Review

Therapeutic peptides in inflammatory bowel disease Klaus R Herrlinger, Eduard F Stange & Klaus Fellermann† †

1.

Introduction

2.

TNF-inhibitors in Crohn’s disease

3.

TNF inhibitors in ulcerative

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colitis 4.

Novel therapeutic peptides in IBDs

5.

Expert opinion

University Hospital Schleswig-Holstein, Division of Gastroenterology, Department of Internal Medicine I, Lu¨beck, Germany

Introduction: Therapeutic peptides in inflammatory bowel diseases essentially comprise cytokines affecting immune response, growth factors and monoclonal antibodies directed against key targets of mucosal inflammation, in particular, tumor necrosis factor-a (TNF-a). The latter have revolutionized standard medical treatment which previously was restricted to mesalamine, corticosteroids or classical immunosuppressants. Areas covered: We review current evidence of the use of the so-called biologicals, including the well-established TNF-a antagonists and novel peptides and monoclonal antibodies developed for these diseases. The focus is on controlled clinical trials and meta-analyses, if available. Limitations and biases of these studies are important but tend to be ignored. Safety is also an important issue with opportunistic infections and lymphoma as relevant risks. There is significant heterogeneity between different countries, guidelines and opinions within the scientific community regarding clinical indications, even apart from pharmacoeconomics and reimbursement. Expert opinion: TNF blockers have greatly extended medical options in inflammatory bowel diseases. Their more or less extensive use in nearly all patients or only a few selected indications is a matter of debate. It proved difficult to reproduce this success with other antibody targets as well as with immunomodulatory cytokines and growth factors. The most promising novel peptide is vedolizumab, an antibody against a4b7 integrin. Keywords: biologicals, cytokines, inflammatory bowel disease, tumor necrosis factor-a Expert Opin. Biol. Ther. (2014) 14(4):455-466

1.

Introduction

Inflammatory bowel diseases (IBDs) represent a serious, lifelong handicap for the patient, an enigmatic and difficult-to-treat disease for the physician and a major issue of health economics. The majority of patients with Crohn’s disease are prone to sometimes repetitive surgical interventions, and in ulcerative colitis a sizable minority is doomed to the final removal of the colon following failure of medical treatments or development of dysplasia or cancer. In contrast to the traditional pathogenetic concept of an overresponse of T-cellmediated adaptive immunity, recent developments suggest a barrier defect of innate immunity (defensins and mucus) toward gut bacteria [1]. Whole genome analysis maintains that indeed both systems of defense are involved [2]. Although it would make perfect sense to seal off the gut lining against bacterial invasion to avoid inflammation altogether, this approach has not been realized as yet. Rather, the ‘old paradigm’ of a causative T-cell hyperreactivity has laid the ground for the classical standard treatment with corticosteroids, thiopurines or methotrexate as suggested in the guidelines as an initial step in the step-up approach with relatively inexpensive and safe therapies [3,4]. The introduction of more targeted therapies with monoclonal antibodies against the key cytokine TNF-a has revolutionized the field by adding additional armamentarium in those refractory to the small molecules. 10.1517/14712598.2014.880109 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. . . .

TNF antagonists are established treatment options in IBD, but not the gold standard. Classical immunosuppressants are not outdated so far, modern therapy turns out to be combination treatment. Novel therapeutic peptides have mostly failed.

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This box summarizes key points contained in the article.

The main mechanism of action seems to be the induction of apoptosis of T lymphocytes and macrophages. For the first time, effective long-term treatment also of Crohn’s fistulae became possible [5]. Suddenly, IBDs entered a booming market that attracted many innovative pharmaceutical companies to develop novel antibodies against TNF-a or new targets like other cytokines or integrins known to be involved in the inflammatory cascades. Other peptides like immunomodulatory cytokines or growth factors did not succeed in modifying disease course sufficiently to survive clinical development. The downside of anti-TNF antibodies with a rise in sometimes lethal opportunistic infections, including miliary tuberculosis [6] or cerebral JC-virus infection, following administration of the anti-integrin natalizumab [7] did not deter the companies or physicians while attempting to repeat the anti-TNF success story. This remarkable change in therapeutic attitude of accepting mortality as most serious adverse event has come overnight and largely unnoticed. In this article, we discuss the pros and cons of the standard established TNF antibodies and the prospects of novel peptides in succeeding in supplementing therapeutic options. It should be noted that in most studies therapeutic benefit was defined as ‘response’, meaning a diminished disease activity (e.g., by 70 -- 100 points of a Crohn’s disease activity index) or full remission. Responding patients feel better but only those in remission feel fine. 2.

