Abstract
Fundamental insights into the pathogenesis of inflammatory bowel diseases (IBD) have led to the development of new therapies and lots of experimental compounds in the pipeline. Our treatment of IBD is therefore constantly evolving. In this editorial, we postulate that bi- or even polyspecific therapy will be an important mainstay of future IBD treatment. Moreover, we highlight some promising new therapeutic concepts currently under investigation and point at the outstanding and growing importance of personalized medicine to assign drugs from the increasing pool of options to the individual patient.
Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), are chronic relapsing inflammatory conditions of the intestine with a multifactorial pathogenesis that includes genetic susceptibility, impaired barrier function, altered gut flora and a dysregulated immune response.[Citation1] As it develops rather early in life in most cases, it is often required to treat patients over years and to adapt the therapy repeatedly with respect to flares, complications, personal circumstances or loss of effect of previous medication. This can be a quite challenging task for the clinician but recent advances in understanding the nature of IBD have helped and will help to develop new and future therapies, which will enable us to improve our strategies regarding these needs. Collectively, our current therapeutic concepts for IBD will progressively evolve to become broader in general options but though more targeted and individualized in single patients. In this editorial we will outline a vision of how new developments could profoundly change therapy of IBD in the next decades.
Bi- or polyspecific and multimodal therapy
Following the breakthrough of TNF-α blockade by neutralizing antibodies in both CD and UC a magnitude of therapeutic agents inhibiting the activity of pro-inflammatory cytokines or supporting the action of anti-inflammatory cytokines was evaluated for IBD treatment. Unfortunately, many of them failed in clinical studies or had beneficial effects in subgroups of patients only,[Citation1] which underscores the notion that cytokine networks in human IBD are more complex than assumed before and may vary between different patients.
This poses the question how further and profound progress can be made on the field of targeting cytokines in IBD. A possible answer is to aim at several cytokines at the same time, either through combination of different targeted antibodies, through interfering with overlapping intracellular signaling pathways or through additional enhancement of anti-inflammatory cytokines.
First encouraging, but with certainty not the last steps in this direction are already made today. For example, ustekinumab, a monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23,[Citation2] thus targeting both cytokines at the same time, is currently evaluated in phase III studies. Although inhibition of TNF-α is a very successful standard therapy in IBD today, decreasing or even loss of effectiveness over time is often noticed. Ustekinumab seems to be especially promising in this context. In a phase II trial in CD patients resistant to anti-TNF-α treatment, a significantly greater portion of patients receiving ustekinumab had a clinical response than those receiving placebo. Among responding patients, prolonged ustekinumab treatment significantly increased response and remission rates.[Citation3]
Another experimental drug inhibiting several cytokines simultaneously is tofacitinib. It blocks the signal transduction by Janus kinases (JAKs) and thereby downregulates the signaling of interleukin (IL)-2, −4, −7, −9, −15 and −21. A phase II trial comprising 194 patients with UC reported significantly higher clinical response and remission rates.[Citation4] As for the most compounds in the pipeline potential long-term toxic effects are still unclear.
After years without approval of IBD therapies with conceptual novelty, vedolizumab was introduced into clinical practice recently. Vedolizumab is a monoclonal antibody that impedes gut homing of lymphocytes by blocking the adhesion of integrin α4β7 to its receptor MAdCAM-1,[Citation5] which seems to be exclusively expressed on the intestinal endothelium. It has to be noted, that this principle had already been implemented earlier through the α4β1 antibody natalizumab but was abandoned later due to the occurrence of progressive multifocal leukencephalopathy cases probably arising from simultaneous blockade of α4β1-mediated brain homing.[Citation6] Vedolizumab is successfully used in both UC [Citation7] and CD, [Citation8] and further drugs directed at gut homing are under investigation. Again, bispecific approaches are auspicious, as etrolizumab will probably become a successor of vedolizumab. Etrolizumab recognizes the integrin β7 subunit, which appears not only in combination with α4 but also with αE. The interaction of αEβ7 with its receptor E-Cadherin is believed to be involved in the retention of homed lymphocytes and simultaneously targeting α4β7 and αEβ7 might therefore extend the efficacy of single α4β7 blockade. A phase II trial in patients with UC demonstrated a significantly increased number of patients with clinical remission upon etrolizumab treatment.[Citation9]
Aside from these three quite advanced approaches of bi- or polyspecificity, even more fundamental novelties are possible. Currently investigated compounds make use of overlapping epitopes or shared signaling pathways, but the emerging field of bioengineering might offer the possibility to generate antibodies that target two completely different antigens simultaneously through combination of different binding sites within the same antibody.[Citation10]
Moreover, polyspecificity can be reached by concurrent use of several drugs. An already existent example is the combination of TNF-α blockade with azathioprine, which has to be cautiously used due to some reports of association with hepatosplenic T-cell lymphoma.[Citation11] Basically, many other combinations of current and future drugs could also be useful for multimodal IBD treatment. Furthermore, even agents that have failed to prove efficacy when administered alone [Citation1], could augment the therapeutic power of a combination therapy and might therefore be reconsidered in this setting. However, it does not seem very wise to randomly test possible combinations. Instead, it is imperative that we increase our knowledge about the pathogenesis of IBD in general and learn to assess the potentially varying contribution of different pathogenetic aspects in individual patients before being able to pointedly assemble sets of agents. Complementarily, if we really want to target complex and interfering networks rather than single cytokines or receptors, it is essential to take efforts to better understand how new and future drugs work, as it seems that efficacy and safety of drugs are often proven earlier than the mechanism of action in vivo.[Citation5]
New avenues for IBD treatment
Our future treatment options for IBD will not only be extended by simultaneously targeting several pathogenetic players through combinations of existing strategies but also by the introduction of drugs with completely new targets.
