induction therapy, the rate of clinical remission was significantly higher among the patients treated with 200 mg of filgotinib than among those treated with placebo in study A (32.9% vs 19.8%; P=.017) and in study B (26.7% vs 14.8%; P=.0023) (Figure 7). However, the rates of endoscopic response were not significantly different for filgotinib vs placebo in either study A or study B (P>.05). In the maintenance portion of the study, the only comparison that was significant was the rate of endoscopic response in patients who received 200 mg of filgotinib for both induction and maintenance vs the rate in patients who initially received the higher dose of filgotinib and were then randomized to placebo for maintenance (30.4% vs 9.4%; P=.0038).
The international phase 2b/3 SELECTION study compared filgotinib at 100 or 200 mg daily vs placebo in 1348 patients with moderately to severely active UC.3 In a safety analysis, patient data from the 2 studies were used to compare filgotinib toxicity in patients with UC vs toxicity in patients with CD.4 Filgotinib was generally well tolerated, with no new safety signals arising. Rates of specific AEs, such as serious infections, malignancies excluding nonmelanoma skin cancer, venous thromboembolism, and major adverse cardiovascular events, were similar among patients with CD and those with UC. A gastrointestinal perforation developed in 11 of the patients with CD, but none was considered related to filgotinib therapy. No deaths occurred that were considered related to study treatment.
References
1. Jyseleca [filgotinib] summary of product characteristics. Galapagos NV; Belgium. 2023.
2. Vermeire S, Rubin DT, Watanabe M, et al. Safety of filgotinib in Crohn’s disease compared with ulcerative colitis: data from the phase 3 DIVERSITY1 and phase 2b/3 SELECTION studies. Abstract P0737. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
3. Feagan BG, Danese S, Loftus EV, Jr., et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397(10292):2372-2384.
4. Vermeire S, Rubin DT, Watanabe M, et al. Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn’s disease: results from the phase 3 randomized, double-blind, placebo-controlled DIVERSITY1 study. Abstract P0272. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
Highlights in Crohn’s Disease From the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting: Commentary
David T. Rubin, MD
Joseph B. Kirsner Professor of Medicine
Chief, Section of Gastroenterology, Hepatology, and Nutrition
Director, Inflammatory Bowel Disease Center
The University of Chicago Medicine
Chicago, Illinois
The American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting, which was held in Vancouver, Canada, this October, provided valuable insights into the management of Crohn’s disease (CD). Data focused on the efficacy, safety, and utilization of treatment options among several single-agent therapies, including upadacitinib, filgotinib, risankizumab, guselkumab, ustekinumab, and vedolizumab.
Upadacitinib
Upadacitinib is a synthetic small-molecule therapy that targets the Janus kinase (JAK) mechanism of inflammation. JAK is a transmembrane enzyme that activates inflammatory pathways, and upadacitinib inhibits primarily JAK1.1,2 In a study analyzing the safety of upadacitinib in an inflammatory bowel disease (IBD) pooled analysis of phase 3 maintenance studies, Panaccione and co-investigators reviewed trials in both CD and ulcerative colitis (UC) to explore the safety profile of this therapy for patients with these disorders.3 The study included 2 phase 3 double-blind placebo control trials and more than 1400 patients, with 246.4 patient-years of exposure to placebo, 353.1 patient-years of exposure to upadacitinib at 15-mg dosing, and 395.7 patient-years of exposure to upadacitinib at 30-mg dosing. Notably, the frequencies of serious adverse events (AEs), events leading to treatment discontinuation, and serious infections were similar with the 2 doses of upadacitinib (15 and 30 mg) and lower than those observed in the placebo group. This trend is often seen in trials of moderate to severe CD, in which patients receiving a placebo during maintenance phases tend to experience disease relapse or progression because of the lack of treatment. The adjudicated AEs did not show any cardiovascular events, nor were any significant venous thromboembolic (VTE) events noted among a cohort of patients who had severe IBD and would otherwise have had a higher risk for VTE. This analysis is of specific interest because the drug class labeling advises screening and risk assessment for thromboembolic complications, on the basis of prior studies in a high-risk cohort of patients with rheumatoid arthritis who were treated with tofacitinib.4 Overall, this analysis was helpful. It showed the benefit of the treatment in patients with moderate to severe CD and moderate to severe UC from a safety point of view. Also, it provided reassurance by not showing any additional safety signals associated with this specific therapy.