TNF-inhibitors in Crohn’s disease

2.1

Infliximab Infliximab for luminal Crohn’s disease

2.1.1

When published in 1997 the concept of a selective blockade of one of the proinflammatory key players revolutionized the understanding and the treatment options of Crohn’s disease. Targan et al. published the results of a 12-week multicenter, double-blind, placebo-controlled trial on 108 patients with moderate-to-severe Crohn’s disease who had received a chimeric antibody against TNF-a called cA2. At 4 weeks, 81% of the patients who were given 5 mg/kg of cA2 had a clinical response, as compared to only 17% of patients in the placebo group. About 33% achieved remission as compared to only 4% of the patients given placebo [8]. Re-treatment every 8 weeks of patients responding to this antibody later named infliximab resulted in maintaining the clinical benefit in ‘nearly all patients’ [9]. Maintenance therapy with infliximab 456

has been further investigated in the large ACCENT I trial [10]. After an initial infusion of infliximab, patients responding to therapy were randomized to receive either infliximab 5, 10 mg/kg or placebo 8-weekly. At week 58, that is, 8 weeks after the last infliximab infusion, 38% of patients had achieved sustained remission. Although this trial shows efficacy of infliximab in remission, maintenance results have to be interpreted with caution. The inclusion of only those patients responding to the initial infusion results in a selection bias favoring the infliximab results. The long-term remission rate with infliximab referring to the whole population is only 26%. If maintenance therapy with infliximab is aimed for, response should be evaluated after 2 -- 3 infusions and therapy should be stopped if response is insufficient. Safety data from ACCENT I revealed as side effects infusion reactions in 17% of patients, serum-sickness-like reactions in 2% and serious infections in 4%. Infliximab for fistulizing Crohn’s disease Infliximab has shown efficacy in fistulizing Crohn’s disease as well. In a cohort of 95 patients with draining perianal or abdominal fistulae, three infusions of 5 mg/kg infliximab resulted in closure of 55% of all fistulae in comparison to only 13% in the control group [5]. Similar to the maintenance results with infliximab in luminal Crohn’s disease, long-term therapy with infliximab was somewhat less effective. When giving infliximab 8-weekly, every third patient initially responding remained in remission. Similar to the abovedescribed luminal maintenance study, these results have to be interpreted carefully due to selection bias. Again the strategy of only randomizing the responders results in a bias. When referring to remission rates in the whole cohort, long-term remission can be achieved in about 20% of patients [11]. These studies included patients mainly with perianal or enterocutaneous fistula. In a post-hoc analysis from the ACCENT II study, infliximab was also efficacious in rectovaginal fistulas with short-term closure of 44.8% of fistula after three infusions at week 14 [12]. Nevertheless, without maintenance treatment fistulae recurred after a median duration of 46 weeks. Abscess formation was not more frequent in the infliximab group compared to placebo. 2.1.2

2.2

Adalimumab Adalimumab for luminal Crohn’s disease

2.2.1

A problem with the chimeric infliximab is the antibody formation against the murine parts of this peptide leading to loss of response and the need for concomitant immunosuppression with azathioprine. Adalimumab is a fully humanized anti-TNF antibody that has proven efficacy in Crohn’s disease. In the first trial called CLASSIC I 299, patients were randomized to receive three different dosages of subcutaneous adalimumab or placebo [13]. Treatment was repeated after 2 weeks with 50% of the initial dose. After 4 weeks, 36% of patients achieved remission with the optimal dose (160/80 mg) of adalimumab. The most common side effects were injection

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Therapeutic peptides in IBD

site reactions. About 3% of patients receiving the highest adalimumab dose experienced infections that were reported as serious adverse events. A follow-up study showed that this remission could be obtained in responders by continuing the adalimumab therapy. Patients with a stable remission after three doses of adalimumab (55/299) were randomized to either receive adalimumab 40 mg every 2 weeks or placebo [14]. After 54 weeks, 79 and 84%, respectively, of these highly selected responders were still in remission. Nevertheless, when referring to the initial study population, < 30% of all patients who had received adalimumab achieved sustained long-term remission. Frequency of infectious adverse events was not more frequent in the adalimumab group. About 2.6% of patients developed antibodies against adalimumab. In a further randomized long-term study (CHARM), adalimumab has been given to patients with chronic active Crohn’s disease [15]. All patients received adalimumab 80 mg followed by 40 mg after 2 weeks. Responders at week 4 were randomized to receive either adalimumab 40 mg or placebo weekly or 2-weekly. After 56 weeks, remission rates in the adalimumab groups were 41 and 36%, respectively. Similar to the ACCENT I data on infliximab, these results should be interpreted with caution. Again, when referring to the complete study population, long-term remission rates with adalimumab are very similar to the infliximab data approaching only 20 -- 25% of patients. Interestingly, roughly 50% of the patients had received immunosuppression with purine analogs or methotrexate in parallel so that the therapeutic effect cannot be attributed solely to the adalimumab. Overall, infectious complications were not more frequent in the adalimumab groups. Two cases of pulmonary tuberculosis were reported in adalimumab-treated patients. Adalimumab for fistulizing Crohn’s disease Data on the efficacy of adalimumab in fistulizing Crohn’s disease come from a subgroup analysis of the CHARM trial. A total of 117 patients had draining fistulas, and according to the CHARM protocol, 70 patients were randomized to receive adalimumab versus 47 who were to receive placebo [16]. About 59% of adalimumab-treated patients had fistula closure after 2 years of therapy. Although adalimumab apparently shows efficacy in fistulizing Crohn’s disease, results have to be interpreted with caution. First, data come from a post-hoc analysis; second, again there was a selection bias by selecting responders and third, data on fistula closure in the placebo group are not given. Eight patients in the adalimumab group developed abscess formation. 2.2.2

