A Review of Selected Presentations From the 14th Congress of the European Crohn’s and Colitis Organisation (ECCO) • March 6-9, 2019 • Copenhagen, Denmark
VARSITY: A Double-Blind, Double-Dummy, Randomized Controlled Trial of Vedolizumab Versus Adalimumab in Patients With Active Ulcerative Colitis
In the late-breaking abstract session, Dr Stefan Schreiber and colleagues presented results of the phase 3b VARSITY study (A Double-Blind, Double-Dummy, Randomised, Controlled Trial of Vedolizumab Versus Adalimumab in Patients With Active Ulcerative Colitis), which compared vedolizumab vs adalimumab for the treatment of ulcerative colitis.1 Vedolizumab is a gut-selective, humanized immunoglobulin G1 monoclonal antibody directed against the α4β7 integrin. It is administered intravenously (IV). Adalimumab is a subcutaneously (SC)-administered human immunoglobulin G1 monoclonal antibody that binds to and neutralizes the cytokine tumor necrosis factor α (TNFα) with systemic effects. VARSITY is one of the first large clinical trials to conduct a head-to-head comparison of 2 biologic agents in patients with inflammatory bowel disease (IBD). The trial followed a randomized, double-blind, double-dummy, multicenter, active-control phase 3b design to compare the efficacy and safety of vedolizumab vs adalimumab at week 52 in patients with moderately to severely active ulcerative colitis.
After an initial screening period, patients were randomly assigned to 52 weeks of treatment with vedolizumab (300 mg IV at weeks 0, 2, 6, and every 8 weeks thereafter) or adalimumab (160 mg SC at week 0, 80 mg SC at week 2, and 40 mg SC every 2 weeks thereafter).1 To keep the study double-blind, patients in the vedolizumab arm were additionally treated with a SC placebo, and patients in the adalimumab arm received an IV placebo. Patients were assessed at baseline and at weeks 14 and 52 by endoscopy. After the 52-week study was completed, patients were followed for an additional 18 weeks via clinic visits, and then by telephone for up to 6 months after completing their last dose.
The primary endpoint of the VARSITY study was the proportion of patients achieving clinical remission at week 52. Clinical remission was defined as a complete Mayo score of 2 or lower and no individual subscore higher than 1. Secondary endpoints included the proportion of patients achieving mucosal healing (Mayo endoscopic subscore, ≤1) at week 52 and the proportion of patients who discontinued oral corticosteroids and were in clinical remission at week 52.
The study randomly assigned 771 patients with ulcerative colitis to treatment with vedolizumab or adalimumab in a 1:1 fashion. The baseline characteristics were balanced between the 2 treatment arms. The mean age was 40.8 years in the vedolizumab arm and 40.5 years in the adalimumab arm; 60.8% and 56.0% of patients in each arm, respectively, were male. At baseline, the rates of severe ulcerative colitis (Mayo score 9-12) were 56.4% in the vedolizumab arm and 54.4% in the adalimumab arm. Moderate disease (Mayo score 6-8) was reported in 40.0% of the vedolizumab arm and 43.8% of the adalimumab arm. Mild disease (Mayo score <6) was reported in 2.3% vs 1.3%, respectively. The mean duration of ulcerative colitis disease was 7.25 years in the vedolizumab arm and 6.35 years in the adalimumab arm. Previous treatment with anti-TNF therapy was reported by 20.8% vs 21.0%. Concomitant corticosteroids were used by 36.1% vs 36.3% of patients, respectively, and concomitant immunomodulators were used by 26.2% vs 25.9%. A total of 74.5% of patients in the vedolizumab arm completed treatment as planned, compared with 61.9% of patients in the adalimumab arm.
In the primary analysis of the overall intention-to-treat population, the primary endpoint of clinical remission at week 52 was reached by 31.3% of the vedolizumab arm vs 22.5% of the adalimumab arm (95% CI, 2.6-15.0; P=.0061; Figure 1). In a prespecified subgroup analysis of patients who had not received prior treatment with anti-TNF therapy, the rates of clinical remission at week 52 were 34.2% with vedolizumab vs 24.3% with adalimumab (95% CI, 2.8-17.1; nominal P=.0070). Among patients who had received prior anti-TNF agents, clinical remission occurred in 20.3% vs 16.0%, respectively (95% CI, –7.7 to 16.1; nominal P=.4948). Assessment of clinical response rates over the 52-week study showed that treatment differences began to emerge between weeks 6 and 14.
In the overall intention-to-treat population, the secondary endpoint of mucosal healing at week 52 was reported in 39.7% of the vedolizumab arm vs 27.7% of the adalimumab arm (95% CI, 5.3-18.6; P=.0005; Figure 2). Among patients who had not received prior treatment with anti-TNF therapy, these rates were 43.1% with vedolizumab vs 29.5% with adalimumab (95% CI, 6.0-21.1; nominal P=.0005). The difference in mucosal healing was not statistically significant among patients who had received prior anti-TNF treatment, at 26.6% with vedolizumab vs 21.0% with adalimumab (95% CI, –7.6 to 18.8; nominal P=.4136). The clinical responses according to study visit are shown in Figure 3. The proportion of patients who achieved corticosteroid-free remission at week 52 was 21.7% with adalimumab vs 12.6% with vedolizumab, although this difference did not reach statistical significance. The study investigators noted that the absolute reduction in corticosteroid use was greater with vedolizumab, but the difference was not significant.
Treatment-related adverse events occurred in 17.0% of the vedolizumab arm vs 22.3% of the adalimumab arm. Serious adverse events related to the study treatment were reported in 1.8% of the vedolizumab arm and 2.6% of the adalimumab arm. Treatment was discontinued owing to an adverse event in 4.4% vs 6.5%, respectively. An analysis of selected exposure-adjusted adverse events showed that an infection or infestation occurred in 33.5% vs 43.5%. Most of these events were upper respiratory tract infections.
The study investigators concluded that the results support the use of vedolizumab before adalimumab in patients with moderately to severely active ulcerative colitis.1 Both treatments were generally safe and well-tolerated.
Reference
1. Schreiber S, Peyrin-Biroulet L, Loftus EV, et al. VARSITY: a double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis [ECCO abstract OP34]. J Crohns Colitis. 2019;13(suppl 1).
Analyses of Data From the VISIBLE 1 and 2 Trials: Vedolizumab in Patients With Ulcerative Colitis or Crohn’s Disease
Several abstracts reported results from the VISIBLE 1 and 2 trials. The VISIBLE 1 trial (Efficacy and Safety of Vedolizumab Subcutaneously [SC] as Maintenance Therapy in Ulcerative Colitis) was a pivotal, multicenter, randomized, double-blind, double-dummy phase 3 study that evaluated vedolizumab SC as maintenance treatment for ulcerative colitis.1 The rate of clinical remission at week 52 was 46.2% with vedolizumab SC maintenance treatment vs 14.3% with placebo (P<.001), a significant difference that met the primary endpoint. VISIBLE 2 (Efficacy and Safety of Vedolizumab Subcutaneous [SC] as Maintenance Therapy in Crohn’s Disease) is an ongoing, similarly designed phase 3 trial evaluating vedolizumab SC in patients with Crohn’s disease.2 Both studies enrolled patients who had exhibited an inadequate response, loss of response, or intolerance to previous treatment that included corticosteroids, immunosuppressive agents, and/or anti-TNF therapy.