The second study of interest, which I had the honor of leading, focused on the efficacy of upadacitinib in patients with CD; the Crohn’s Disease Activity Index (CDAI) was used as a measure of efficacy.5 This study holds relevance because of the difference in requirements between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in assessing therapeutic efficacy for CD. In Europe, new therapies are evaluated with patient-reported outcomes of stool frequency and abdominal pain scores, without utilization of the CDAI, whereas in the United States, the FDA has continued to use the CDAI. The reanalysis of the efficacy of upadacitinib in moderate to severe CD with the CDAI was performed to evaluate whether this therapy had a similar benefit when that index was used. The post hoc analysis included 857 patients with a baseline CDAI of 220 points or more. The patients received 12 weeks of a 45-mg induction dose of upadacitinib or placebo. In all, 343 patients from the maintenance trial achieved a clinical response of a 100-point improvement in the CDAI at the 45-mg dose. They were then rerandomized to a maintenance dose of either 15 or 30 mg of upadacitinib or to placebo. The bottom line here for clinicians is to understand that when this other measure of response and remission and inclusion criteria were used, the efficacy of upadacitinib was similar to what had been described when the patient-reported outcomes were used alone. This finding reaffirms our current understanding and does not alter our perspective on this treatment approach.
Another noteworthy abstract involving upadacitinib, presented at the ACG meeting by Krugliak Cleveland, explored the utility of point-of-care intestinal ultrasonography (IUS) as a way to assess response to therapy and adjust treatments.6 The study was based on the hypothesis that if a clinician knows that disease is active or not responding to therapy as expected, the therapy can be adjusted sooner than can be done while waiting for the results of standard tests, such as colonoscopy and stool markers, or waiting for complications to arise. The study reviewed 30 of 105 patients receiving upadacitinib at our center, and these patients were stratified into groups; 11 received management guided by IUS, and 19 matched controls underwent conventional management without IUS. Among those patients who had access and were monitored with IUS, therapy was adjusted and remission was achieved statistically sooner than among those managed conventionally. This finding demonstrates the spreading wave of knowledge and excitement about IUS, both in the United States and globally, as point-of-care testing facilitates real-time decision making and therapy adjustments.
Filgotinib
Filgotinib is a different synthetic small molecule that selectively targets JAK1. Vermeire and colleagues presented the phase 3 DIVERSITY1 study, which looked at the efficacy and safety of filgotinib as a treatment for moderate to severe CD.7 The study compared 2 different doses (200 and 100 mg) with a placebo during a 10-week induction, followed by a subsequent maintenance study extending to week 58. In the maintenance study, patients responding to filgotinib were randomized in a 2:1 ratio to their specific induction dose or to placebo if they had an endoscopic response or a clinical remission. The disappointing result was that filgotinib at 200 mg was not superior to placebo in regard to both coprimary endpoints during the induction phase. However, it did prove efficacious in inducing CDAI clinical remission by week 10. Among patients achieving either endoscopic response or clinical remission in terms of abdominal pain and stool frequency by week 10, filgotinib at 200 mg demonstrated efficacy in sustaining endoscopic response until week 58 in the maintenance trial. Despite these positive aspects, because the therapy failed to meet its primary endpoints, it will not be considered an option for patients with CD. If you look at the trial results, a notable observation is the relatively high placebo rate during induction, which may have been due to concomitant therapies, including corticosteroids.
Schreiber and colleagues also assessed the safety of filgotinib by looking at data from various trials, including DIVERSITY1 in CD and SELECTION in UC.8 Given the availability of other JAK inhibitors to treat IBD and the efficacy of filgotinib in treating moderate to severe UC in Europe and other regions, it is worth noting that the safety profile of filgotinib as a JAK inhibitor is similar to what has been observed with tofacitinib and upadacitinib, showing no new so safety signals. Infections were reported in approximately 25% to 34% of patients with CD and in 23% to 34% of patients with UC, with the rate of serious infections remaining below 2% in both populations. Malignancy occurred only in 1 patient with CD and 1 patient with UC. In the maintenance studies, 1 patient with CD and 1 patient with UC experienced a VTE event; similarly rare occurrences of major adverse cardiovascular events were noted, without any additional concerns raised. Importantly, no deaths occurred in the DIVERSITY1 trial. In the SELECTION trial, 2 deaths occurred, but neither was related to the drug as reported by the investigator and adjudicated by the steering committee.9 Overall, the safety assessment for filgotinib provides us with valuable information about the particular mechanism in patients with CD and UC, offering reassurance in terms of safety. However, it is disappointing that filgotinib will not be considered an option to treat patients with moderate to severe CD. Of note, it is not available for UC in the United States.
