Data from Stephen Smith - Curated by EPG Health - Last updated 30 October 2018

Advances in IBD

Anti-TNF therapies transformed the management of moderate-to-severe IBD; however, a substantial number of patients fail to respond or lose response to them. In recent years, the addition of anti-IL-12/23 and anti-integrin α4β7 has provided effective, additional options for refractory patients with Crohn’s disease and ulcerative colitis, but extra therapies are still urgently needed. Several therapies with a variety of modes of action are on the horizon. At UEG Week, a number of presentations and abstracts shared updates on the latest developments for many of these treatments. Here we provide insights into the latest data for novel treatments targeting Janus kinase (JAK) signalling, MAdCAM-1-mediated adhesion and the interleukin IL-23.

Targeting JAK signalling in IBD

The JAK kinases are a crucial component in the signalling pathways of a variety of cytokines involved in the inflammatory process. A number of therapies targeting the JAK family of kinases are under development with differences in their specificity likely to influence their resulting efficacy and tolerability (Verstockt et al., 2018). Here, we will explore some of the data from UEG Week that looked at the recently approved tofacitinib, and upadacitinib which is currently in Phase III clinical trials.

In August 2018, the oral, non-selective, small molecule JAK inhibitor tofacitinib received European approval for the treatment of adults with moderate-to-severe ulcerative colitis who had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent (European Medicines Agency, 2018; Xeljanz® Summary of Product Characteristics, 2018). Open-label, long-term extension studies are ongoing and Dr Stuart Bloom from University College London Hospital, UK, presented an interim-analysis of patients with up to 4.9 years of treatment. Patients were enrolled from the Phase III clinical trial programme with those who were in remission at Week 52 of the OCTAVE Sustain trial maintained on tofacitinib 5 mg BID (n = 175), while those who failed treatment or were non-responders in OCTAVE Sustain or OCTAVE Induction 1 and 2 received tofacitinib 10 mg BID (n = 769). Selected efficacy endpoints (non-responder imputation) are shown in figure 1. 

Figure 1: Remission and mucosal healing in patients who received tofacitinib 5 mg BID (previous responders) or tofacitinib 10 mg BID (previous relapse/non-responders). Non-responder imputation data; R


Figure 1: Remission and mucosal healing in patients who received tofacitinib 5 mg BID (previous responders) or tofacitinib 10 mg BID (previous relapse/non-responders). Non-responder imputation data; Remission defined as total Mayo score ≤2, no individual subscore >1 and rectal bleeding subscore = 0. 

Treatment-emergent adverse events were observed in 78.9% of both groups while severe adverse events were observed in 8.0% of the 5 mg BID group and 10.3% of the 10 mg BID group. Meanwhile serious infections were reported in 2.9% and 3.0% of patients in the 5 mg and 10 mg BID groups, respectively. While long-term efficacy was observed in many patients treated with tofacitinib, discontinuation due to adverse events excluding worsening disease was observed in 6.9% of patients with a further 34.5% discontinuing due to insufficient clinical response. 
Tofacitinib is a non-selective JAK inhibitor, but some JAK inhibitors in development target specific members of the JAK family. One such drug is upadacitinib, an oral selective JAK1 inhibitor that is being evaluated for the management of ulcerative colitis and Crohn’s disease. Professor Subrata Ghosh from the University of Birmingham, UK, presented results from the Phase IIb/III U-ACHIEVE study addressing the use of upadacitinib as induction therapy in patients with active ulcerative colitis who had previously been intolerant or had an inadequate response to prior therapy. 

A total of 250 patients were randomised to receive 7.5, 15, 30, or 45 mg of upadacitinib once daily or placebo for 8 weeks. Enrolled patients had a mean ulcerative colitis duration of 8 years and at baseline 83% reported bowel urgency on 3 out of each 3-day period and 41% had an average abdominal pain score >1. By Week 8, no bowel urgency was reported in 9% of placebo patients compared to 19% (not significant), 33% (p<0.01), 29% (p<0.05) and 46% (p<0.001) of patients receiving 7.5, 15, 30, and 45 mg of upadacitinib, respectively. Similar results were reported for abdominal pain scores of 0, Mayo rectal bleeding subscore of 0 and Mayo stool frequency subscore of ≤1. Importantly, significant improvements in bowel urgency and abdominal pain were reported as early as Week 2. 