Certolizumab-Pegol Certolizumab is a PEGylated antibody containing the TNF-binding Fab fragment that in contrast to infliximab and adalimumab does not induce apoptosis of T lymphocytes and monocytes. Certolizumab has been tested in a Phase II study in a cohort of nearly 300 patients with moderate-tosevere Crohn’s disease [17]. Patients were given certolizumab 2.3

in three different dosages or placebo subcutaneously every 4 weeks. After 12 weeks of treatment, remission rate with optimal dosing of certolizumab was 27% and not significantly different from the placebo results (23%). Nevertheless, another two studies were initiated, named PRECISE 1 and PRECISE 2. In the first study, 662 patients were randomized with respect to the elevation of the patients’ C-reactive protein to receive either 400 mg certolizumab or placebo subcutaneously for 26 weeks [18]. Similar to the Phase II study, there was no difference concerning remission rates between certolizumab and placebo at the primary end points at weeks 6 and 26, regardless of the C-reactive protein. The second study (PRECISE 2) used the usual study design for biological therapies described above [19]. A total of 668 patients received three subcutaneous injections of certolizumab at weeks 0, 2 and 4. For reasons unknown the response rate at week 6 was markedly higher when compared to results from the equally designed PRECISE- 1 (64 vs 37%). Only responders were then randomized to receive certolizumab or placebo for another 24 weeks. At week 26, 48% of patients in the certolizumab group were in remission compared to only 29% in the placebo group. Referring to the initial cohort this translates into an overall remission rate of 31% after 26 weeks. In the PRECISE 2 study, the rate of serious infections was significantly higher in the certolizumab group compared to placebo (3 vs < 1%). The results from these three studies did not convince the authorities, and certolizumab is not licensed in Europe apart from Switzerland. Taken together the results from the large trials on infliximab and adalimumab clearly show efficacy in Crohn’s disease. The two anti-TNF antibodies licensed for Crohn’s disease infliximab and adalimumab are potent agents for remission induction, but sustained maintenance of remission is the exception rather than the rule. Open questions There are some questions that are currently discussed, which are dealt with in the following subsections. 2.4

Infliximab plus/minus azathioprine? Should infliximab be combined with azathioprine? The rational for this approach is the frequent antibody formation against the murine parts of the chimeric antibody resulting in a loss of response to infliximab. The first randomized study to investigate this approach compared the combination of infliximab (three infusions, 5 mg/kg infliximab) and azathioprine with azathioprine alone in steroid-dependent Crohn’s disease [20]. One-half of the patients were azathioprine--naı¨ve and the other one-half had received azathioprine previously. Results are difficult to interpret due to the rather small subgroups with about 30 patients each. The main message is that combination therapy was significantly superior when compared to the azathioprine monotherapy. Steroid-free remission rates at week 24 were 63% for the infliximab group versus 32% for the formerly azathioprine-naı¨ve group. 2.4.1

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Nevertheless, this superiority was less pronounced after 52 weeks (52 vs 32%, n.s.). These results encouraged the designing of the so-called SONIC study. In this landmark trial, 508 early Crohn’s disease patients naı¨ve to immunomodulator and biological therapy were randomized to either receive infliximab or azathioprine or the combination of both [21]. Primary end point of this study was the steroidfree remission at week 24. The combination of infliximab and azathioprine was significantly more effective in inducing remission (56.8%), when compared to infliximab (44.4%) or azathioprine alone (30.6%). These results are convincing but the study design raises several questions: Included were patients with moderate-tosevere Crohn’s disease resistant to mesalazine or budesonide. Due to these inclusion criteria, a substantial proportion of patients in the SONIC study have not been treated optimally before randomization to a rather aggressive therapy regime. Further, the authors state that 93 patients had no endoscopic evidence of active disease and endoscopic results could not be evaluated in a further 90 patients. This also raises doubt about the severity of disease at inclusion. Should SONIC change our treatment algorithms and should the combination of infliximab and azathioprine be given to (almost) all patients with Crohn’s disease early in the course of disease? Reflecting on the facts that the SONIC trial included inadequately treated patients and that about one-third of patients showed no or doubtful endoscopic evidence for active disease the relevance of SONIC for daily practice is questionable, especially as the results cannot be extrapolated to more advanced disease or a disease duration of > 2 years. Interestingly, still one-third of patients responded to azathioprine alone, although the classical steroid induction necessary to optimize azathioprine results was missing in the azathioprine arm. Step-up or top-down? At present, there is much debate about which aggressive therapy should be chosen in Crohn’s disease. The ‘classical’ conservative approach is a ‘step-up’-principle that foresees a stepwise escalating therapy, and the ‘top-down’ approach promotes an early aggressive therapy, including the biological agents, that is anti-TNF antibodies. The rational for this latter approach is the new paradigm that ‘mucosal healing’ should be more than a secondary treatment goal. The anti-TNF antibodies as well as the classical immunomodulators azathioprine, mercaptopurine and methotrexate are capable of inducing improvement in mucosal lesions. In contrast, corticosteroids, the ‘gold-standard’ for inducing remission in Crohn’s disease, although extremely effective in inducing clinical remission are generally not [22]. To date there is only a single study comparing the two treatment approaches in a patient cohort with early Crohn’s disease [23]. The first group received the ‘classical’ step-up approach, starting with systemic steroids followed by azathioprine and adding infliximab if necessary. In the second group, all patients received infliximab combined with azathioprine (top-down). After 2 years 2.4.2

