UEGW 2018: Future therapies in IBD

Professor Stefan Schreiber (Germany) discusses  the future of therapies in IBD.

Interviews by Hannah Chatfield. Written by Maria Dalby

An educational symposium at UEG Week 2018 discussed future therapies in IBD, including new directions for manipulating the immune response, modifying the microbiota and utilising stem cells.

Professor Yehuda Chowers from Haifa in Israel highlighted a key challenge with interventions that target the immune system, namely the difference in predicting the response due to the complexity of the dynamic interactions between components in the immune system and the environment, including the microbiome. As an example, Professor Chowers mentioned vedolizumab which is regarded as having a comparatively straightforward mechanism of action – however, pharmacologic characterisation has shown that vedolizumab is capable of binding to a wide range of cells in the immune system including memory CD4+ T lymphocytes, eosinophils, B lymphocytes and natural killer cells.¹ The fact that vedolizumab binds IL-17-producing T lymphocytes was thought to be a key therapeutic benefit;¹  however, targeting IL-17 directly with monoclonal antibody secukinumab proved ineffective with an unfavourable safety profile in a placebo-controlled proof-of-concept study.² FOXP3-positive T lymphocytes have been found which produce IL-17 and are believed to act as potent suppressors of inflammation in the intestinal mucosa of CD patients, giving this cytokine a complex dual role in the disease mechanism of CD.³ Future development of treatments targeting the immune system will require better tools for predicting the response to therapy and better analytical and statistical methods for understanding the underlying mechanisms. Statistical deconvolution, disruption networks and betweenness centrality nodes are methodologies used in oncology that could be applied for this purpose.

Cross talk between the intestinal mucosa and microbiome is known to play a critical role for maintaining homeostasis and controlling inflammation in the human gut. Professor Cyriel Ponsioen discussed ways in which the microbiome can be modified to achieve favourable outcomes in IBD. The first and perhaps most obvious alternative, antibiotics, has been shown to be effective in CD and UC but cannot be considered a viable option for the future due to the risk of antibiotic resistance. Another option is probiotics, which have been shown to have a modest effect for maintaining remission in UC and pouchitis.⁴ The greatest potential for significantly altering the microbiome is offered by faecal microbial transfer (FMT); the first recording of therapeutic use of FMT dates back to the 4^th century AD in China, but it was not until 1989 that “implantation of normal colonic flora” was successfully attempted in IBD.⁵ To date FMT has been documented in four randomised clinical trials in UC; no randomised trials have as yet been published in CD. In the TURN trial 37 patients with mild to moderate UC were randomised to FMT or placebo and although a numerically higher proportion of patients in the FMT arm achieved the primary endpoint of clinical and endoscopic remission at 12 weeks, this difference did not reach statistical significance.⁶ In contrast, more recent clinical studies carried out in Canada⁷ and Australia^{8, 9} showed significantly higher remission rates in patients treated with FMT compared with placebo, and a systematic review and meta-analysis confirmed that FMT is effective for inducing remission in active UC with no major short-term safety signals.¹⁰ Learnings from the Human Microbiome Project suggest that while the microbial taxa of the microbiome may vary greatly between individuals, the metabolic output of compounds such as short-chain fatty acids required for maintaining homeostasis is relatively stable.¹¹ As an example, UC patients receiving FMTs from donors with known butyrate producers and overall increased butyrate production capacity have been shown to achieve sustained remission over follow-up periods of more than one year.¹² More than 20 phase 2b trials investigating FMT in UC, CD and pouchitis are currently in progress.

Professor Marc Ferrante from Leuven in Belgium reminded the audience of the rationale for using haematopoietic stem cell transplantation (HSCT) in patients with treatment-refractory CD that is too extensive for surgical resection, which is to ‘reset’ the immune system and restore T-cell and T-cell receptor diversity.¹³ HSCT has been documented in a number of case reports and case series but as yet only one randomised clinical trial, Autologous Stem Cell Transplantation International Crohn Disease (ASTIC), has been published.¹⁴ In this study 23 CD patients underwent stem cell mobilisation followed by immunoablation and HSCT and 22 patients had stem cell mobilisation only. The primary endpoint was a very strict outcome of clinical remission, no immunomodulatory treatment for three months and no evidence of any kind of active disease; only a very small number of patients (two patients in the HSCT arm and one patient in the control arm) achieved this endpoint. However, trends in favour of HSCT were seen for some of the components of the primary outcome, and for secondary outcomes including change in CDAI and SES-CD from baseline. However, the rate of serious adverse events was very high and one patient in the HSCT arm died from sinusoidal obstructive syndrome, and the investigators concluded that HSCT was not suitable for widespread use in refractory CD.¹⁴ A recent analysis which also included patients in the control arm who underwent HSCT at a later time point and which assessed traditional study endpoints showed that HSCT resulted in a remarkable drop in absolute CDAI and a remission rate of around 50% one year after the procedure.¹⁵ Patients in the HSCT arm also experienced highly significant improvements in CDAI, IBDQ scores and SES_CD from baseline, but once again the rate of serious adverse events was very high.¹⁵ Professor Ferrante advised that while HSCT may be an option in selected multi-refractory CD patients it should only be performed in experienced centres with expertise in both haematology and IBD, and patients should be enrolled in trials where possible.

Perianal fistulas remain a major challenge in the treatment of CD and predict poor long-term outcomes. Professor Julián Panés from Barcelona summarised data from well-designed clinical trials that show that local injections of mesenchymal stromal cells (MSCs) can induce remission and reduce the need for systemic immunosuppression in patients with perianal fistulising CD, including a placebo-controlled phase 3 study in which more than 50% of patients treated with local MSC injections achieved remission by week 24, compared with only 35% in the placebo arm (p=0.021).¹⁶ One year after treatment, 56.3% of patients in the MSC arm remained in remission compared with 38.6% in the placebo arm.¹⁷ The clinical benefit of the MSC injections was seen after a median of only 6.7 weeks and the safety profile was comparable to the placebo arm.^{16, 17} MSCs can also be administered as systemic infusion for the treatment of refractory luminal CD, with response rates of around 60% and clinical remission rates of around 40% reported in the literature.¹⁸ Future directions for the development of MSC-based therapies will include gaining a better understanding of the immunomodulatory mode of action and identifying therapeutic biomarkers, expanding the safety profile to comprise longer follow-up and higher doses, and optimising dosing schedules and routes of administration.

References

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