Data from Stephen Smith - Curated by EPG Health - Last updated 30 October 2018
Real-world insights into current IBD treatment
In recent years, the range of available biologics for the treatment of inflammatory bowel disease (IBD) has expanded beyond the anti-TNF therapies to include inhibitors of IL-12/23 and integrin α4β7. While the clinical trials demonstrated the efficacy of these agents in ulcerative colitis and/or Crohn’s disease, it is apparent that patients enrolled into clinical trials are not representative of the general patient population. Real-world evidence offers the chance to fill this gap and provide insights into how these treatments perform in everyday clinical practice. In today’s article we review some of the real-world data shared at UEG Week on vedolizumab and ustekinumab, as well as comparison of the originator and biosimilar versions of infliximab.
Real-world effectiveness of vedolizumab
The integrin α4 521; 93% previously received an anti-TNF therapy), 62% of patients responded to treatment and 47% were in remission at Week 14 (defined with the Harvey Bradshaw Index (HBI) for Crohn’s disease and the Partial Mayo Score for ulcerative colitis). Interestingly, multivariate analysis to identify factors associated with impairing vedolizumab response included having Crohn’s disease versus ulcerative colitis (OR = 0.3; 95% CI, 0.3–0.9), higher C-reactive protein (CRP) at baseline (OR = 0.9; 95% CI, 0.8–0.9), previous intestinal resection (OR = 0.4; 95% CI, 0.3–0.9) and mild versus severe disease at baseline (OR = 8; 95% CI, 4–16).
The long-term effectiveness of vedolizumab was assessed in 307 patients who had at least responded to induction therapy. After a median follow-up of 13 months, 25.7% of patients had discontinued vedolizumab with 70% of these being due to a loss of response. The discontinuation rate of 22% per patient-year translated into 81% of patients remaining on vedolizumab at 12 months, 60% at 24 months and 38% at 36 months. While a reasonable number of patients discontinued treatment over time, only 7% of patients reported adverse events and just 3% discontinued due to adverse events.
The Spanish registry demonstrated that in a largely refractory cohort of IBD patients, vedolizumab could induce a response in a substantial number of patients. However, it also suggested that patients with ulcerative colitis might respond more effectively than those with Crohn’s disease; is this the case in other cohorts? Dr Ulf Helwig from Oldenburg in Germany presented two posters describing a retrospective chart review from 15 German sites that identified patients with ulcerative colitis or Crohn’s disease who had been treated with vedolizumab or an anti-TNF between July 2014 and October 2015.
For patients with ulcerative colitis, 76 were identified who received vedolizumab (29% biologic-naïve) while 57 had received an anti-TNF (70% biologic-naïve; 12, 14 and 31 patients received adalimumab, golimumab and infliximab, respectively). Despite the vedolizumab group having a higher proportion of refractory patients, more patients met the defined outcomes (figure 1). While the differences observed didn’t meet statistical significance (log-rank test; clinical remission p=0.081; rectal bleeding p=0.066; stool frequency p=0.411), this could be a consequence of the relatively small number of patients in the study.
Figure 1: Percentage of patients with ulcerative colitis achieving clinical remission, rectal bleeding resolution and stool frequency resolution following treatment with vedolizumab or an anti-TNF therapy after 6, 14 and 26 weeks. Clinical remission, total or partial Mayo score ≤2 and no subscore >1; rectal bleeding resolution, score of 0; stool frequency resolution, score of 0 or 1; VDZ, vedolizumab; TNF, anti-TNF.
Comparable remission rates were observed in this and the ENEIDA cohort study; however, more patients reported adverse events in the German cohort. In the vedolizumab group, 39% of patients reported adverse events compared to 44% in the anti-TNF group. Meanwhile, the Spanish registry reported that vedolizumab might be less effective in patients with Crohn’s disease. A similar outcome was seen in the German study, with 14% of patients receiving vedolizumab achieving clinical remission at Week 26 (HBI <5) versus 33% in the anti-TNF group although this was not statistically significant. It is important to highlight though, that just 14% of the vedolizumab group were biologic naïve whereas this was the case for 62% of the anti-TNF group who also had a shorter disease duration on average (10 vs. 6 years). A Canadian retrospective cohort study provided some additional insights on this issue by looking at the effectiveness and safety of vedolizumab in biologic-naïve patients with Crohn’s disease or ulcerative colitis. While the data was collected by Dr Brian Bressler from St Paul’s Hospital in Vancouver, Canada, it was Dirk Demuth from Takeda who got to share the results. Among the 156 patients (108 with ulcerative colitis), 83.8% were still receiving vedolizumab at 12 months. Importantly, the results from the study appear to correlate with what was observed in the other studies. At 12 months, 54.1% of patients with ulcerative colitis had achieved clinical remission compared to 28.6% in the Crohn’s disease group. Despite this, mucosal healing at 12 months was comparable between the two patient groups (62.1% in the ulcerative colitis group and 75.0% in the Crohn’s group) although small patient numbers in this interim analysis indicate we need to wait for the final results before drawing any firm conclusions.