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significantly more patients in the top-down arm (75%) achieved ‘mucosal healing’ when compared to the step-up arm (21%). Mucosal healing Probably everyone in the field agrees that a normal is better than an inflamed appearing mucosa but what price are we willing to pay for this goal? In a Scandinavian study, 141 patients were followed up clinically and endoscopically for over 5 years [24]. Only a few patients with improved mucosa on treatment (pre-anti-TNF-aera) suffered from fistulae and needed systemic steroids. Nevertheless, there was no significant decrease in the flare frequency or the need for surgery, comparing patients with or without ‘mucosal healing’. Recently, another small study has been published as a follow up of the above-mentioned step-up versus top down study [25]. After 2 years, follow-up patients in the ‘mucosal healing’ cohort reported significantly more often a stable and steroidfree remission when compared to patients with macroscopically inflamed mucosa (70.8 vs 27.3%, p < 0.04, odds ratio = 4.4). Interestingly, there was no difference in the outcome of patients with respect to the former treatment. Thus, there is a strong signal that ‘mucosal healing’ is beneficial regardless how and by which means it is achieved. Are these results convincing enough to predict the disease course in the individual patient based on the mucosal findings? And are we willing to escalate therapy in a clinically well patient on the ground of the endoscopical findings having in mind that therapeutic options are limited and side effects are potentially severe? We think that a more conservative approach and a more restrictive use of anti-TNF antibodies in Crohn’s disease is advisable. This is based on two principal considerations. On the one hand, there is a substantial proportion of patients with Crohn’s disease who will never require azathioprine or anti-TNF antibodies in their life. In the step-up versus top-down trial by D’Haens et al. [23], only 60% of patients in the step-up arm had a need for azathioprine and only 20% for infliximab during the first 2 years. This means that an unselective early use of these agents results in a significant and avoidable overtreatment of a substantial proportion of patients. The second consideration is that due to the limited treatment options in Crohn’s disease, the most effective (and aggressive) treatment options should be reserved for the severe and refractory cases. Otherwise no conservative treatment options are left once (aggressive) first-line therapy has failed or the patient relapses early and surgery is the only possible approach. 2.4.3

Exit strategies Regardless of when, in the course of disease, remission has been achieved by a combination of anti-TNF antibodies and azathioprine, the question is how remission should be maintained. This is especially important with respect to the risk for opportunistic infections and lymphoma under 2.4.4

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Therapeutic peptides in IBD

combination of immunosuppressants. Van Assche et al. randomized 80 patients with stable remission under combination therapy of infliximab and immunomodulators (azathioprine, mercaptopurine or methotrexate) to either continue both therapies or to stop immunomodulators [26]. There was no difference between both groups regarding the need for additional infliximab or for stopping infliximab treatment due to intolerance. The authors concluded that there is no benefit when continuing combination therapy for longer than 6 months and azathioprine can be stopped. Nevertheless, in both groups roughly 50% of patients needed additional infliximab infusions due to increasing disease activity. Almost every fourth patient had to stop infliximab due to loss of response or intolerance. The alternative to avoid double immunosuppression is to stop infliximab and continue the immunomodulator therapy. This has been tested in a study with 115 patients in stable steroid-free remission after 6 months of combination therapy. Similar to the previous study, 43.9% of patients relapsed within 12 months [27]. Remarkably, in 88% of patients, remission could be achieved again by reinducing infliximab therapy. In our opinion, the latter approach seems to be more plausible. First, a stable remission of > 50% of patients under azathioprine alone is a convincing result. Second, the option of an effective ‘rescue’ therapy in case of relapse still exists. Adalimumab or infliximab? Now, which of the two agents should be used first? Is there an advantage of one therapeutic peptide over the other? There is no direct head-to-head comparison of infliximab and adalimumab. In general, infliximab will be combined with azathioprine initially in order to minimize antibody formation. Nevertheless, in the large adalimumab trials, a substantial proportion of patients have received immunomodulators in parallel as well. Given the similar efficacy, decision will mainly rely on the patient’s preference regarding the route and frequency of administration. Once decision has been made and therapy is initiated, an unnecessary change of agents should not be undertaken. In a study on 73 patients with stable remission under infliximab, patients were switched to adalimumab. Almost 50% of patients did not benefit and had to increase the adalimumab dose or to stop treatment [28]. The situation is different if patients lose response or tolerance to infliximab. A trial randomized 325 patients with infliximab failure to either receive adalimumab (160/80 mg) or placebo. After 4 weeks, 21% of patients in the adalimumab group but only 7% in the placebo group achieved remission again [29]. Therefore, a second antiTNF antibody is an option if the first one has failed. 2.4.5