One of them might be Mongersen, an antisense oligonucleotide directed against SMAD7, a signaling molecule that inhibits the activity of transforming growth factor β (TGF-β). TGF-β is important for the development and signaling of induced regulatory T cells (iTregs) in the gut and SMAD7 has been shown to disrupt this process. Thus, Mongersen is thought to restore TGF-β-mediated Treg function and subsequent suppression of inflammation. A recent phase II study evaluated the drug in CD and reported striking effects: Clinical remission was noted in up to 65% compared with 10% in the placebo group and clinical response was up to 72% as opposed to 17% in patients treated with placebo.[Citation12] While it is beyond question, that these results have to be confirmed by phase III data before full confidence can be placed in them, Mongersen’s potency to induce remission in CD seems remarkable.
Another cytokine whose pro-inflammatory and carcinogenic role in IBD is addressed in ongoing studies of several antibodies is IL-6 and its receptor, respectively. In spite of ambiguous results in the first clinical trials, especially the implication of IL-6 in colitis-associated cancer makes it a potential target of great interest.[Citation13]
In vitro expansion of Treg cells and subsequent adoptive transfer is another cutting-edge concept to treat IBD. A pioneer trial in 20 patients with refractory CD demonstrated dose-dependent efficacy of ovalbumin-specific Treg transfer.[Citation14] Further studies will be needed to implement a future role for this novel approach.
What could lead to a revival of the so far disappointing attempts to exploit anti-inflammatory cytokines for IBD therapies are innovative forms of application. For example, commensal bacteria can be modified to express immunosuppressive cytokines and might therefore represent a way to topically deliver high concentrations.[Citation15]
Some other interesting and promising examples of conceptually new strategies in IBD treatment include the fortification of impaired epithelial barrier by topical application of phosphatidylcholine, stimulation of innate immune processes via toll-like receptor agonists or the modulation of the intestinal flora in IBD.[Citation16] We will therefore face times in which IBD therapy will be based on significantly more pillars than today.
These new compounds will be accompanied by new concepts of therapeutic goals and monitoring of therapy. With the traditional focus on clinical parameters inadequate decisions may be triggered by overlooking biochemical, endoscopic or histological signs of inflammation. Therefore, “mucosal healing” – commonly defined as endoscopic remission – and “deep remission” – mainly understood as the combination of biochemical, endoscopic and histological signs of remission – have appeared as new constructs in assessing therapy responses and are increasingly evaluated in clinical studies.[Citation17] That way, our knowledge about the impact of both current and future therapeutic interventions below the surface of clinical symptoms will increase and help us to decide, when and how long to treat with a certain drug.
Personalized medicine
While the presumed increase in therapeutic options will be basically helpful, it will also complicate the selection of the medication a physician has to make when he encounters an individual patient.
We will therefore experience the necessity to predict therapy responses through pre-treatment evaluation of appropriate biomarkers. Regarding TNF-α blockade, a pilot study showed that a high level of membrane-bound TNF-α expression (as assessed by topical administration of fluorescent-labeled adalimumab and subsequent quantification by confocal laser endomicroscopy during colonoscopy) prior to initiation of adalimumab treatment had a significant correlation with response rates.[Citation18] Similarly, in the phase II trial of etrolizumab high αE integrin expression went along with higher rates of clinical remission.[Citation9]
Additionally, it would be highly desirable to identify reliable biomarkers to predict disease courses by characterization and subcategorization of the IBD of individual patients. Possibly, such “IBD profiling” will be routinely established one day and the combination of forecasting disease course and treatment response might enable us to choose a highly selective and promising drug or drug combination right after diagnosis or in response to flares and complications. Regarding these prospects of personalized medicine in combination with greater therapy options, the unresolved controversy whether “step up” (i.e., gradually escalating therapy over the course of the disease) or “top down” (i.e., starting with maximal therapy in the hope to prevent progression) is the right approach to treat IBD patients might soon be superseded. Once we are sufficiently able to predict individual disease courses and therapeutic responses through the assessment of biomarkers, the most encouraging approach will be selected on an individual basis.
Financial & competing interests disclosure
S Zundler is supported by the Interdisciplinary Center for Clinical Research (IZKF) programme of the University Erlangen-Nuremberg, Germany. The research of MF Neurath is supported by the Clinical Research Group (CEDER) of the German Research Council (DGF), the DFG Collaborative Research Centers 643, 796 and 1181, the German Cancer Aid Organization, the United European Gastroenterology Research Prize, the DFG Graduate School of Excellence in Advanced Optical Technologies, the Excellence Programme (Ludwig Demling Center) and the IZKF and ELAN programmes of the University Erlangen-Nuremberg. He has served as an advisor for MSD, AbbVie, Janssen, Boehringer Ingelheim, Pentax and Giuliani. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Additional information
Notes on contributors
Sebastian Zundler
Markus F. Neurath
References
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