ECCO 2018: Novel treatments in IBD

The current research and development pipeline of novel biologic therapies and small molecule drugs promises improved efficacy and safety in the treatment of IBD in the near future. However, the complexity and heterogeneity of the disease means it is unlikely that one single therapy will meet all clinical needs; instead rational use of combination therapy and multidisciplinary management will provide a bridge to fully personalised therapy…

Article by Maria Dalby. Interviews by Peter Mas Mollinedo.

Dr Tim Raine (Addenbrooke’s Hospital, Cambridge, UK) discusses updates on combining therapies in IBD.

The current research and development pipeline of novel biologic therapies and small molecule drugs promises improved efficacy and safety in the treatment of IBD in the near future. However, the complexity and heterogeneity of the disease means it is unlikely that one single therapy will meet all clinical needs; instead rational use of combination therapy and multidisciplinary management will provide a bridge to fully personalised therapy.

In a plenary talk on combination therapies, Dr Shomron Ben-Horin from Tel Aviv discussed how, far from being a novel concept, drug combinations are being used in daily IBD practice – often based on very little evidence as in the case of adding glucocorticosteroid therapy in patients with acute severe UC flares whilst on 5-ASA.¹ A common rationale for combining anti-TNF therapy with immunomodulatory drugs is to reduce the risk of anti-drug antibodies;² however, the latter may also have different immune effects and may indeed target other pathogenic mechanisms in IBD, such as microbiota dysbiosis.^{3, 4} Combination biologic therapy has been investigated in rheumatology, where multiple studies have compared anti-TNF monotherapy with combination therapy with other biologics including abatacept, rituximab, and anakinra, but so far failed to show a conclusive treatment benefit.^5-7 In contrast, a single randomised controlled study in CD patients showed higher response rates with combination therapy with natalizumab and infliximab compared with infliximab alone, with a similar rate of adverse events.⁸ Anecdotal evidence from smaller case series and case reports in IBD patients suggests that efficacy can be improved without increasing adverse event rates by using combination therapy with vedolizumab and an anti-TNF or ustekinumab.^9–15 A retrospective case-control study in which patients where co-exposed to vedolizumab and anti-TNF therapy showed no increase in adverse event rates or vedolizumab drug concentrations.¹⁶ An open-label single-arm study, EXPLORER, is currently underway to assess the efficacy of vedolizumab in combination with adalimumab and methotrexate versus vedolizumab alone in CD patients at high risk of complications. A further option for combination biologic therapy is offered by bi-specific antibodies which provide a means of combining monoclonal antibodies with different targets in a single molecule. Bi-specific antibodies are already in clinical development in haematological oncology and rheumatology and are showing promising efficacy.^17,18

Dr Amy Lightner (Mayo Clinic, Rochester, USA), Professor Jean-Frederic Colombel (Icahn School of Medicine at Mount Sinai, NY, USA), Mr Kapil Sahnan (St Mark’s Hospital, London) and Dr Michael Scharl (University Hospital, Zurich) discuss the various studies using stem cell therapy for perianal fistulizing Crohn’s Disease.

A tandem talk by gastroenterologist Professor Silvio Danese from Milan and surgeon Dr Amy Lightner from Mayo Clinic in Rochester, Minnesota highlighted how stem cell therapy can facilitate multidisciplinary management of perianal CD. A large proportion of CD patients will at some point in the course of their disease develop perianal fistulas, an aggressive complication with frequent hospitalisations and a high degree of social and sexual disability due to pain and incontinence. Treatment recommendations issued by ECCO advocate a combination of anti-TNF therapy and surgical management for improved closure rates compared with anti-TNF alone,¹⁹ but Professor Danese stressed that there is still a huge unmet need for more effective treatment options. Using mesenchymal stem cells is one such option; unlike surgical methods such as seton placement, fistulotomy or diversion, stem cells offer a minimally invasive option with no risk of faecal incontinence. Stem cells are used to treat a number of other medical conditions including myocardial infarction and stroke; they exert immunomodulatory effects through upregulation of Treg cells and promote tissue repair and regeneration, and they migrate spontaneously to sites of inflammation. The first patient to receive stem cell treatment for a CD fistula was a young female patient with a recurrent rectovaginal fistula which healed within three months of treatment with stem cell therapy.²⁰ Since then more than 300 patients have been treated in phase 1 and 2 trials, and a phase 3 randomised, double-blind trial in 212 CD patients with refractory complex perianal fistulas confirmed that stem cell therapy resulted in significantly higher remission rates at 24 weeks compared with placebo, with a favourable safety profile.²¹ The clinical benefit observed at 24 weeks was sustained at 52 weeks.²² Important research questions that remain to be answered include the optimal dosing, source and mode of delivery of stem cells and translation into systemic therapy for luminal CD.

Professor Laurent Peyrin-Biroulet (Nancy University Hospital, France), Dr Tim Raine (Addenbrooke’s Hospital, Cambridge, UK) and Professor Stefan Schreiber (Kiel, Germany) review updates at ECCO on small molecules for treating IBD.

Concluding the session, Professor Laurent Peyrin-Biroulet from France predicted the return of small molecules in IBD in the near future. Although the principal focus in IBD drug development in recent years has been on monoclonal antibodies following the revolutionary introduction of infliximab in the late 1990s, biologic treatments have many limitations including moderate efficacy, need for parenteral administration, immunogenicity, and high costs.^23–26 This has led to renewed interest in small molecules that are suitable for oral administration, target intracellular structures and have short serum half-lives.²⁷ The two main classes of small compounds in the IBD pipeline are JAK inhibitors and S1P modulators. Non-specific JAK inhibitor tofacitinib has been shown to induce and maintain remission in moderate to severe UC.²⁸ Specific inhibition of JAK1 with filgotinib and upadacitinib may improve the risk-benefit ratio with respect to herpes zoster and other infections, and lipid profile alterations. Likewise in the S1P modulator class there is a trend towards more specific receptor targeting with ozanimod and etrasimod, to improve safety outcomes.²⁹ Professor Peyrin-Biroulet pointed out that whilst newer small molecules may not necessarily be cheaper than biologic drugs, the benefits in terms of high persistence rates and no need for therapeutic drug monitoring could potentially meet important needs in the current IBD treatment paradigm.

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