Risks of anti-TNF antibodies in Crohn’s disease Mortality is increased with anti-TNF antibodies. Most data are available for infliximab, but due to the similar mechanism of action no major differences are expected between infliximab and adalimumab. Three large cohort studies report an increased mortality rate with infliximab treatment up to 2.5

2.8% [30,31]. The largest of these studies is a retrospective evaluation of 500 patients from the Mayo Clinic. Of the 500 (6%) patients, 30 had severe side effects associated with infliximab and the infliximab-associated mortality was 1%. Special attention has to be paid to the development of opportunistic infections. Especially when using combination immunosuppression with steroids and/or immunomodulators, the risk for opportunistic infections increases exponentially [32]. To date, there are limited data on the risk for lymphoma under anti-TNF therapy. In a meta-analysis of patients with rheumatoid arthritis, anti-TNF antibodies increased the risk for lymphoma threefold [33]. Undoubtedly, the risk is increased by the combination of thiopurines and anti-TNF antibodies. In the large CESAME cohort, including almost 20,000 patients, the combination therapy increased the risk for lymphoma 10-fold [34]. Alarming are data on the occurrence of lethal hepatosplenic T-cell lymphomas in mainly young male patients on combination therapy [35]. Although overall rare, this association also calls for a restricted use of combination immunosuppression and is another argument against an unselected ‘top-down’ strategy. 3.

TNF inhibitors in ulcerative colitis

Although ulcerative colitis shares some similarities with Crohn´s disease, it is obviously not the same. The disease is almost limited to the colon, is non-transmural in nature and colectomy is able to eliminate the affected organ. Apart from complications related to operation and restorative pouch formation itself (e.g., pouchitis, fecal incontinence, impaired fertility), the inflammation subsides. Hence, ulcerative colitis may be termed a time-limited disorder. With respect to pathogenesis, inflammation in ulcerative colitis is thought to be Th2-driven or dominated, highlighted by the induction of IL 4, 5 and 10. As in Crohn’s disease high TNF-a levels can be found in mucosal tissue exemplified by release from lamina propria mononuclear cells [36,37]. Hence, this proinflammatory cytokine is involved in ulcerative colitis and a mechanistic approach may indicate that blocking TNF is effective. Indeed, early series showed a mixed response on administration of infliximab as the first anti-TNF-a antibody in ulcerative colitis. But which ulcerative colitis patient requires TNF antagonist treatment? The mainstay of remission induction and maintenance in mild disease is 5-aminosalicylic acid. More severe forms have a favorable outcome with systemic steroids and steroid sparing may be accomplished by use of purine analogs in the long term. Data from the IBSEN cohort revealed an intermittent course in 37% and ongoing activity in 6% [38] of patients. On the opposite, no intensified therapy is warranted in about 50% of patients. Analysis from Edinburgh in a cohort of steroid-treated patients reported a steroid dependency in 17% of patients and steroid refractoriness in another 18% [39], which resembles data from USA [40]. To sum up, 40% of patients do need continuous therapy at some time point.

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Infliximab as the first approved anti-TNF agent appeared to have modest activity in small series in ulcerative colitis. But the efficacy was lower in Crohn’s disease and therefore the study programs headed for Crohn’s disease in the beginning. This changed with the two ACT studies in 2005, which were launched in parallel to define the role of infliximab in ulcerative colitis [41]. Patients eligible for ACT1 and 2 encompassed moderate-to-severely active ulcerative colitis. Overall, 364 patients were randomized for each of the two studies and assigned to placebo, 5 or 10 mg/kg infliximab at weeks 0, 2 and 6. In ACT1, treatment was continued on an 8-weekly basis up to 46 weeks, and in ACT2, treatment was continued for 22 weeks with a follow up of 54 and 30 weeks, respectively. More than 50% of the patients received corticosteroids (> 20 mg prednisolone/day in 40%), one-third of them were deemed to be steroid-refractory. Almost every second patient received a purine analog. Clinical response at week 8 was considered as the primary end point. This was achieved with 5 mg infliximab in 69.4/61.5% (ACT1/2), with 10 mg infliximab in 61.5/69.2% and with placebo in 37.2/29.3%. Remission at week 8 was less (5 mg infliximab 38.8/33.9%, 10 mg infliximab 32/27.5%, placebo 14.9/5.7%). The mucosal healing rate at week 8 was astonishingly high while on infliximab (60%) and twice as high compared to placebo. Another secondary end point was sustained clinical remission, meaning remission at weeks 8, 30 (ACT2) and 54 (ACT1), if accessible. Overall, one out of five patients achieved this goal with infliximab (5 mg infliximab 19.8/14.9, 10 mg infliximab 20.5/22.5%), the placebo rate was about 5%. The data did not show major differences in efficacy between the two doses. Thus, the authors concluded 5 mg infliximab to be the preferred initial dosing regimen. A post-hoc analysis tried to define the surrogate marker mucosal healing as a predictor for the further course in the ACT studies [42]. Although mucosal healing at week 8 was associated with a beneficial outcome, for example, no need for subsequent colectomy or sustained remission, it became clear that this was not better than easily accessible clinical parameters. At the same time, another interesting investigation was published. Ja¨rnerot et al. undertook a randomized placebocontrolled trial in steroid-refractory ulcerative colitis [43]. Patients received either placebo or 5 mg infliximab as a single infusion after failure of systemic corticosteroids. The need for colectomy at 3 months was the suggested primary end point. While 67% of the placebo-treated patients underwent an operation, the same percentage (71%) of patients with infliximab circumvented surgery. This dramatic therapeutic advantage decreased over time, but still 50% of the patients in the infliximab arm had a favorable outcome after 3 years -- one predictor being mucosal healing at 3 months [44]. The fully humanized antibody adalimumab was also evaluated in ulcerative colitis. Two studies in parallel were conducted to establish efficacy and safety in patients with moderate-to-severe disease activity. In comparison to the ACT studies, patients in ULTRA2 were more often pretreated 460

