DDW 2018: IBD Study Updates

This article summarises some of the key study updates presented at DDW 2018.

Interview by Hannah Chatfield

Dr James Lindsay (UK) discusses the key outcomes of the PANTS study, and the potential impact of these data for the UK

PANTS

Dr Tariq Ahmad from the University of Exeter reported on the clinical effectiveness and safety outcomes at week 54 of the PANTS study, a three-year prospective, observational study designed to document the clinical effectiveness and safety of originator and biosimilar (CT-P13) infliximab and adalimumab in patients with active CD. A total of 1,601 patients were enrolled at 118 sites across the UK. At week 12–14, 21% of patients in each of the treatment arms receiving originator and biosimilar infliximab, respectively, and 26% of patients in the adalimumab arm showed primary non-response. Significant risk factors for primary non-response were older age, higher BMI and low drug plasma levels. At week 54, remission rates were 40%, 40% and 34%, and immunogenicity rates 26%, 28% and 11% in the originator infliximab, biosimilar infliximab and adalimumab arms, respectively. After three years immunogenicity rates had increased to 42%, 38% and 23%, respectively, and the difference between infliximab and adalimumab was statistically significant. Immunogenicity was a significant risk factor for non-remission at week 54. Concomitant immunomodulatory use reduced the risk of immunogenicity both in the infliximab and adalimumab arms. A total of 140 patients (9%) withdrew due to serious adverse events and there were five deaths.

Professor Stefan Schreiber (Germany) describes data presented at DDW looking at ‘super-responders’ to vedolizumab who benefit from rapid remission

GEMINI

Several post hoc analyses from the GEMINI trial programme for vedolizumab were presented as posters at DDW 2018. Professor Edward Loftus and colleagues reported on an analysis from the pivotal GEMINI 1 trial, in which vedolizumab was shown to be significantly superior to placebo for inducing and maintaining remission in moderate to severe UC.² This post hoc analysis showed that a significantly greater proportion of patients in the vedolizumab arm achieved sustained steroid-free clinical remission over 52 weeks of treatment compared with placebo, both in the study population overall and in anti-TNF-naïve patients (poster Sa1776). A similar post hoc analysis was performed for the GEMINI 2 trial in CD and showed that vedolizumab significantly increased the rate of sustained clinical remission through to week 52 in patients who were in clinical remission at week 14 compared with placebo, suggesting that remission at week 14 is a marker of favourable long-term outcomes with vedolizumab. Vedolizumab was also shown to increase clinical remission rates compared with placebo in patients who were no longer responding to anti-TNF therapy (poster Sa1772). In addition, a post hoc analysis from the GEMINI Long Term Safety Study included 421 patients who had been recruited directly to the study with no previous vedolizumab exposure. The results of this analysis showed that in this de novo cohort, nearly two thirds of the UC patients and more than half of the CD patients in the study persisted with vedolizumab treatment for three years. More than three out of four patients had a treatment response by week 12, and these patients were more likely to persist with treatment for three years than those who had a later response. Patients who were biologic naïve were also more likely to persist with treatment than those with prior anti-TNF failure. The majority of patients were able to discontinue systemic steroids while on vedolizumab. The investigators concluded that this analysis supports the long-term effectiveness and safety of vedolizumab in UC and CD (poster Sa1766).

CALM – factors driving treatment escalation in CD

The CALM study was designed to evaluate whether patients with moderate to severe CD who were treated according to a tight-control (TC) algorithm with treatment escalation based on symptoms and biomarkers (CRP and faecal calprotectin) had better clinical and endoscopic outcomes than patients who received conventional treatment. The primary results, which were published at the end of 2017, confirmed that this was indeed the case.¹ At DDW 2018, Professor Walter Reinisch from the Medical University of Vienna presented an analysis of the drivers of treatment escalation, based on the four failure criteria that were applied in the TC arm: CDAI ≥150, CRP ≥5mg/l, faecal calprotectin ≥250µg/g, or prednisone use during the week prior to visit. At the start of the study patients in the TC arm commenced induction therapy with adalimumab 160/80 mg and then 40 mg every other week if they met at least one of the failure criteria. After 12, 24, and 36 weeks patients who met at least one of the criteria were escalated to the next treatment option (adalimumab 40 mg every week followed by adalimumab 40 mg every week plus azathioprine 2.5 mg/kg). At the start of treatment close to 70% of patients met at least three criteria. After 11 weeks 34% of patients met no criteria, and this proportion increased to 78% after 35 weeks. At the start of treatment the proportion of patients meeting each criterion was 84% for CDAI, 80% for faecal calprotectin, 76% for CRP and 60% for prednisone use. At subsequent visits faecal calprotectin was the most frequent single reason for treatment escalation, alone or in combination with CRP; prednisone was the least frequent reason. The investigators concluded that these findings highlight the importance of monitoring biomarkers alongside clinical symptoms for better outcomes.