A study evaluated the exposure-response relationship of vedolizumab SC in patients with ulcerative colitis enrolled in the VISIBLE 1 study.3 Vedolizumab trough concentrations were measured at weeks 6 and 46 and grouped into quartiles. The proportion of patients treated with vedolizumab SC for maintenance therapy (n=106) who achieved a clinical remission increased from 50% in quartile 1 to 83% in quartile 4 (Figure 4). Rates of mucosal healing increased from 50% in quartile 1 to 89% in quartile 4. Similar pharmacokinetic trends were observed among patients randomly assigned to maintenance treatment with vedolizumab IV (n=54). The immunogenicity rate for patients receiving vedolizumab SC was low, at 6%, and similar to that in the vedolizumab IV arm.
Dr Séverine Vermeire and coworkers measured health-related quality of life and work productivity among patients with ulcerative colitis who received vedolizumab in the VISIBLE 1 study.4 Mean total IBD questionnaire (IBDQ) scores improved markedly over time in both the vedolizumab SC and IV groups vs placebo. At week 52, clinically meaningful improvements in mean total IBDQ scores were observed with vedolizumab SC (180.7) and vedolizumab IV (170.7), as compared with placebo (135.2). Changes in the total IBDQ score from baseline to week 52 were significantly higher for both vedolizumab SC (+65.3) and vedolizumab IV (+58.6) vs placebo (P<.001 for both comparisons). In contrast, patients randomly assigned to the placebo arm showed substantial worsening in the IBDQ score through week 52. Similar trends in improvements were observed across the individual IBDQ subscale components, including bowel symptoms, emotional function, social function, and systemic symptoms. Changes in the EuroQoL Quality of Life 5D visual analogue scale score were also significantly greater for vedolizumab SC (+27.1) and vedolizumab IV (+22.6) vs placebo (P≤.001 for both comparisons). Work productivity, as assessed by the Work Productivity and Activity Impairment–Ulcerative Colitis score, also showed improvements with both vedolizumab SC and vedolizumab IV compared with placebo. These improvements were initially observed at week 6 and sustained through
week 52.
Dr Edward V. Loftus Jr and colleagues analyzed data from VISIBLE 1 (patients with ulcerative colitis) and VISIBLE 2 (patients with Crohn’s disease) to evaluate the efficacy and safety of 2 vs 3 induction doses of vedolizumab IV.5 In both studies, patients received open-label vedolizumab IV induction therapy at weeks 0 and 2. Patients classified as nonresponders at week 6 received a third IV induction infusion at this time, and were reassessed for response at week 14. In contrast, patients with a clinical response at week 6 entered the maintenance phase of the study.
Among the 383 patients with ulcerative colitis, 85.9% had a clinical response after 2 or 3 induction infusions of vedolizumab IV.5 In patients with ulcerative colitis, 56.1% had a clinical response at week 6 after 2 IV infusions. Among the remaining patients with ulcerative colitis, who were classified as nonresponders and received a third induction dose, the rate of clinical response at week 14 was 79.7%. Among the 644 patients with Crohn’s disease, 82.6% had a clinical response after either 2 or 3 induction infusions of vedolizumab IV. In patients with Crohn’s disease, 63.7% had a clinical response at week 6 after 2 IV infusions. Among the remaining nonresponding patients, who were treated with a third induction dose, the clinical response rate at week 14 was 63.2%. The investigators concluded that patients who do not respond to 2 induction doses with vedolizumab IV appear to benefit from a third induction dose. The safety and tolerability profiles during the induction phase of these studies were consistent with previous reports.
References
1. Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the VISIBLE 1 phase 3 trial [UEG abstract LB03]. United European Gastroenterol J. 2018;6(8 suppl).
2. ClinicalTrials.gov. Efficacy and safety of vedolizumab subcutaneous (SC) as maintenance therapy in Crohn’s disease. https://clinicaltrials.gov/ct2/show/NCT02611817. Identifier: NCT02611817. Accessed April 8, 2019.
3. Rosario M, Polhamus D, Dirks N, et al. Exposure–response relationship of vedolizumab subcutaneous treatment in patients with ulcerative colitis: VISIBLE 1 [ECCO abstract P529]. J Crohns Colitis. 2019;13
(suppl 1).
4. Vermeire S, Krznarić Ž, Kobayashi T, et al. Effects of subcutaneous vedolizumab on health-related quality of life and work productivity in patients with ulcerative colitis: results from the phase 3 VISIBLE 1 trial [ECCO abstract P374]. J Crohns Colitis. 2019;13(suppl 1).
5. Loftus EV, Sandborn WJ, Wolf D, et al. Efficacy and safety of 2 or 3 vedolizumab intravenous infusions as induction therapy for ulcerative colitis and Crohn’s disease: results from VISIBLE 1 and 2 [ECCO abstract P499]. J Crohns Colitis. 2019;13(suppl 1).
Improved Endoscopic Outcomes and Mucosal Healing of Upadacitinib as an Induction Therapy in Adults With Moderately to Severely Active Ulcerative Colitis: Data From the U-ACHIEVE Study
The double-blind, placebo-controlled phase 2 U-ACHIEVE study was a dose-ranging trial that evaluated upada-citinib, an oral selective Janus kinase 1 inhibitor, in patients with moderately to severely active ulcerative colitis. Patients had exhibited an inadequate response, loss of response, or intol-erance to conventional treatment with corticosteroids, biologic agents, or immunosuppressants. The study randomly assigned 250 patients to 5 treatment arms, consisting of 4 different daily doses of upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg) or placebo. All patients had ulcerative colitis (confirmed by colonoscopy) diagnosed at least 90 days prior to baseline. Moderately to severely active ulcerative colitis was defined as an adapted Mayo score (which did not include the Physician’s Global Assessment) of 5 to 9 points, with an endoscopic subscore of 2 to 3.
Results from the primary analysis of the U-ACHIEVE trial were presented at the 2018 United European Gas-troenterology Week.1 Treatment with upadacitinib (at doses ≥30 mg/day) was associated with statistically significant improvements in all pri-mary and ranked secondary endpoints vs placebo. The safety profile and drug discontinuation rates were similar between the treatment arms. Adverse events of special interest were uncommon with upadacitinib (<5%), with the exception of lymphopenia, hepatic disorder, and creatine phos-phokinase elevation.
A report from Dr William J. Sandborn and colleagues provided data for endoscopic and histologic outcomes after induction therapy with upadacitinib in the U-ACHIEVE study.2 Endoscopic and histologic outcomes were assessed at week 8. Endoscopic improvement was defined as an endoscopic subscore of 1 or lower, and endoscopic remission was considered an endoscopic subscore of 0. Histologic improvement was defined as any decrease from baseline in the Geboes score, and histologic remission was defined as a Geboes score of less than 2. Mucosal healing was defined as an endoscopic subscore of 0 and a Geboes score of less than 2.
At week 8, rates of endoscopic impr-ovement were significantly higher across all upadacitinib doses vs placebo (Figure 5). Endoscopic improvement was seen in 35.7% of the 45-mg arm vs 2.2% of the placebo arm (P<.001). Rates of endoscopic remission were 0% in the placebo arm, vs 9.6% in the 30-mg arm (P<.05) and 17.9% in the 45-mg arm (P<.01).
Rates of histologic improvement at week 8 were significantly higher across all upadacitinib doses vs placebo. These rates were 51.0% with
15 mg, 44.2% with 30 mg, and 48.2% with 45 mg, vs 6.5% with placebo (P<.001). Histologic remission rates were 2.2% with placebo, vs 30.8% in the 30-mg arm (P<.001) and 41.1% in the 45-mg arm (P<.001).