Upadacitinib is also being investigated for the management of Crohn’s disease and Professor Laurent Peyrin-Biroulet from Lorraine University, Nancy, France, presented data from the CELEST trial exploring patient-reported outcomes after 52 weeks of upadacitinib therapy. In this Phase II extension study, all patients who completed the 16-week induction phase were re-randomised to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks. However, the 24 mg arm of the study was stopped, and an intermediate 6 mg BID arm initiated. Among Week 16 clinical responders, more patients in the BID groups achieved IBD Questionnaire (IBDQ)-defined response (≥16-point increase from baseline) and IBDQ-defined remission (IBDQ score ≥170) at Week 52 compared with the QD group. Remission at Week 52 was observed in 31.6% of patients in the 24 mg QD group versus 43.8%, 50.0% and 41.4% of the 3 mg BID, 6mg BID, and 12 mg BID groups, respectively. Meanwhile, improvements in the EuroQoL and Work Productivity and Activity Impairment questionnaires were also observed at Week 52 among the BID groups versus the QD patients. These interesting results suggest that upadacitinib may be an effective treatment in both ulcerative colitis and Crohn’s disease – results from the Phase III trials are eagerly awaited.

Targeting MAdCAM-1 to reduce lymphocyte homing

The anti-integrin α4β7 treatment vedolizumab is approved for the management of both ulcerative colitis and Crohn’s disease. However, additional therapies targeting lymphocyte adhesion and homing within the gut are under investigation. One such therapy is SHP647, an anti-MAdCAM-1 monoclonal antibody that also prevents the interaction between integrin α4β7 on the surface of lymphocytes and MAdCAM-1 on the gut endothelium. 

Data from the TURNADOT Phase II trial demonstrated that SHP647 was more effective than placebo at inducing remission at 12 weeks in patients with ulcerative colitis. Professor Walter Reinisch from the Medical University of Vienna, Austria shared data from the extension phase of the study (TURNADOT II) that evaluated the safety and tolerability of SHP647 in patients who completed the induction phase of the study. At baseline, patients were re-randomised to 75 mg or 225 mg subcutaneous SHP647 every 4 weeks for 18 months, although those patients receiving 75 mg who relapsed or failed to respond by Week 8 could have their dose escalated to 225 mg every 4 weeks. At the end of this 18-month period, all patients were treated with 75 mg SHP647 every 4 weeks for a further 18 months and then followed-up for safety at 3 and 6 months after treatment cessation. 

In total, 331 patients entered the study (75 mg, n = 165; 225 mg, n = 166) and during the first phase where dose escalation was possible, 94 patients receiving 75 mg every 4 weeks had their dose increased. While 180 patients completed the first 18 months of the study, the likelihood of achieving this was similar between the 75 mg (54.9%) and the 225 mg (54.2%) groups. However, the completion rate was actually higher in the 75 mg group for those patients who did not undergo dose escalation to 225 mg (81.4% vs. 35.1%, respectively). The primary safety endpoints in the TURNADOT II study were comparable between the two groups. On-treatment adverse events were observed in 89.0% of the 75 mg group and 88.6% of the 225 mg group while serious adverse events were seen in 20.7% and 24.1%, respectively. Overall, ulcerative colitis was the most frequently-reported adverse event at 10.0% and it was also the most common adverse event leading to treatment withdrawal. In total 7.3% of patients receiving 7.5 mg every 4 weeks discontinued treatment due to an adverse event versus 13.9% in the 225 mg group. 
Are comparable results seen in patients with Crohn’s disease? Professor Geert D’Haens shared data from the Phase II extension study OPERA II that is evaluating the long-term efficacy and safety of SHP647 in moderate-to-severe Crohn’s disease. In this study, 268 patients were enrolled who had completed the 12-week induction phase of OPERA I or had a clinical response to 225 mg SHP647 in the open-label TOSCA study. All patients received 75 mg of subcutaneous SHP647 every 4 weeks up to Week 72 although dose de-escalation to 22.5 mg was possible in response to intolerance/treatment-emergent adverse events and dose escalation to 225 mg could be performed in case of clinical deterioration/poor response. Of the 268 patients who started the study, no patients de-escalated their dose, but 157 patients did increase their dose to 225 mg every 4 weeks. These patients who had a dose escalation appeared to have more severe disease with higher levels of high-sensitivity C-reactive protein and faecal calprotectin at baseline than patients who remained on 75 mg every 4 weeks. Ultimately, 149 patients completed the 72-week study with discontinuation due to adverse events observed for 19.8% of patients in the treatment period. In total, 92.9% of patients experienced a treatment-emergent adverse event, but these were deemed to be treatment-related in only 46.3% of patients. These data support the long-term tolerability of SHP647 and indicate the continued progress of this possible future treatment for ulcerative colitis and Crohn’s disease.