with immunosuppressants including anti-TNF agents. ULTRA1 was designed for remission induction only [45]. Roughly, 40% of patients received corticosteroids and 20% of them received immunosuppressants. In the end 576 patients had been enrolled and randomized to placebo, and one out of two induction arms (adalimumab 160/80 and 80/40 mg), according to the amended protocol. This was followed by two additional adalimumab 40 mg injections, all of them 2 weeks apart. The primary efficacy end point was remission at week 8 (Mayo score £ 2). In the intention-totreat analysis, remission was obtained in 18.5% with the high dose, 10% with the low dose as compared to 9.2% with placebo. Treatment benefit was somewhat more impressive which increased over time to the end of the study when focusing on the clinical Mayo subscore (~ 38 vs 18%, high dose vs placebo). Clinical response was observed in 54.6, 51.5 and 44.6% with high and low dose adalimumab induction and placebo, respectively. Hence, only the high-dose induction regimen was significantly better than placebo regarding clinical response and in the same range as infliximab. Interestingly, mucosal healing was accomplished in 38 -- 47% with no apparent differences among the groups; reasons for the impressing placebo response were not obvious and in disparity with the findings for infliximab in the ACT studies. The long-term induction and maintenance study ULTRA2 included 494 patients with moderate-to-severely active ulcerative colitis [46]. Prior treatment overall consisted of corticosteroids (58.7%), purine analogs (35%) and notably anti-TNF therapy (40.3%). Patients were allocated to receive induction with adalimumab 160/80 mg followed by 40 mg every other week or placebo up to week 50. Remission (Mayo score £ 2) was predefined as the primary outcome variable. At week 8, this was achieved in 16.5 and 9.3% with adalimumab and placebo, respectively. This did not change dramatically at week 52 (17.3 and 8.5%). Hence, remission occurred twice as often with in the adalimumab group resembling the results of ULTRA1. However, when taking remission based on the clinical Mayo subscore into account, remission was approximately 22 and 12% at week 52 (28 and 16% at week 8). The efficacy peaked at week 16 and leveled off thereafter for unknown reasons. All the above-mentioned trials revealed an acceptable safety profile of infliximab and adalimumab in ulcerative colitis. No deaths occurred, no cases of tuberculosis were recorded and the rate of serious adverse events was comparable to placebo. Infusion reaction and injection site reactions were handled by conservative measures. Hence, meticulous testing seems to dampen early threats of anti-TNF agents. Other indicators of efficacy were provided for both antibodies. Hospitalization and surgery rates decreased over time with infliximab as well as adalimumab [47,48]. Is TNF blocker monotherapy equivalent to dual treatment options? Preliminary data from the UC SUCCESS trial, which is similar to the SONIC trial in Crohn’s disease,

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indicate that a combination of infliximab and azathioprine is more effective than every agent alone [49]. Results of monotherapy with infliximab or azathioprine did not show differences in steroid-free clinical remission at week 16 (24 vs 22%, combination 40%). However mucosal healing rates were lowest with azathioprine, followed by infliximab, all of them being higher than steroid-free remission rate. The timeline of 16 weeks is a matter of debate as it may take longer for azathioprine to act. What is now the place for anti-TNF antibodies in ulcerative colitis? The authors of ULTRA2 state that it may be used on the moderate-to-severely diseased or impaired outpatient. We would like to add, those who failed classical immunosuppression as a considerable portion of patients benefit from purine analogs. Do we have an alternative in severe disease? Calcineurin inhibitors have indeed been shown to induce remission in up to 80% of steroid-refractory patients [50-53]. A recent comparative trial of the GETAID has elegantly shown that infliximab and cyclosporine are equally effective in the short term [54]. Treatment failure and colectomy rates at 3 months were indistinguishable. The preference for one of the drugs relies in our view on prior treatment with purine analogs. As calcineurin inhibitors should not be administered for maintenance, purine analog nonresponders or failures should be allocated to infliximab or adalimumab. In naı¨ve steroid-refractory patients, calcineurin inhibition is clearly an option. 4.