There were no reports of mucosal healing among patients in the placebo group. In contrast, mucosal healing occurred with all of the upadacitinib doses, at rates of 2.1% with 7.5 mg, 2.0% with 15 mg, 5.8% with 30 mg, and 14.3% with 45 mg. These differences did not achieve statistical significance vs placebo. In a post hoc analysis that defined mucosal healing as an endoscopic subscore of 1 or lower and a Geboes score of less than 2, the rates rose to 25.0% with upadacitinib at 45 mg (vs 0% with placebo; P<.01), 13.5% with 30 mg, and 16.3% with 15 mg (P<.05 for both comparisons with placebo).
References
1. Sandborn WJ, Ghosh S, Panés J, et al. Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study U-ACHIEVE [UEG abstract OP195]. United European Gastroenterol J. 2018;6(8 suppl).
2. Sandborn WJ, Schreiber S, Lee SD, et al. Improved endoscopic outcomes and mucosal healing of upadacitinib as an induction therapy in adults with moderately to severely active ulcerative colitis: data from the U-ACHIEVE study [ECCO abstract OP14]. J Crohns Colitis. 2019;13(suppl 1).
Long-Term Safety of Vedolizumab in Ulcerative Colitis and Crohn’s Disease: Final Results From the GEMINI LTS Study
Dr Remo Panaccione presented the final results from the GEMINI LTS study (An Open-Label Study of Vedolizumab [MLN0002] in Participants With Ulcerative Colitis and Crohn’s Disease Long-Term Safety) of vedolizumab in ulcerative colitis and Crohn’s disease.1 GEMINI LTS was a multinational, multicenter, open-label phase 3 study conducted between May 2009 and October 2017. The study enrolled rollover patients from several studies: the phase 2 LTS (29 with ulcerative colitis and 8 with Crohn’s disease), GEMINI 1 (675 with ulcerative colitis), GEMINI 2 (726 with Crohn’s disease), and GEMINI 3 (384 with Crohn’s disease). The study also enrolled de novo patients with ulcerative colitis (n=190) or Crohn’s disease (n=231) who had not previously received treatment with vedolizumab. In GEMINI LTS, all patients received vedolizumab at 300 mg IV every 4 weeks. The primary endpoint of the study was long-term safety of vedolizumab in ulcerative colitis and Crohn’s disease. Long-term efficacy was an exploratory endpoint. Interim analyses of efficacy from the GEMINI studies in both ulcerative colitis and Crohn’s disease have previously been reported.2,3 Among patients with ulcerative colitis who responded to vedolizumab induction, the rates of remission were 88% after 104 weeks of treatment and 96% after 152 weeks.2 Among patients with Crohn’s disease with a response at week 6 in GEMINI 2 who received vedolizumab continuously, the remission rates were 83% after 104 weeks and 89% after 152 weeks.3
The investigators noted that this final analysis represented the longest study to date of continuous treatment with vedolizumab. A total of 894 patients with ulcerative colitis and 1349 patients with Crohn’s disease were included. For patients with ulcerative colitis, the mean age was 41.2 years, and the mean disease duration was 8.1 years. The mean partial Mayo score in patients with ulcerative colitis was 6.0. Among patients with ulcerative colitis, previous treatments consisted of corticosteroids in 97%, immunomodulators in 74%, and anti-TNF agents in 46%. For patients with Crohn’s disease, the mean age was 37.8 years, and the mean disease duration was 10.1 years. The mean Harvey-Bradshaw Index score was 1.9, and the mean Crohn’s Disease Activity Index (CDAI) score was 314.0. In patients with Crohn’s disease, prior treatments consisted of corticosteroids in 96%, immunomodulators in 86%, and anti-TNF agents in 67%. The median duration of exposure to vedolizumab was 43.0 months (range, 1 day to 113.7 months) in patients with ulcerative colitis and 31.9 months (range, 1 day to 101.7 months) in patients with Crohn’s disease.1
Among patients with ulcerative colitis, most adverse events were mild (18%) or moderate (50%) in severity. Severe events occurred in 24% of patients. An adverse event led 15% of patients with ulcerative colitis to discontinue treatment. The following adverse events were reported among this group: disease exacerbation (36% [105.2 incidence rate per 1000 patient-years]), nasopharyngitis (28% [93.9]), arthralgia (17% [51.6]), abdominal pain (12% [34.4]), upper respiratory tract infection (19% [55.7]), and headache (18% [55.5]). The rate of treatment-related adverse events in patients with ulcerative colitis was 40%.
Among patients with Crohn’s disease, most adverse events were mild (17%) or moderate (49%). A severe event occurred in 31% of patients with Crohn’s disease. A total of 17% of these patients discontinued treatment owing to an adverse event. The following adverse events were reported: disease exacerbation (35% [121.4 incidence rate per 1000 patient-years]), nasopharyngitis (25% [94.1]), arthralgia (24% [90.3]), abdominal pain (23% [80.0]), headache (21% [76.4]), and upper respiratory tract infection (16% [53.2]). The rate of treatment-related adverse events in patients with Crohn’s disease was 46%.
Disease exacerbation was the most frequent serious adverse event, occurring in 13% of patients with ulcerative colitis and 17% of patients with Crohn’s disease (Table 1). Treatment-related serious adverse events were reported in 4% of patients with ulcerative colitis and 6% of patients with Crohn’s disease. Four patients with ulcerative colitis and 6 patients with Crohn’s disease died during the study (a rate of 0.4% for each group).
Several adverse events of special interest were also examined. There were no cases of progressive multifocal leuko-encephalopathy in either group of patients. Serious infections occurred in 7% of patients with ulcerative colitis and 11% of patients with Crohn’s disease. The rate of Clostridium difficile infections was 1.7% vs 1.2%, respectively. Malignancies occurred in 6% vs 7%, infusion reactions in 4% vs 5%, and hepatic events in 3% vs 5%.
Rates of disease-related hos-pit-alization, surgery, or another pro-cedure (excluding colonoscopy) were 16.8% in the ulcerative colitis population and 28.1% in the Crohn’s disease population. Among all patients, 10.0% (224 of 2244) underwent surgery. Among the patients who underwent surgery, infectious complications occurred in 5 and serious complications in 10. Two of the serious complications were considered related to treatment.
Efficacy outcomes, an exploratory endpoint, were also briefly reported. The study investigators noted that the rates of clinical response and remission were similar in patients with ulcerative colitis or Crohn’s disease. Response and remission were maintained long-term in patients who continued to receive vedolizumab. The study investigators noted that these analyses were limited by protocol-defined patient loss to follow-up (eg, owing to market approval or expanded-access program availability).
The investigators concluded that these results supported the safety and tolerability of vedolizumab for the long-term treatment of IBD.1 Long-term use of vedolizumab did not increase the risk of clinically important safety concerns for patients with IBD, including progressive multi-focal leukoencephalopathy, seri-ous infections, or infusion react-ions. The rates of arthralgia were consistent with those previously reported in the pivotal GEMINI studies. Patients in the GEMINI LTS study showed evidence of continued efficacy with vedolizumab. These final data were consistent with the known safety profile of vedolizumab previously reported in published clinical trials and real-world studies.2-6
References
1. Vermeire S, Colombel J-F, Feagan BG, et al. Long-term safety of vedolizumab in ulcerative colitis and Crohn’s disease: final results from the GEMINI LTS study [ECCO abstract OP26]. J Crohns Colitis. 2019;13(suppl 1).
2. Loftus EV Jr, Colombel JF, Feagan BG, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 2017;11(4):400-411.
3. Vermeire S, Loftus EV Jr, Colombel JF, et al. Long-term efficacy of vedolizumab for Crohn’s disease. J Crohns Colitis. 2017;11(4):412-424.
4. Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.
5. 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.
6. Schreiber S, Dignass A, Peyrin-Biroulet L, et al. Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inflammatory bowel disease. J Gastroenterol. 2018;53(9):1048-1064.
Pediatric Crohn’s Disease Adalimumab Level–Based Optimization Treatment (PAILOT) Randomized Controlled Trial
Dr Amit Assa and coworkers presented the efficacy results from the PAILOT trial (Pediatric Crohn’s Disease Adalimumab Level-Based Optimization Treatment), a nonblinded, randomized controlled study of adalimumab among pediatric patients with Crohn’s disease.1 PAILOT aimed to determine whether rates of clinical remission were improved with proactive vs reactive measurement of drug levels. With the proactive strategy, therapeutic drug monitoring was used to maintain serum levels of adalimumab above 5 µg/mL. With the reactive strategy, drug levels were measured when clinically indicated. The primary endpoint was sustained corticosteroid-free clinical remission (Pediatric Crohn’s Disease Activity Index score <10) during the study period (weeks 8-72).
The study population consisted of 78 children (ages 6-17 years) with luminal Crohn’s disease. The patients had not received previous treatment with a biologic therapy. They had responded to adalimumab induction at week 4. The study randomly assigned patients into proactive and reactive groups. In the proactive group, trough adalimumab concentrations were measured at weeks 4 and 8, and then every 8 weeks thereafter until week 72. The dose of adalimumab was adjusted (when <40 mg) or treatment intervals were modified to maintain drug levels of 5 μg/-mL or higher. In the reactive group, physicians were informed of the trough levels only when clinically indicated, based on symptoms or elevated levels of C-reactive protein (CRP) or fecal calprotectin. The dose or treatment intervals of adalimumab were then adjusted based on the trough levels.
The rate of sustained cor-ti-costeroid-free remission (weeks 8-72) was 82% in the proactive group vs 48% in the reactive group (P<.01; Figure 6). The rate of a sustained CRP level of 0.5 mg/dL or lower (weeks 8-72) was 74% vs 57%, a difference that was not statistically significant (P=.11). A significant difference was seen with the rates of a sustained fecal calprotectin level of 150 µg/g or lower, at 47% in the proactive arm vs 22% in the reactive arm (P=.02). The composite outcome for these 2 measurements was 42% vs 12% (P=.003).
Proactive measurements reduced the risk for mild exacerbations, but not for moderate to severe exacerbations. The patients who underwent proactive measurement had a higher rate of adalimumab intensifications (primarily early in the study) and longer periods in which the defined adalimumab trough thresholds were exceeded. The overall rates of adverse events between the 2 groups were similar (13% in the proactive group and 15% in the reactive group).
The investigators noted limita-tions to the study, such as the non-blinded design and the lack of endoscopic assessment.1 They con-cluded that pediatric patients with Crohn’s disease undergoing treatment with adalimumab may benefit from proactive monitoring of trough adalimumab levels. However, they acknowledged that proactive monitoring had no significant effect on the rate of severe exacerbations. They concluded that intensification of adalimumab should be considered a standard strategy, particularly for early optimization of trough adalimumab concentrations.
Reference
1. Assa A, Matar M, Turner D, et al. Proactive adalimumab trough measurements increase corticosteroid-free clinical remission in paediatric patients with Crohn’s disease: the paediatric Crohn’s disease adalimumab-level-based optimisation treatment (PAILOT) trial [ECCO abstract OP18]. J Crohns Colitis. 2019;13(suppl 1).
Maintenance Treatment With Mirikizumab, a P19-Directed IL-23 Antibody: 52-Week Results in Patients With Moderately to Severely Active Ulcerative Colitis
Dr Geert R. D’Haens and colleagues presented the results of a phase 2 trial of maintenance treatment with mirikizumab, a humanized p19-directed interleukin (IL) 23 antibody.1 The study randomly assigned patients to receive placebo or mirikizumab at 1 of 3 doses: 50 mg with the possibility of exposure-based dose increases, 200 mg with the possibility of exposure-based dose increases, or 600 mg at a fixed dose. Data from the induction period of the study were previously reported, showing efficacy and tolerability at week 12 in patients with moderately to severely active ulcerative colitis.2 The rates of clinical remission were 4.8% with placebo compared with 15.9% in the 50-mg arm (P=.066), 22.6% in the 200-mg arm (P=.004), and 11.5% in the 500-mg arm (P=.142).
During the maintenance phase of the study, the objective was to determine the efficacy and safety of maintenance mirikizumab in patients who responded to 12 weeks of induction therapy.1 Endpoints were measured at week 52. At week 12, patients (n=93) who responded to induction therapy were randomly assigned to maintenance treatment with mirikizumab at 200 mg every 12 weeks (q12w) or every 4 weeks (q4w). Baseline demographics were balanced between these 2 arms. Notably, no prior biologic therapy exposure was reported in 50.0% of the q12w arm and 44.7% of the q4w arm. One prior biologic therapy was reported in 37.0% vs 25.5%. At -baseline, concomitant therapies included 5-aminosalicylate acid (87.0% in the q12w arm vs 78.7% in the q4w arm), corticosteroids (41.3% vs 46.8%), and thiopurines (19.6% vs 31.9%).
The rate of clinical remission at week 52 was 37.0% with mirikizumab q12w and 46.8% with mirikizumab q4w (Figure 7). A subgroup analysis evaluated outcome according to prior treatment with a biologic therapy. The rates of clinical remission were 36.0% in the q12w arm vs 47.8% in the q4w arm among the biologic-naive patients and 38.1% vs 46.2%, respectively, among those previously treated with biologic therapy. The rates of clinical remission at both weeks 12 and 52 were 38.5% in the q12w arm and 61.6% in the q4w arm. Among patients with a clinical response at week 12, the rates of clinical remission at week 52 were 36.4% in the q12w arm and 37.9% in the q4w arm.
Endoscopic healing was seen in 47.8% of the q12w arm and 57.4% of the q4w arm. Endoscopic remission was reported in 28.3% vs 14.9%.
A treatment-emergent adverse event occurred in 67.4% of patients in the q12w arm and 76.6% of patients in the q4w arm. The most common of these events in the q12w arm consisted of nasopharyngitis (15.2%), worsening of ulcerative colitis (15.2%), and headache (6.5%). Arthralgia (12.8%), nasopharyngitis (10.6%), headache (10.6%), and upper respiratory tract infections (10.6%) were the most common treatment-emergent adverse events in the q4w arm. Adverse events led to treatment discontinuation in 2.2% of the q12w arm and no patients in the q4w arm.
References
1. D’Haens GR, Sandborn WJ, Ferrante M, et al. Maintenance treatment with mirikizumab, a p19-directed IL-23 antibody: 52-week results in patients with moderately-to-severely active ulcerative colitis [ECCO abstract OP38]. J Crohns Colitis. 2019;13(suppl 1).
2. Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of anti-interleukin-23 therapy with mirikizumab (LY3074828) in patients with moderate-to-severe ulcerative colitis in a phase 2 study [DDW abstract 882]. Gastroenterology. 2018;154(6 suppl 1).