IL-23 and inflammatory diseases

Risankizumab is a monoclonal antibody that targets the p19 subunit of IL-23 making it a specific IL-23 inhibitor unlike ustekinumab that targets the p40 subunit present in both IL-12 and IL-23. Recent data has shown risankizumab to be a promising new therapy for psoriasis, but what about IBD? Published Phase II studies have demonstrated the efficacy of risankizumab for the induction and maintenance of patients with moderate-to-severe Crohn’s disease (Feagan et al., 2017a; Feagan et al., 2017b). In this presentation, Professor Marc Ferrante from the University Hospital Leuven, Belgium, provided an update on the interim efficacy and safety of risankizumab maintenance for up to two years in an open-label extension of the Phase II study. 
Patients from the induction phase who experienced a clinical response but didn’t achieve remission by Week 26 or achieved a clinical response and/or remission at Week 52 were enrolled and received 180 mg subcutaneous risankizumab every 8 weeks for up to 216 weeks. Meanwhile, patients who lost clinical response or remission after completion of the previous study were re-induced with 600 mg intravenous risankizumab at weeks 0, 4 and 8. In total, 65 patients were included in the study including four who were re-induced. Of the enrolled patients, 92.3% had previously received an anti-TNF therapy.

Figure 2: Proportion of patients achieving clinical remission by visit. Non-responder imputation data. Clinical remission defined as CDAI <150.


Figure 2: Proportion of patients achieving clinical remission by visit. Non-responder imputation data. Clinical remission defined as CDAI <150.

In addition to clinical remission, endoscopic remission was also maintained over the study period. At baseline, 41.5% of patients were in endoscopic remission (Crohn’s Disease Endoscopic Index of Severity [CDEIS] ≤4 or CDEIS ≤2 for patients with initial isolated ileitis) while by Week 48 this had increased to 53.8% of patients. The safety profile of risankizumab was also highlighted as consistent with previously published reports. During the study, 89.2% of patients experienced an adverse event with the most commonly reported being nasopharyngitis (26.2%), fatigue (16.9%), arthralgia (15.4%) and worsening Crohn’s disease (also 15.4%). Meanwhile, 27.7% of patients had a serious adverse event.

Same drug, new route of administration?

While infliximab has been an effective treatment for many patients with IBD over the years, the intravenous route of administration can be inconvenient and a barrier to its use for some patients (Stoner et al., 2014). To overcome this, and offer patients the chance of infliximab self-injection, Dr Shomron Ben-Horin from the University of Tel Aviv, Israel shared data on attempts to produce a subcutaneous formulation of the infliximab biosimilar CT-P13. In this study that enrolled patients with Crohn’s disease and patients with rheumatoid arthritis, the efficacy and immunogenicity of the subcutaneous formulation was compared to the intravenous formulation. After two loading doses of intravenous CT-P13, patients who subsequently received the subcutaneous formulation achieved more stable steady-state therapeutic blood levels of CT-P13 and had a lower rate of anti-CT-P13 antibodies compared to those who continued with intravenous treatment. Further studies are required to confirm these results, but it appears that CT-P13 may not be the only drug attempting to expand its possible routes of administration. Professor William Sandborn from the University of California San Diego, USA, shared results from a Phase III trial evaluating a new subcutaneous formulation of vedolizumab. Following induction with intravenous vedolizumab, Professor Sandborn concluded that the use of subcutaneous vedolizumab as a maintenance therapy was comparable to the intravenous formulation and was efficacious, generally safe and well-tolerated in patients with ulcerative colitis. 

Thanks for following our coverage of UEG Week 2018, we've collated all the highlights for you: UEG Week 2018 | Daily reports | Read more

References
European Medicines Agency. Xeljanz. 2018. Available at: https://www.ema.europa.eu/medicines/human/EPAR/xeljanz. 
Feagan BG, Sandborn WJ, D'Haens G, Panés J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017a.29;389(10080):1699–1709.
Feagan BG, Panés J, Ferrante M, Kaser A, D’Haens GR, Sandborn WJ, et al. Efficacy and safety of open-label maintenance therapy with subcutaneous risankizumab in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2017b;152:S1310.
Stoner KL, Harder H, Fallowfield LJ, Jenkins VA. Intravenous versus subcutaneous drug administration. Which do patients prefer? A systematic review. Patient. 2014. [Epub ahead of print].
Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment option for inflammatory bowel diseases. J Gastroenterol. 2018;53:585–90.
Xeljanz® Summary of Product Characteristics. 2018. Available at: https://www.medicines.org.uk/emc/product/2500/smpc. 

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