Novel therapeutic peptides in IBDs

Here, we focus on those therapeutic peptides that we find most promising to reach the market and benefit patients (Table 1). The different compounds are in various stages of development and may still fail in final steps of their premarketing career. Some negative instances are also considered which failed clinical studies but provided insight into the value of novel therapeutic concepts. However, as somebody noted before, predictions are difficult, especially concerning the future. Golimumab Golimumab is a novel antibody against TNF-a that is administered subcutaneously. The low injection volume and chemical composition are associated with minimal local irritation. In Europe, the drug is marketed under the name Simponi by Merck Sharpe and Dohme and is approved by the European Medicines Agency (EMA) for the treatment of rheumatoid arthritis, Bechterew’s disease and psoriasis. Evidence for efficacy in moderate-to-severe ulcerative colitis is based on the combined large Phase II and III trials recruiting a total of 1064 adults [55]. Patients selected had disease activity refractory to conventional treatment. In Phase III, rates of clinical response at 6 weeks were 51.8 -- 55% versus 29.7% in the placebo group. Rates of clinical remission, mucosal healing and IBD questionnaire scores were also significantly higher in 4.1

both golimumab dose groups compared to placebo. Serious adverse events and serious infections were numerically higher in the placebo compared to golimumab groups. This induction trial was followed by the PURSUIT study which selectively recruited golimumab responders to receive 50 or 100 mg of golimumab or placebo. At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab every 4 weeks were in remission and had mucosal healing (28.6 and 43.5%) than patients given placebo (15.4 and 26.9%) or 50 mg golimumab (23.5 and 41.8%, respectively). Serious adverse events were observed in 7.7, 8.4%and 14.3% and serious infections in 1.9, 3.2 and 3.2% of the placebo, 50 or 100 mg golimumab groups, respectively. Among all patients given golimumab in the study, three died from sepsis, tuberculosis and cardiac failure and four developed active tuberculosis. Notably, large trials on Crohn’s disease are lacking and are eagerly awaited. In Europe, approval of the drug for ulcerative colitis is imminent and will add another TNF-antibody to the therapeutic armamentarium. However, it is unclear whether it does indeed provide additive benefit to the patients who are intolerant or refractory to the established infliximab or adalimumab. Again, the results are skewed due to the bias of recruiting the drug responders. In total, taking both studies together, only a small minority of patients achieved longterm remission and mucosal healing, if the starting cohort is taken as the denominator. In addition, the side-effect profile is not perfect and demonstrates similarity to the other anti-TNF antibodies. Vedolizumab This compound may be considered to be a successor of natalizumab, both being antibodies directed against an integrin. Integrins a2b2, a4b1 and a4b7 are expressed on leukocytes as well as other mammalian cells and mediate tissue immigration by binding to their respective endothelial receptors intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and Mad-CAM 1. Antibody blocking of the integrin interferes with cellular tissue invasion of the inflammatory cells carrying the antigen. The anti-a4 antibody natalizumab acted broadly on various tissues, including the brain where it may lead to reactivation of human polyoma JC-virus infections and subsequent progressive multifocal leukoencephalopathy (PML) in about 1/500 treated patients. The compound is approved for multiple sclerosis as well as therapy refractory Crohn’s disease in the USA but it is not licensed for Crohn’s disease by the EMA. A meta-analysis concluded [56] that natalizumab is superior to placebo in achieving remission in Crohn’s disease but since lethal JC-virus infection may occur in about 1/1000 patients it is probably wise to avoid its use in a non-lethal disease. In contrast, vedolizumab specifically attacks a4b7 and does not appear to increase PML risk. This integrin is significantly expressed in the gut and results have been positive in both ulcerative colitis and Crohn’s disease. Pharmacokinetic and 4.2

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Table 1. Evolution of therapeutic peptides in IBD.

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Compound Infliximab Adalimumab Certolizumab Golimumab Vedolizumab Ustekinumab Secukinumab Interleukins 10/11 Interferon b G-CSF/GM-CSF

Target/function

Disease

TNF a TNF a TNF a TNF a a4b7 integrin ILs-12/23 IL-17 Regulatory cytokines Regulatory cytokine Growth factors

CD, CD, CD UC CD, CD CD CD CD, CD

UC UC

UC

UC

Status in IBD On market On market On market in some countries Approved for UC Approval expected 2014 Approved for psoriasis, not IBD Negative trial Negative trials Negative trials Negative trials

CD: Crohn’s disease; IBD: Inflammatory bowel diseases; UC: Ulcerative colitis.

pharmacodynamic studies demonstrated that a4b7 receptors on peripheral lymphocytes are maximally saturated at all serum concentrations tested [57]. The clinical evidence of efficacy is somewhat less convincing for Crohn’s disease [58] than for ulcerative colitis [59]. In the latter disease, two integrated randomized, double-blind, controlled trials were performed and at 6 weeks 47.1% of vedolizumab-treated patients responded compared to 25.5% on placebo. Again, responders were picked to continue on the antibody or on placebo, resulting in 41.8 -- 44.8% in remission on the drug given every 4 -- 8 weeks versus 15.9% on placebo. The frequency of adverse events was similar in all groups. In similar consecutive trials in Crohn’s disease, only 14.5% were in remission at week 6 as opposed to 6.8% on placebo. This amounts to a number needed to treat of 13, that is, 13 patients have to be treated to achieve one additional remission. Of those responding, 36.4 -- 39% of patients were in remission at week 52, as compared to 21.6% on placebo. Taking the 6-week response and the 52% remission rate together a mere 12.2% of the starting population ended up in remission at the end of the trial. The corresponding number in the ulcerative colitis trials was 21.1%, that is, around 4/5 patients fail to achieve long-term remission in ulcerative colitis and 7/8 in Crohn’s disease. It is expected that vedolizumab will be granted approval by the European authorities in mid-2014. However, based on the numbers given above, it is clear that blocking a4b7 integrin is of only limited long-term benefit to patients with IBDs, although having further options extending to new targets is valuable.