Real-World Effectiveness and Safety of Vedolizumab and Anti-TNF Therapy in Biologic-Naive Patients With Ulcerative Colitis or Crohn’s Disease: Results From the EVOLVE Study
Two studies reported out-comes from EVOLVE, a multi-coun-try, multicenter, ret-ro-spective chart review study that evaluated the real-world safety and efficacy of vedolizumab and anti-TNF agents. Patients in the study were naive to biologic therapy at initiation of vedolizumab or anti-TNF therapy during the eligibility period (May 2014 to July 2017) and had at least 6 months of follow-up data.1,2
Dr Andres Yarur and colleagues reported on outcomes among patients with ulcerative colitis in the EVOLVE study.3 Among the 527 patients with ulcerative colitis, 325 initiated treatment with vedolizumab and 202 with an anti-TNF agent. Throughout the first 24 months of treatment, 75.1% of the vedolizumab group remained on treatment vs 53.8% of the anti-TNF therapy group (P<.01). The most common reasons for treatment discontinuation included primary nonresponse (11.1% for vedolizumab vs 16.3% for anti-TNF therapy) and secondary loss of response (8.4% vs 9.4%). A dose escalation in the initial 24 months of treatment was required by 24.7% of the vedolizumab group vs 30.5% of the anti-TNF therapy group (unadjusted P<.05).
Among evaluable patients, clinical outcomes at 24 months were similar between the treatment groups. A clinical response was seen in 90.8% of the vedolizumab arm and 85.7% of the anti-TNF therapy arm (P=.82). Rates of clinical remission were 79.0% vs 66.2% (P=.37). Mucosal healing occurred in 92.0% vs 84.4% (P=.67). After adjustment for baseline confounders, there were no significant differences in these clinical outcomes. After adjustment, disease exacerbation was less common with vedolizumab vs the anti-TNF therapy (HR, 0.7; 95% CI, 0.5-0.9). However, the rate of colectomies did not differ between the treatment groups.
After adjustment for baseline confounders, serious adverse events were less common with vedolizumab vs anti-TNF therapy (HR, 0.5; 95% CI, 0.3-0.8). The most frequent serious adverse event was anemia in the vedolizumab arm (12.0%) and pain in the anti-TNF therapy arm (12.0%). The rates of serious infections were similar between the treatment groups.
Dr Brian Bressler and colleagues reported on patients with Crohn’s disease in the EVOLVE study.4 Among the 419 patients with Crohn’s disease, 177 initiated treatment with vedolizumab and 242 began treatment with an anti-TNF agent. More patients in the vedolizumab arm remained on treatment at 12 months (85.6% vs 76.0% in the anti-TNF arm; P=.02) and 18 months (78.8% vs 70.2%; P=.04). At 24 months, the difference was not statistically significant (71.4% vs 70.7%; P=.11). The most common reasons for treatment discontinuation with vedolizumab were primary nonresponse (9.0%) and secondary loss of response (4.0%). Among patients in the anti-TNF agent arm, the primary reasons for treatment discontinuation were nonserious adverse events (6.7%) and primary nonresponse (4.6%). Throughout a 24-month period, the cumulative probability for dose escalation was similar for patients treated with vedolizumab or an anti-TNF agent.
A comparison of clinical out-comes at 12, 18, and 24 months is shown in Figure 8. Clinical outcome at 24 months was similar between the treatment groups. A clinical response was seen in 74.5% of the vedolizumab arm vs 73.4% of the anti-TNF therapy arm. A clinical remission occurred in 69.7% vs 66.4% (P=.80). Mucosal healing was reported in 100% vs 90.1% (P=.82). After adjustment for baseline confounders, there were no significant differences in these clinical outcomes.
There were no significant diff-erences in the rates of disease exa-cerbation or disease-related surgery between the groups after adjustment for baseline confounders. Rates of serious adverse events and serious infections were not significantly different after adjustment. Among vedolizumab-treated patients, the most common serious adverse event was small bowel obstruction (28.6%). Among patients who received an anti-TNF agent, gas-trointestinal (GI) infection (17.0%) was the most frequent ser-ious adverse event.
References
1. Bressler B, Bassell M, Stein D, et al. Vedolizumab outcomes in real-world bio-naive ulcerative colitis and Crohn’s disease patients (EVOLVE) in Canada: treatment patterns, clinical effectiveness and safety [UEG abstract P0353]. United European Gastroenterol J. 2018;6(8 suppl).
2. Yarur A, Bassell M, Stein D, et al. Vedolizumab outcomes in real-world bio-naive ulcerative colitis and Crohn’s disease patients (EVOLVE) in North America [ACG abstract P1356]. Paper presented at: the American College of Gastroenterology Annual Scientific Meeting; October 5-10, 2018; Philadelphia, PA.
3. Yarur A, Mantzaris G, Silverberg M, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naïve ulcerative colitis patients: results from the EVOLVE study [ECCO abstract P573]. J Crohns Colitis. 2019;13(suppl 1).
4. Bressler B, Mantzaris G, Silverberg M, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naïve Crohn’s disease patients: results from the EVOLVE study [ECCO abstract P621]. J Crohns Colitis. 2019;13(suppl 1).
A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of a Targeted-Release Oral Cyclosporine Formulation in the Treatment of Mild to Moderate Ulcerative Colitis: Efficacy Results
Dr Stuart Bloom and coworkers reported on the preliminary res-ults from a randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the benefit of a targeted-release oral cyclosporine formulation in patients with mild-to-moderate ulcerative colitis.1 This novel formulation, known as ST-0529, incorporates polymer-coated multiparticulate beads and is designed for the targeted release of the cyclosporine drug in the ileum and colon to avoid systemic absorption. A phase 1 dose-ranging study determined that twice daily dosing of ST-0529 improved colonic tissue concentrations of cyclosporine.2
The study by Dr Bloom included 118 patients with a baseline modified Ulcerative Colitis Disease Activity Index (mUCDAI) of 4 to 10 and a diagnosis of either mild (mUCDAI score <6) or moderate (mUCDAI score ≥6) disease.1 Exclusion criteria included severe or fulminant ulcerative colitis and rectum-limited disease. Patients were also excluded if they had received treatment with topical therapies, corticosteroids at 10 mg/day or higher within the 4 weeks before study initiation, or biologic therapies in the 2 months before the start of the study. Treatment with concomitant medications was permitted. At baseline, the mean total patient mUCDAI score was 7.2 ±1.81 in the ST-0529 arm vs 7.5 ±1.72 in the placebo arm. The mean disease duration was 6.14 ±5.47 years vs 9.60 ±7.51 years, respectively.
All patients received 4 weeks of treatment with ST-0529 (75 mg/day) or placebo. The study design included reassessment during a follow-up visit at week 8. The primary study endpoint was clinical remission, defined as an mUCDAI score of 2 or lower, with no individual score higher than 1 and a rectal bleeding subscore of 0 or 1. Secondary study endpoints included clinical response, mucosal and histologic healing, and safety and tolerability. Clinical response was defined as a reduction in the mUCDAI score of 3 or higher at week 4, with a decrease in the rectal bleeding subscore of 1 or more or with an absolute rectal bleeding subscore of 0 or 1.
At the time of this preliminary analysis, the rates of study discon-tinuation were 18.9% with ST-0529 vs 35.4% with placebo. Among patients in the ST-0529 arm, the primary reasons for discontinuation were an adverse event (11.3%) and lack of efficacy (7.5%). In the placebo arm, more patients discontinued owing to an adverse event (24.6%), and a similar proportion discontinued owing to a lack of efficacy (7.7%).
In the overall population, clin-ical remission occurred in 13.2% of the ST-0529 arm vs 6.3% of the placebo arm; this difference was not statistically significant (P=.2175). The rate of response was 30.2% with ST-0529 vs 18.5% with placebo, but this difference was also not statistically significant (P=.1915; Figure 9). A post hoc analysis examined response among the 93 patients with moderate disease. The response rate was 35.0% with ST-0529 vs 17.0% with placebo (P=.0499).