CELEST

CELEST is a 16-week phase 2 study which demonstrated that induction therapy with the selective JAK 1 inhibitor upadacitinib is associated with endoscopic improvements and clinical benefit in moderate to severe CD.³  A poster presented by Professor Stefan Schreiber and colleagues showed that the higher clinical remission rate achieved with upadacitinib compared with placebo in the CELEST induction phase was evident from week four onwards, and that a clinical response was seen as early as two weeks into treatment. Likewise, significant improvements in inflammatory biomarkers including CRP and faecal calprotectin were seen after two and four weeks of induction therapy (poster Sa1755). Professor Julián Panés from Barcelona presented results from a 36-week extension phase of CELEST which included patients who responded to induction therapy with upadacitinib. The ITT population in this analysis included two subpopulations: patients who achieved a clinical response (n=94), and patients who achieved clinical and endoscopic response (n=54). The results showed continued clinical and endoscopic improvements throughout maintenance therapy, as well as reductions in inflammatory biomarkers. The safety profile was consistent with that seen in previous studies, with infections being the most commonly reported adverse event.

SVEAH

Two posters were presented with results from the SVEAH study, a prospective, observational, multi-centre cohort study carried out at centres in Sweden and which includes patients with active UC and CD, respectively, who initiated vedolizumab treatment between June 2015 and September 2017. The primary outcome in each analysis was clinical remission at week 52, defined as Harvey Bradshaw Index (HBI) <5 in the CD study and Mayo score ≤2 with no subscore >1 in the UC study. The CD study included 104 patients who completed the 52-week study period; at 52 weeks 68% of patients were still on vedolizumab treatment and 43% were in clinical remission. Significant clinical improvements and reductions of inflammatory markers were seen among patients who continued treatment to week 52, as well as improvements in quality of life (poster Mo1892). In UC, 60 patients completed 52 weeks of treatment by which time 60% were still on vedolizumab, 43% had achieved clinical remission and 27% were in clinical and endoscopic remission. Again, improvements were seen throughout the study in clinical disease activity, inflammatory markers and quality of life (poster Mo1894).

Apremilast in UC

Apremilast, an oral small-molecule phosphodiesterase (PDE) 4 inhibitor which is approved for active psoriatic arthritis, is currently in phase 2 clinical development for the treatment of UC. Professor Silvio Danese from Milan presented the results of a phase 2 randomised, placebo-controlled study in which 170 biologic-naïve patients with active UC who had failed at least one conventional therapy were randomised to apremilast at a dose of 30mg twice daily (n=57) or 40mg twice daily (n=55) or placebo (n=58). The primary efficacy analysis showed that remission rates at the end of the 12-week randomised induction period were significantly higher in the apremilast 40mg arm (31.6%; p=0.0301) and numerically higher in the apremilast 30mg arm (21.8%) compared with placebo (13.8%). Significantly higher proportions of patients in the apremilast 30mg arm achieved an endoscopic subscore ≤1 or clinical remission as defined by the partial Mayo score compared with placebo, whereas a higher proportion of patients on apremilast 40mg achieved a clinical response. No new safety signals were detected, and the investigators concluded that apremilast can achieve clinically meaningful improvements in disease activity in active UC.

References

1. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 2018;390:2779-2789.
2. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699-710.
3. Sandborn WJ, Feagan BG, Panes J, et al. Safety and Efficacy of ABT-494 (Upadacitinib), an Oral Jak1 Inhibitor, as Induction Therapy in Patients with Crohn’s Disease: Results from Celest. Gastroenterology 2017;152:S1308-S1309.