Ustekinumab This antibody is directed against both IL-12 and -23 and is approved in psoriasis. In a large trial [60] with 526 antiTNF-a-refractory patients, the primary end point of induction response at 6 weeks was reached in 34.1 -- 39.7% of ustekinumab-treated patients at three different doses of 1 -- 6 mg/kg versus 23.5% in the placebo group, whereas 4.3

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remission rates at this time point were not statistically significantly different. At 22 weeks, the difference between remission rates compared to placebo was only 14.3% (41.7 vs 27.4%) in the 145 patients studied. Serious infections occurred in 7 patients of whom 6 were on the antibody during induction and 11 patients during maintenance, 4 of whom were receiving ustekinumab. It remains to be seen whether these very limited effects suffice for registration in this disease. Secukinumab The monoclonal antibody secukinumab binds IL-17A and is proven effective in psoriasis and rheumatoid arthritis. Polymorphisms in the IL-23 gene have suggested that the IL-23 to IL-17 axis may be important in IBD pathogenesis. Surprisingly, this compound was not only ineffective in Crohn’s disease but also deteriorated its course compared to placebo [61]. It is likely that IL-17A, and may be many other ILs, serves a dual, both proinflammatory and protective function. Thus, if a protective effect is blocked and if this exceeds the relative proinflammatory impact of a given target deterioration may result. 4.4

Interleukins and growth factors The quest for the therapeutic application of potentially ‘antiinflammatory’ ILs has been similarly frustrating. Initially as one of these immunomodulatory natural peptides IL-10 was studied in Crohn’s disease but the results were disappointing [62]. It was argued that at the doses administered very little of the peptide would reach the site of inflammation and a way to enhance local delivery was to administer transgenic bacteria expressing IL-10 [63]. Unfortunately, even this ingenious approach did not benefit patients with Crohn’s disease. It remains to be studied whether certain subpopulations, for example, those with a genetic defect of IL-10, could experience a relief if substituted with the missing IL but this necessarily is a very small subgroup. We have then attempted the clinical application of IL-11 but have also failed to show clear benefit [64]. With interferon-b, the trial results are very 4.5

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Therapeutic peptides in IBD

heterogeneous but the conclusion has to be that in the controlled trials it did not work [65,66]. Finally, a series of growth factors related to innate immunity such as granulocyte or granulocyte/monocyte colony stimulating factor (G-CSF and GM-CSF) have been subjected to clinical trials but in the end all failed [67].

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5.

Expert opinion

Among the therapeutic peptides in IBD, anti-TNF antibodies clearly have the leading edge. They were proven to be effective both in Crohn’s disease and ulcerative colitis and both in induction as well as maintenance. For obvious reasons, the pharmaceutical producers and some clinical advisors prefer a top-down strategy implementing early use of these compounds in the course of disease. On this behalf even novel end points such as mucosal healing or ‘deep remission’ have been developed which require very aggressive treatment. Although the end points are certainly nice to have with respect to reduced hospitalization or surgery, these end points are achieved only in a fraction of patients. In addition, with an annual cost of US$116.291 per responder for infliximab in the United States [68], this treatment is excessively expensive. In some countries cost for these antibodies has become the major part of total expenditure for IBD patients. It should also be considered that with only around 20% of the treated patients in remission after 1 year, there is a large majority of patients requiring other options, including surgery. In terms of side effects, anti-TNF doubles the risk of opportunistic infections in a recent meta-analysis [69]. Cancer incidence in treated patients in the short term is reassuringly low [70] but lymphoma is an issue [34,71]. It is also unfortunate that postoperative complications appear to increase in these Bibliography

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Affiliation Klaus R Herrlinger1, Eduard F Stange2 & Klaus Fellermann†3 † Author for correspondence 1 Asklepios Hospital Nord -- Heidberg, Department of Internal Medicine I, Tangstedter Landstr. 400, 22417 Hamburg, Germany 2 Robert Bosch Hospital, Department of Internal Medicine I, Auerbachstr. 110, 70376 Stuttgart, Germany 3 University Hospital Schleswig-Holstein, Division of Gastroenterology, Department of Internal Medicine I, Ratzeburger Allee 160, 23538 Lu¨beck, Germany Tel: +0049 451 500 6245; Fax: +0049 451 500 6242; E-mail: [email protected]

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Therapeutic peptides in inflammatory bowel disease.

Therapeutic peptides in inflammatory bowel diseases essentially comprise cytokines affecting immune response, growth factors and monoclonal antibodies...
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