Adverse events deemed treatment-related as well as treatment-emergent occurred in 20.8% of the ST-0529 arm vs 27.7% of the placebo arm. Treatment-emergent serious adverse events occurred in 9.4% vs 7.7%.
The investigators mentioned sev-eral limitations to this study, including an imbalance in the ran-domization of patients between the placebo and ST-0529 arms and the short duration of treatment (4 weeks). No data were collected at the week 8 follow-up. There was early discontinuation within the first 2 weeks of the study. The investigators further noted that the formulation of ST-0529 has since been optimized, and a new formulation of the drug is under evaluation in an ongoing phase 2 trial.3
References
1. Bloom S, Iqbal T, Nwokolo C, et al. A randomised, multi-centre, double-blind, placebo-controlled study of a targeted release oral cyclosporine formulation in the treatment of mild-to-moderate ulcerative colitis: efficacy results [ECCO abstract OP16]. J Crohns Colitis. 2019;13(suppl 1).
2. ClinicalTrials.gov. PK, safety & tolerability of CyCol® versus Sandimmune® in healthy subjects (CYC102). https://clinicaltrials.gov/ct2/show/NCT02130414. Identifier: NCT02130414. Accessed April 2, 2019.
3. ClinicalTrials.gov. A study evaluating the efficacy and safety of ST-0529 in subjects with moderately to severely active ulcerative colitis. https://clinicaltrials.gov/ct2/show/NCT03844932. Identifier: NCT03844932. Accessed April 4, 2019.
Real-World Analyses of IBD Patients Treated With Vedolizumab
A retrospective study compared treatment patterns and health care resource utilization among biologic-naive patients with IBD initiating treatment with infliximab or vedolizumab in the United States.1 The observational analysis included 1068 patients with IBD, of whom 27.3% were treated with vedolizumab and 72.7% with infliximab. At 12 months, the rates of treatment persistence were 86.8% with vedolizumab vs 77.7% with infliximab (P=.0099). Similar results were observed at 24 months, at 79.6% vs 62.4% (P=.0006). Among patients with ulcerative colitis, the rate of treatment persistence at 24 months was 81.5% with vedolizumab vs 65.4% with infliximab, a difference that was not statistically significant (P=.1354). A significant difference was seen for treatment persistence among patients with Crohn’s disease, at 78.1% vs 66.0% (P=.0437). Overall, the rate of increased dosing frequency was 8.4% with vedolizumab vs 14.4% with infliximab (P=.05) at 12 months, and 15.5% vs 20.8% (P<.0470) at 24 months (Figure 10). The rate of increased dosing frequency at 24 months was highest among patients with ulcerative colitis treated with infliximab, at 24.1% (vs 10.9% in the vedolizumab arm). Among patients with Crohn’s disease, the rate of increased dosing frequency at 24 months was 17.9% in the infliximab arm vs 18.5% in the vedolizumab arm. The 24-month rates of health care resource utilization were 54.0% with vedolizumab vs 58.9% with infliximab (P=.0457).
A retrospective cohort study from Singapore analyzed patients treated with vedolizumab.2 Among the 25 patients with ulcerative colitis, the rates of corticosteroid-free clinical remission at weeks 14, 24, and 54 were 68.0%, 66.7%, and 80.0%, respectively. Among the 28 patients with Crohn’s disease, these rates were 42.9%, 45.0%, and 46.2%. After a median treatment duration of 31 weeks, endoscopic remission was reported in 35.3% of patients with ulcerative colitis and 30.8% of patients with Crohn’s disease. The radiologic remission rate (documented in Crohn’s disease only) was 22.2%. Treatment was discontinued by 7 patients with Crohn’s disease and 6 with ulcerative colitis. An adverse event occurred in 47.2% of patients. The most common adverse event was infection (37.7%). No malignancies or deaths were reported.
A prospective cohort study from Korea evaluated patients with either Crohn’s disease or ulcerative colitis who initiated treatment with vedolizumab after an inadequate response to anti-TNF therapy.3 The co–primary outcomes of the study were corticosteroid-free clinical remission at week 14 (for both ulcerative colitis and Crohn’s disease patients) and endoscopic remission and response at weeks 53 to 57 (for ulcerative colitis patients).
Among the 18 patients with ulcerative colitis, at week 14, the rate of corticosteroid-free clinical remission was 16.7%, and the rate of corticosteroid-free clinical response was 38.9%. In the 35 patients with Crohn’s disease, these rates were 38.9% and 33.3%, respectively. At weeks 53 to 57, the rates of corticosteroid-free clinical remission were 28.6% in patients with ulcerative colitis and 60.0% in those with Crohn’s disease. The rates of corticosteroid-free clinical response were 42.9% and 60.0%. Among patients with ulcerative colitis, the Mayo Endoscopic Score–defined endoscopic remission rate at weeks 53 to 57 was 33.3%, and the Mayo Endoscopic Score–defined endoscopic response rate was 50%.
A serious adverse event occurred in 30.2% of the cohort, and 15.1% discontinued vedolizumab owing to a poor response. Adverse events included nasopharyngitis (24.5%), arthralgia (22.6%), and headache (22.6%).
References
1. Latremouille-Viau D, Burne R, Shi S, Adsul S, Patel H. Comparison of real-world treatment outcomes with infliximab vs. vedolizumab in biologic-naïve patients with inflammatory bowel disease [ECCO abstract P379]. J Crohns Colitis. 2019;13(suppl 1).
2. Gan ATM, Chan WPW, Ling KL, et al. Real-world data on the efficacy and safety of vedolizumab therapy in patients with inflammatory bowel disease: a retrospective nation-wide cohort study in Singapore [ECCO abstract P634]. J Crohns Colitis. 2019;13(suppl 1).
3. Kim J, Ham NS, Oh EH, et al. Real life effectiveness and safety of vedolizumab induction and maintenance therapy for Korean IBD patients in whom anti-TNF treatment failed: a prospective cohort study [ECCO abstract P277]. J Crohns Colitis. 2019;13(suppl 1).
Highlights in IBD From the 14th Congress of ECCO: Commentary
Edward V. Loftus Jr, MD
Presentations at the 14th Congress of the European Crohn’s and Colitis Organisation (ECCO) provided important, practice-changing insights into the management of inflammatory bowel disease (IBD).
Vedolizumab
In many ways, the phase 3b VARSITY trial of vedolizumab vs adalimumab was the most important study presented at the congress. Dr Stefan Schreiber and colleagues provided the results of this late-breaking abstract.1 VARSITY is the first trial to compare 2 biologic therapies for IBD. Previously, when evaluating data for biologic therapies, it was necessary to rely on cross-trial comparisons or network meta-analyses. Head-to-head, randomized controlled trials provide the highest level of evidence when comparing treatments. VARSITY used a “treat-straight-through” design; in other words, patients were not reassigned to a different treatment arm. All patients continued treatment with their initial therapy, so this trial was more rigorous than those that permit patients to cross over to a different treatment. Results favored vedolizumab over adalimumab for the primary endpoint of clinical remission. These rates were 31.3% for vedolizumab vs 22.5% for adalimumab (P=.0061). Vedolizumab also improved a major secondary endpoint, “mucosal healing” or endoscopic improvement. These rates were 39.7% with vedolizumab vs 27.7% with adalimumab (P=.0005). (The study used the term “mucosal healing.” However, the better current term is “endoscopic improvement,” because the US Food and Drug Administration [FDA] has now suggested that the term “mucosal healing” should not be used to describe an endoscopic endpoint without an accompanying histologic endpoint.2) The rates of adverse events were approximately the same for both treatments. Numerically, there were fewer overall infections with vedolizumab. Results from the VARSITY trial will likely influence many practitioners. Vedolizumab appears to have moderate superiority vs adalimumab in ulcerative colitis, and it should be considered a first-line biologic therapy.