Ustekinumab in real-world clinical practice
The anti-IL12/23 antibody ustekinumab is indicated for the treatment of Crohn’s disease in patients who have failed or are intolerant to conventional therapy or anti-TNF treatment. While results from the ongoing Phase III trials continue to be shared, some real-world data is also starting to become available. One such study was presented by Dr Karima Farrag from Goethe University, Frankfurt, Germany who shared results from a retrospective analysis of patient records from three German IBD centres. Identification of 80 patients who had not responded, lost response or were intolerant to conventional immunosuppressive therapies or anti-TNFs and were subsequently treated with ustekinumab were included and stratified based on their inflammatory status before initiating ustekinumab (CRP ≥5 mg/L = active disease and CRP <5 mg/L = remission). After 17–22 weeks, 36.4% of patients in the active disease group had achieved remission while another 36.4% had a partial response (CRP decrease of ≥50%). Meanwhile, in the patients who were in remission at baseline, 57.9% maintained remission. Importantly, ustekinumab was generally well tolerated, with 8.75% of patients experiencing a drug-related adverse event. Furthermore, discontinuation was observed in 12.5% of patients with most of those being a consequence of a lack of response rather than adverse events. Dr Farrag concluded by stating that while ustekinumab appears well tolerated and to have long-term effectiveness in many patients, for those who do not respond within 24 weeks, their therapy should be evaluated and optimised to increase the chance of long-term remission.
How similar is similar? A look at biosimilars in a real-world setting
While adalimumab biosimilars have finally reached the European market in recent weeks, biosimilars for infliximab have been available in Europe for a number of years. There is a general consensus that the infliximab biosimilar CT-P13 (Remsima®/Infectra®) is comparable to the originator drug in terms of efficacy, safety and immunogenicity (British Society of Gastroenterologists, 2016). However, is this the case in a real-world setting?
A French nationwide prospective study of CT-P13 assessed its effectiveness in patients across the infliximab indications, including 282 patients with IBD (176 with Crohn’s disease, 106 with ulcerative colitis). In this study by Professor Yoram Bouhnik and Professor Stephane Nancey, over 90% of enrolled patients had previously received CT-P13. In this cohort of patients who largely had controlled disease at baseline, the proportion of patients who were in remission at 6 and 12 months were 59.8% and 77.8%, respectively for the patients with Crohn’s disease and 48.7% and 69.2% for the patients with ulcerative colitis indicating that remission levels were maintained at 12 months in the majority of patients. Meanwhile, no additional safety signals were observed; 15.1% of patients with ulcerative colitis and 18.8% of patients with Crohn’s disease reported at least one adverse event.
The large majority of patients in the French study were started on CT-P13, but what about patients who switch from the originator infliximab? Results from the pivotal trials suggested that switching in patients with Crohn’s disease may lead to disease worsening – is this trend replicated in the real world? The details of an independent, prospective, randomised, double-blind trial that assessed patient outcomes following switching were shared by Dr Helene Röder from the Ludwig-Maximillian’s University in Munich, Germany. Patients who had responded to originator infliximab for at least 3 months were educated about the possibility of switching resulting in 200 patients (68%) consenting for inclusion in the study. Following randomisation, 111 patients were switched to CT-P13 while 89 were maintained on originator infliximab. Discontinuation of the study drug was comparable between the two groups with 25.2% of the CT-P13 group stopping treatment due to loss of response or side effects versus 18% in the originator group (p=0.219). The primary endpoint was clinical remission and continuation of study drug to 52 weeks and was achieved in 62.2% of patients in the CT-P13 group and 73.0% of patients in the originator group (p=0.104) suggesting that patients can be successfully switched from originator infliximab to a biosimilar version. However, Dr Röder and colleagues did highlight that the NOR-SWITCH study, also showed a non-significant increase in patients discontinuing treatment following switch to CT-P13 (Jørgensen et al., 2017) and suggested that results from larger, long-term switch trials are required to clarify this possible issue.
It is apparent that while we continue to learn more about the treatments we have available for the management of IBD questions remain over their optimisation in clinical practice. Join us tomorrow for our final article where we will be turning our attention to the future and looking at the new therapies appearing on the horizon.
British Society of Gastroenterologists. BSG guidance on the use of biosimilar infliximab CT-P13 in IBD. 2016. Available at: https://www.bsg.org.uk/resource/bsg-guidance-on-the-use-of-biosimilar-infliximab-ct-p13-in-ibd.html
Entyvio® Summary of Product Characteristics. 2018. Available at: https://www.medicines.org.uk/emc/product/5442
Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389:2304–16.