Ustekinumab
Ustekinumab, a monoclonal antibody that targets the protein p40, effectively inhibiting both interleukin 12 (IL-12) and IL-23, is available as a treatment for moderate to severe CD and moderate to severe UC. The highly anticipated additional results of the POWER study, initially introduced earlier in the year, were presented at ACG.10 This study compared the efficacy and safety of an additional intravenous (IV) dose of ustekinumab for reinduction vs subcutaneous dosing in patients who had lost response to standard ustekinumab maintenance therapy. Loss of response to various therapies in CD is well described and unfortunately remains a challenge in managing this condition. Therefore, understanding the potential to optimize existing therapies before transitioning to other treatments is of great interest. The hypothesis here is based on the presumption that subtherapeutic levels of the drug may be affecting change in patients, leading to a loss of response. The thought was to investigate whether providing an additional IV dose could boost efficacy and recapture and redirect the patient’s response. At ACG, Feagan and colleagues presented updated results of the POWER study, also delving into the details inherent to the hypothesis and the study design, such as how the pharmacokinetics, exposure-response relationships, and the potential for immunogenicity affect how the drug works.11 In the study, patients who had initially responded to induction with IV ustekinumab but later lost response were identified either by a rising CDAI score plus elevated C-reactive protein and fecal calprotectin levels or with endoscopy. This dual assessment ensured confirmation of a biological relapse, differentiating it from a merely symptomatic relapse. When a patient’s loss of response is assessed, it is important to distinguish between symptoms caused by active disease and those unrelated, always seeking objective measures to comprehend the situation, and also, naturally, to exclude infection. The bottom line from this complex analysis revealed that among 2015 patients with ustekinumab concentration data and one or more collected blood samples, on the basis of week 16 trough concentrations, no substantial difference was observed between those who were successfully recaptured and those who were not. However, patients did show increased trough levels with the IV dose vs continuation of the subcutaneous dose, which would have been expected. Although higher drug levels were observed, no significant difference in the clinical response was noted between the IV and the subcutaneous strategies. In a quartile analysis, a relationship was noted between increased exposure in the IV arm and differences in endoscopic remission, but not in the clinical response. The takeaway message for this study is that IV reinduction does not offer much clinical benefit and therefore would not be routinely recommended.
Risankizumab
Risankizumab, which has received approval for treating moderate to severe CD, belongs to the new generation of IL-23 inhibitors. The drug operates as a monoclonal antibody; targeting the protein p19, it is selective for IL-23 and does not affect IL-12.12 This particular study, presented by Zinger and colleagues at ACG, focuses on the real-world experience when this therapy was used at the University of Chicago and reports induction data outcomes.13 The study involved a prospective analysis of clinical outcomes in patients with CD who received risankizumab. Clinical evaluations were performed at weeks 0, 2, 4, 8, and 12 with the Harvey Bradshaw Index (HBI). In all, 94 patients underwent ongoing follow-up for 12 weeks. After a rapid onset of action of risankizumab, with a median HBI reduction as early as 2 weeks, a plateau was reached by week 8, even before the 12-week endpoint. By week 12, 78% of the patients had achieved a clinical response, and 70% achieved clinical remission. Of great interest in this particular study was that most patients had previously received ustekinumab. Interestingly, when patients who had received ustekinumab were compared with those who were ustekinumab-naive, no statistical difference was seen in the likelihood of response. Given the similarity in the mechanisms of action of these 2 therapies, this finding is particularly noteworthy. Notably, the rate of corticosteroid-free clinical remission was higher in ustekinumab-naive patients than in those who were ustekinumab-experienced. Overall, the safety profile aligned with what has been observed in this class of therapy, demonstrating excellent safety. This real-world experience closely mirrors or even slightly surpasses what has been seen in clinical trials and gives us further insight into the utility of this therapy, even in patients previously treated with ustekinumab.
Guselkumab
Guselkumab, another p19 monoclonal antibody that selectively targets IL-23, has been studied in both UC and CD.14 At ACG, Panaccione and colleagues reported updates from the GALAXI 1 study, assessing patients with moderate to severe CD who had not achieved a clinical response at week 12 with guselkumab.15 Of the patients who received guselkumab at various doses, those who did not achieve a response were allowed to continue therapy. This post hoc analysis evaluated the patients who continued treatment. By week 24, 46% of the nonresponders had achieved a clinical response. Among those who were in the maintenance study up to week 48, 58.7% achieved clinical response and 47.6% achieved clinical remission. The concept of delayed response has been well documented with other therapies and is a standard approach in these trials, in which the study design of randomizing responders or focusing on post-induction responders and their maintenance outcomes is of particular interest. The secondary analysis that is often performed explores the outcomes of patients who took longer to respond but eventually did. Repeatedly, we have learned that this group of patients, even if they experience moderate improvement without achieving remission or a defined significant response by the trial endpoint, are likely to respond positively if treatment is continued for an additional induction period—in this case, 12 weeks. Those who do eventually respond are equally likely to do well during maintenance. The interpretation of this study suggests that it is beneficial for some patients to continue the therapy beyond week 12 to assess whether control of their CD can be achieved.