The GEMINI LTS study evaluated long-term safety results with vedolizumab.3 In the GEMINI 1 and GEMINI 2 trials, vedolizumab was shown to be effective for Crohn’s disease and ulcerative colitis.4,5 This study of long-term safety included patients who “rolled over” from multiple vedolizumab clinical trials, as well as de novo patients with IBD. Patients were treated with an every-4-week regimen. Some patients had been receiving treatment for up to 5 years. The final results of the study showed that vedolizumab was both safe and effective, and that many of the patients were able to continue treatment for an extended period. The annualized rates of serious adverse events were approximately 9% among patients with ulcerative colitis and 14.6% among those with Crohn’s disease; however, rates were much lower when limiting the serious adverse events to those that the investigators deemed related to treatment. The annualized rate of serious infections was 1.8% among ulcerative colitis patients and 3.4% among Crohn’s disease patients, and there were no cases of progressive multifocal leukoencephalopathy. There were 2 deaths that were deemed by the investigators to be treatment-related (from West Nile virus encephalitis and hepatocellular carcinoma). Overall, this long-term study showed that vedolizumab has a favorable safety profile with good efficacy.
A post hoc analysis of the GEMINI trials focused on whether early disease control with vedolizumab impacts rates of surgery.6 This analysis was based on data from the GEMINI-2 and GEMINI LTS studies.3,5 Results were stratified according to disease duration. A previously developed clinical decision support tool had been shown to be somewhat predictive of whether a patient with Crohn’s disease would respond to vedolizumab.7 Surgical rates were twice as high among patients with a low probability of response to vedolizumab vs those with a high probability of response (12.9% vs 6.0%). Among patients with a low probability of response, using a cutoff of 5 years’ disease duration, those patients with a shorter duration of disease before treatment had lower rates of surgery than patients with a longer duration. Therefore, among patients with a shorter duration of disease, it may be possible to use vedolizumab regardless of what their predicted probability of response appears to be at baseline.
The VISIBLE trials evaluated whether vedolizumab would be effective when administered as a subcutaneous formulation; the top-line results were presented at the 2018 United European Gastroenterology (UEG) Week.8 The patients began treatment with 2 doses of open-label intravenous vedolizumab at weeks 0 and 2. At week 6, patients with a clinical response were randomly assigned to maintenance treatment with the intravenous formulation at 300 mg every 3 weeks, the subcutaneous formulation at 108 mg every 2 weeks, or a matching placebo. Results presented at earlier meetings showed that subcutaneous administration was equivalent to intravenous administration in regard to efficacy and safety.8 An analysis by Dr Séverine Vermeire and colleagues evaluated quality of life and work productivity among patients with ulcerative colitis.9 The analysis showed significant improvements with vedolizumab, both subcutaneous and intravenous, compared with placebo for the Inflammatory Bowel Disease Questionnaire, the EuroQol 5D Visual Analogue Scale, and the Work Productivity and Activity Impairment questionnaire. These data provide secondary evidence of the benefits associated with vedolizumab. Patients’ quality of life was improved, and they were able to go back to work.
I was the first author on an abstract that assessed response to 2 or 3 doses of open-label intravenous vedolizumab.10 Patients underwent evaluation at week 6. There was no placebo control because the analysis took place before patients were randomly assigned to therapy, when the treatment consisted of open-label intravenous vedolizumab. The overall response rates at week 6 were 56% in patients with ulcerative colitis and 64% in those with Crohn’s disease. Among patients who received a third intravenous infusion, these rates were even higher, at 79% and 63%. After 2 or 3 infusions, a clinical response was seen in 86% of patients with ulcerative colitis and 82% of those with Crohn’s disease. These data show that vedolizumab is effective, and that the drug begins to work by week 6 in many patients. Among patients without a clinical response at week 6, another dose at this time can lead to a response by week 14.
The EVOLVE study retrospectively examined real-world data for patients with ulcerative colitis treated with vedolizumab or anti–tumor necrosis factor (TNF) therapy.11 Approximately 3 and a half years of data on efficacy and safety were gathered from 37 different centers. Patients had not received previous treatment with biologic therapy. The EVOLVE study was not a head-to-head trial, but it does provide some insights. There were differences between the 2 groups. Patients treated with anti-TNF agents were somewhat younger, and they had a shorter disease duration. They had higher levels of C-reactive protein. There were more hospitalizations among patients with ulcerative colitis in the anti-TNF–treated group. However, rates of overall response, remission, and mucosal healing were similar in both groups. The rate of treatment persistence (meaning the duration of treatment) was higher among patients treated with vedolizumab vs anti-TNF therapy. At 24 months, 75.1% of patients continued treatment with vedolizumab vs 53.8% with anti-TNF therapy (P<.01). Patients treated with vedolizumab were significantly less likely than the anti-TNF–treated patients to develop exacerbation of ulcerative colitis (28.3% vs 43.9%) or serious adverse events (4.9% vs 10.4%). These real-world data therefore suggest that the efficacy of vedolizumab is equivalent, or even slightly superior, to that of anti-TNF agents. In terms of safety, vedolizumab is better than the anti-TNF agents. The EVOLVE study suggests that vedolizumab can be used as a first-line biologic agent for ulcerative colitis.
A separate analysis of the EVOLVE study evaluated patients with Crohn’s disease who had not yet received treatment with a biologic therapy.12 Treatment persistence was better with vedolizumab than anti-TNF therapy at 12 months, but there were no differences at 18 and 24 months. The rates of exacerbation of Crohn’s disease and of surgeries, serious adverse events, and infections related to Crohn’s disease were numerically lower with vedolizumab, but the differences were not statistically significant. These data again show that vedolizumab is comparable to anti-TNF agents and therefore should be considered a reasonable treatment choice in biologic-naive patients. In my own practice, when treating a Crohn’s disease patient with fistulizing disease, I would choose an anti-TNF agent first because there are more data supporting the efficacy of this approach.13 However, in a patient with luminal inflammatory disease, vedolizumab is a reasonable option.
Ustekinumab
The UNIFI trial evaluated ustekinumab in patients with ulcerative colitis. Data from the induction phase, presented at the 2018 UEG Week, were positive for the 2 regimens tested.14 Dr William J. Sandborn and colleagues presented data from the maintenance phase.15 The responders in UNIFI were randomly assigned to treatment with either placebo or ustekinumab at subcutaneous doses of 90 mg administered every 12 weeks or every 8 weeks. The primary endpoint, clinical remission (Mayo score, ≤2; with no subscore >1) at week 44, was met. Both doses of ustekinumab significantly improved clinical remission vs placebo; the difference between ustekinumab and placebo ranged from 14% to 19%, which is reasonable. Ustekinumab also significantly improved secondary endpoints, such as clinical response and endoscopic improvement. (I would not characterize this improvement as “endoscopic healing.”) The FDA is currently evaluating ustekinumab for ulcerative colitis.
A French multicenter study evaluated patients with Crohn’s disease treated with ustekinumab who required dose escalation to 90 mg every 4 weeks because of incomplete clinical response or loss of response.16 In more than half of patients, this dose escalation was able to recapture clinical response in the short-term, and it was safe. This strategy is off-label, but it may provide a good option for patients with refractory Crohn’s disease.
Novel Treatments
Dr William J. Sandborn presented the results of a secondary analysis of the induction data for U-ACHIEVE, a trial of upadacitinib in ulcerative colitis.17 Upadacitinib is a second-generation Janus kinase (JAK) inhibitor. The first JAK inhibitor in IBD was tofacitinib for ulcerative colitis. Tofacitinib inhibits JAK1 and JAK3, and, to a lesser extent, JAK2. In contrast, upadacitinib is a selective JAK1 inhibitor. Theoretically, this specificity might translate into better safety and efficacy outcomes. A previous phase 2 trial in Crohn’s disease suggested that upadacitinib was superior to placebo.18 The U-ACHIEVE trial is the first study of upadacitinib in ulcerative colitis. The top-line induction results were presented at the 2018 UEG Week.19 At ECCO this year, Dr Sandborn presented the endoscopic and histologic data.17 The top 2 doses of upadacitinib, 45 mg/day and 30 mg/day, were associated with statistically significant improvements vs placebo for several endoscopic outcomes, including improvement (Mayo endoscopic subscore, 0-1) and remission (Mayo endoscopic subscore, 0). The top 3 doses of upadacitinib, 45 mg/day, 30 mg/day, and 15 mg/day, were associated with statistically significant higher rates of histologic improvement (any decrease from baseline in the Geboes score) and histologic remission (Geboes score, <2). This study incorporated the new definition of mucosal healing as consisting of both endoscopic improvement and histologic remission. The mucosal healing endpoint was significantly higher for the top 2 doses of upadacitinib (25% and 13.5%, vs 0% for placebo). These data corroborate the clinical remission data, which were also positive. Endoscopic and histologic improvements are more objective markers of improvement than symptoms. Overall, the data from this study suggest that upadacitinib has efficacy for ulcerative colitis. Results for maintenance treatment are forthcoming. It will be helpful to have a drug with yet another mechanism of action for both ulcerative colitis and Crohn’s disease.
Mirikizumab is one of many interleukin (IL)-23 antibodies in development for IBD; the others include risankizumab and brazikumab. In comparison to ustekinumab, which blocks both IL-12 and IL-23,20 mirikizumab blocks only IL-23. It may therefore have different efficacy or safety. In a trial of patients with psoriasis, the anti–IL-23 antibody risankizumab was superior to ustekinumab.21 The anti–IL-23 antibodies appear to be safe. They do not have any black box warnings.
Dr Geert R. D’Haens and colleagues presented results from a phase 2 trial of mirikizumab as maintenance treatment.22 Results from the induction phase of the trial were presented at the 2018 Digestive Disease Week.23 This trial is the first to evaluate an IL-23 antibody in ulcerative colitis. This analysis included 93 patients who responded to treatment and continued on the study. They were randomly assigned to 200 mg administered subcutaneously every 12 weeks or every 4 weeks. At week 52, between 37% and 46% of patients were in clinical remission. There were no substantial differences in remission rates between biologic-naive and biologic-experienced patients. The clinical response rate was even higher, at 70% to 80%. Endoscopic improvement ranged from 48% to 57%. Mirikizumab was well-tolerated, with few serious adverse events (3.2% overall). Based on the results of this trial, mirikizumab will be evaluated in a phase 3 development program. Potentially, IL-23 antibodies will provide another mechanism of action in the treatment armamentarium for IBD.
Disclosure
Dr Loftus has consulted for Eli Lilly, Janssen, Takeda, Pfizer, AbbVie, UCB, Amgen, Celltrion Healthcare, Celgene, Allergan, Bristol-Myers Squibb, Gilead, Boehringer Ingelheim, and Genentech. He has also received research support from Janssen, Takeda, Pfizer, AbbVie, UCB, Amgen, Genentech, Celgene, Gilead, MedImmune, Seres Therapeutics, and Robarts Clinical Trials.
References
1. Schreiber S, Peyrin-Biroulet L, Loftus EV, et al. VARSITY: a double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis [ECCO abstract OP34]. J Crohns Colitis. 2019;13(suppl 1).
2. Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry. US Food and Drug Administration. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM515143.pdf. Posted August 2016. Accessed April 15, 2019.
3. Vermeire S, Colombel J-F, Feagan BG, et al. Long-term safety of vedolizumab in ulcerative colitis and Crohn’s disease: final results from the GEMINI LTS study [ECCO abstract OP26]. J Crohns Colitis. 2019;13(suppl 1).
4. Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.
5. 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.
6. Dulai P, Peyrin-Biroulet L, Hahn K, et al. The impact of early disease control with vedolizumab on surgery rates among patients with Crohn’s disease: a post hoc analysis of the GEMINI trials [ECCO abstract P537]. J Crohns Colitis. 2019;13(suppl 1).
7. Dulai PS, Boland BS, Singh S, et al. Development and validation of a scoring system to predict outcomes of vedolizumab treatment in patients with Crohn’s disease. Gastroenterology. 2018;155:687-695.e10.
8. Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the VISIBLE 1 phase 3 trial [UEG abstract LB03]. United European Gastroenterol J. 2018;6(8 suppl).
9. Vermeire S, Krznarić Ž, Kobayashi T, et al. Effects of subcutaneous vedolizumab on health-related quality of life and work productivity in patients with ulcerative colitis: results from the phase 3 VISIBLE 1 trial [ECCO abstract P374]. J Crohns Colitis. 2019;13(suppl 1).
10. Loftus EV, Sandborn WJ, Wolf D, et al. Efficacy and safety of 2 or 3 vedolizumab intravenous infusions as induction therapy for ulcerative colitis and Crohn’s disease: results from VISIBLE 1 and 2 [ECCO abstract P499]. J Crohns Colitis. 2019;13(suppl 1).
11. Yarur A, Mantzaris G, Silverberg M, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naïve ulcerative colitis patients: results from the EVOLVE study [ECCO abstract P573]. J Crohns Colitis. 2019;13(suppl 1).
12. Bressler B, Mantzaris G, Silverberg M, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naïve Crohn’s disease patients: results from the EVOLVE study [ECCO abstract P621]. J Crohns Colitis. 2019;13(suppl 1).
13. Adegbola SO, Sahnan K, Warusavitarne J, Hart A, Tozer P. Anti-TNF therapy in Crohn’s disease. Int J Mol Sci. 2018;19(8). pii:E2244. doi:10.3390/ijms19082244.
14. Sands BE, Sandborn WJ, Panaccione R, et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the phase 3 UNIFI study [UEG abstract 54A]. United European Gastroenterol J. 2018;6(8 suppl).
15. Sandborn WJ, Sands BE, Panaccione R, et al. Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI [ECCO abstract OP37]. J Crohns Colitis. 2019;13(suppl 1).
16. Fumery M, Peyrin-Biroulet L, Nancey S, et al. Effectiveness and safety of ustekinumab 90 mg every 4 weeks in Crohn’s disease [ECCO abstract OP24]. J Crohns Colitis. 2019;13(suppl 1).
17. Sandborn WJ, Schreiber S, Lee SD, et al. Improved endoscopic outcomes and mucosal healing of upadacitinib as an induction therapy in adults with moderately to severely active ulcerative colitis: data from the U-ACHIEVE study [ECCO abstract OP14]. J Crohns Colitis. 2019;13(suppl 1).
18. Panes J, Sandborn WJ, Loftus Jr EV, et al. Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: results from the CELEST study [ECCO abstract P273]. J Crohns Colitis. 2018;12(suppl 1).
19. Sandborn WJ, Ghosh S, Panés J, et al. Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study U-ACHIEVE [UEG abstract OP195]. United European Gastroenterol J. 2018;6(8 suppl).
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