The other study of guselkumab, presented by Afzali and colleagues, reported 3-year outcomes in patients from the GALAXI 1 long-term extension.16 The average duration of follow-up in this analysis from baseline through week 152 was more than 100 weeks in the guselkumab group and 102 weeks in the ustekinumab comparator group. Overall, the 151 patients who were randomized to guselkumab and the 48 patients who were randomized to ustekinumab were treated in the long-term extension. The primary results demonstrated that patients continue to do well, with 54% in CDAI clinical remission and 34% in endoscopic response at week 144. In terms of safety, the mechanism of this particular drug is quite safe. Most infections were not serious and were mild to moderate, resolving without a requirement for drug discontinuation. As we have seen repeatedly with the IL-23 mechanism, no cases of active tuberculosis, opportunistic infections, anaphylaxis or serum sickness, major adverse cardiovascular events, or deaths occurred.
Ustekinumab and Vedolizumab
The EVOLVE expansion study is a multicenter, real-world, retrospective analysis of patients with CD treated with ustekinumab or vedolizumab in Australia, Belgium, and Switzerland from 2016 to 2021. Ferrante and colleagues presented 2 different abstracts at ACG on the relative efficacy and safety of these therapies in patients with complex or noncomplex CD.17,18 The first abstract explored patients with noncomplex CD who were bio-naive and treated with vedolizumab, an anti-integrin therapy that targets the integrins related to lymphocyte trafficking in the gut, or with ustekinumab.17 Among the patients with noncomplex CD, the 2 therapies were similar in efficacy and the safety was excellent, with no significant differences. We have come to appreciate that both mechanisms are safe, and it is helpful to know that the therapies work well, especially in bio-naive patients. In general, when you treat patients with CD earlier, they are more likely to do well, and according to this retrospective multicenter analysis, they are equally likely to do so regardless of which therapy is used.
In the patients who had complex CD—which is of great interest because of the prevalence of complex disease presentations involving draining fistulas, hospitalization, or surgery—rates of efficacy and safety for ustekinumab and vedolizumab were also similar.18 CD exacerbations were reduced with both therapies, with a hazard ratio of 0.89. The rates of CD-related surgeries did not differ with the 2 drugs, and CD-related hospitalizations appeared to be reduced during the 36 months of review. The takeaway for clinicians is that both therapies exhibit efficacy and can be utilized in patients with complex presentations. My message would be to ensure that regardless of the chosen treatment, think carefully about measuring that it is actually doing what you need it to do. Remember too that these therapies have different mechanisms and may not work as well for patients with a variety of extraintestinal manifestations.
Relevant Disclosures
Dr Rubin has received grant support from Takeda; and has served as a consultant for AbbVie, Bristol Myers Squibb, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Biosciences, Reistone Biopharma, Sangamo Therapeutics, Shanghai Pharma Biotherapeutics USA, and Takeda.
References
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3. Panaccione R, Panes J, Peyrin-Biroulet L, et al. Safety of upadacitinib in IBD: pooled analysis of phase 3 maintenance studies, U-ACHIEVE and U-ENDURE, in patients with moderately to severely active ulcerative colitis or Crohn’s disease. Abstract P3631. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
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7. Vermeire S, Rubin DT, Watanabe M, et al. Safety of filgotinib in Crohn’s disease compared with ulcerative colitis: data from the phase 3 DIVERSITY1 and phase 2b/3 SELECTION studies. Abstract P0737. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
8. Schreiber S, Vermeire S, Rubin DT, et al. Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn’s disease: results from the phase 3 randomized, double-blind, placebo-controlled DIVERSITY1 study. Abstract 0272. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
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13. Zinger A, Choi D, Choi N, et al. Effectiveness and safety of risankizumab induction therapy in Crohn’s disease: prospective real-world experience in a large tertiary center. Abstract P3532. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
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15. Panaccione R, Afzali A, D’Haens GR, et al. Efficacy of guselkumab in patients with moderately to severely active Crohn’s disease not in clinical response at week 12: results from the GALAXI 1 study. Abstract 69. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
16. Afzali A, Danese S, Panaccione R, et al. Efficacy and safety of guselkumab for Crohn’s disease through 3 years: GALAXI-1 long-term extension. Abstract P0674. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
17. Ferrante M, Christensen B, Bressler B, et al. Real-world clinical effectiveness and safety of vedolizumab and ustekinumab in bio-naïve patients with non-complicated Crohn’s disease: results from the EVOLVE expansion study. Abstract P3560. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.
18. Ferrante M, Christensen B, Bressler B, et al. Real-world clinical effectiveness and safety of Vedolizumab and Ustekinumab in bio-naive patient with complex Crohn’s disease: results from the EVOLVE expansion study. Abstract 71. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25, 2023; Vancouver, Canada.