Discontinued Drug Perspective
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Inflammatory bowel disease therapies discontinued between 2009 and 2014 1.
Introduction
2.
Search strategy
3.
Results
4.
Conclusion
5.
Expert opinion
Shilan Mozaffari, Shekoufeh Nikfar & Mohammad Abdollahi† †
Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology, Tehran, Iran
Introduction: New therapeutic approaches are currently under development, which consider the fundamental mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). The disease is associated with inflamed intestinal and colonic mucosa in response to the dysregulated immune system. Areas covered: The aim of this article is to review drugs that have been designed for the treatment of IBD and discontinued between 2009 and 2014. Herein, nine molecules with different mechanisms of action are under review. Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from the Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. Finally, NU-206 and alkaline phosphatase also ceased in development during Phase I and II tests. Expert opinion: The development in our knowledge and understanding of the pathophysiology of IBD and the identification of key objectives for the future play significant roles in IBD therapeutic development. Furthermore, well-planned clinical trials with concise measures of efficacy and safety are required to better decide whether to extend or terminate the development process. Some anti-inflammatory cytokines such as IL-2, IL-12, IL-17, IL-18, IL-23 and INF-g could garner more attention in the future. Keywords: Crohn’s disease, discontinued treatment, inflammatory bowel disease, ulcerative colitis Expert Opin. Investig. Drugs [Early Online]
1.
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD) as two inflammatory conditions of the gastrointestinal (GI) tract are generally recognized as inflammatory bowel disease (IBD). The disease is associated with consequent symptoms of the inflamed intestinal and colonic mucosa in response to the dysregulated immune system [1]. Referable to the debilitating effect of disease in affected patients, there are several molecules designed by the pharmaceutical companies that undergo several stages of clinical tests. However, available approved medicines are 5-aminosalicylate (mesalamine and sulfasalazine), corticosteroids, antibiotics, anti-TNF and immunosuppressive drugs (azathioprine, mercaptoprine and methotreaxate) [2-9]. It is suggested that in addition to genetic backgrounds, a recent intestinal infection or alteration of GI microflora, immune dysregulation and some environmental agents such as oxidative stress are involved in the pathophysiology of IBD [10,11]. Regarding the underlying mechanisms involved in the pathogenesis of IBD, there are developing therapeutic options assessed for the treatment or ameliorating the condition. In that respect are several biologic drugs such as adalimumab, 10.1517/13543784.2015.1035432 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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S. Mozaffari et al.
Article highlights. .
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Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from a Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and thus its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. NU-206 and alkaline phosphatase were stopped from developing within Phase I and II trials. As significant high levels of IL-17 have been discovered in the inflamed tissues of the intestine in ulcerative colitis (UC) and Crohn’s disease (CD) patients, inhibiting the expression of IL-17 or blocking its receptor was of clinical importance to bring off the inflammation; however this therapeutic target was not successful. Abatacept did not demonstrate any significant any more beneficial effects in CD patients than placebo and this may indicate that non-specific T-cell inhibition is not enough to keep remission in inflammatory bowel disease (IBD) patients. Increasing the knowledge on the pathophysiology of IBD and identifying the key objectives are role-playing factors in the treatment of IBD. In CD, activation of Th1 and Th17 through IL-12, IL-18 and IL-23 increases the secretion of IL-2, IL-17, INF-g and TNF-a. With UC, inflammation of the colon is associated with Th2 immune responses elicited by an increase of IL-4, IL-5 and IL-13. Well-designed clinical trials with concise measures of efficacy and safety are needed to better decide whether to extend or terminate the development procedure.
This box summarizes key points contained in the article.
certolizumab pegol, etanercept and golimumab that are approved as anti-TNF drugs. In addition, rituximab and abatacept are approved as anti-CD20 and T-cell inhibitors, respectively. Natalizumab and vedolizumab are new medicines with the mechanism of a4 integrin inhibition [12,13]. The lack of either response or maintaining the remission, and initiation of serious adverse events with currently available medicines, make the pharmaceutical companies to continue to look for novel therapies. New designed molecules are being looked into various pre-clinical to Phase III of clinical tests to get the license, but there is forever a possibility for each medication to be taken away in each phase of study. The present review focused on the recently designed molecules for the treatment of UC and CD, which their development has been stopped due to lack of efficacy, presence of adverse events or because of market issues. 2.
Search strategy
Electronic databases, including PubMed, Clinical Trial.gov, Google Scholar and Cochrane Central Register of Controlled trials, were sought for all pre-clinical and clinical trials, which assessed the efficacy and safety of novel drugs for IBD 2
(CD, UC) up to 2014 September. The applied key words were efficacy, safety, UC, CD and IBD. All titles, abstracts and reference sections were studied to find relevant articles evaluating new therapeutics for IBD. The articles in which the investigated drug is approved or is in process were omitted. The included studies were on the efficacy and safety of molecules that their clinical trials have been stopped or failed and pulled back from the development process from 2009 to 2014. The collected available data were summed up in a table according to the drug therapeutic class, mechanism of action, chemical name, administration route and the type of IBD in patients (Table 1). 3.
Results
Brodalumab Brodalumab is a human mAb for IL-17 receptors. It is under development for the treatment of rheumatoid arthritis (RA), psoriasis and CD. Its mechanism of action is via blocking the IL-17, and IL-25 (IL-17E) signaling to control the associated inflammatory pathways. These cytokines can induce NF-kB activation and stimulate the production of other inflammatory cytokins [14,15]. Phase I and II clinical trials in healthy volunteers and patients with psoriasis have been conducted to determine the pharmacokinetics of brodalumab [16]. The results demonstrate the influence of body weight on some pharmacokinetic variations of the drug. The age or disease status did not clinically affect the pharmacokinetics of drug [16]. As brodalumab is being assessed for the treatment of psoriasis, in the major part of studies, its safety and efficacy were evaluated in psoriasis patients [17]. Consequently, at that place are few available data for its efficacy in CD patients. In that location were two registered clinical trials assessing efficacy and safety of brodalumab in CD. A randomized double-blind placebo-controlled Phase II clinical trial has been conducted to assess the efficacy and safety of brodalumab (700 mg intravenous [i.v.]) in 130 CD patients. The work however has been terminated [18]. Another open-label Phase II study evaluated the safety and efficacy of the drug (350 mg i.v. q 4 weeks for 30 months) in 67 CD patients and was also terminated [19]. Brodalumab has not been examined in Phase III trials for CD and then its development has been discontinued for RA and CD. Due to non-published results, no reasons have been noted for termination of studies. 3.1
Daclizumab Daclizumab is a humanized mAb that blocks the receptor of IL-2 (CD25) on T-cells. This contributes to the inhibition of lymphocyte proliferation and differentiation [20]. Daclizumab is approved for the prevention of rejection in organ transplantation. It has been also evaluated for the management of autoimmune disorders, including UC [20]. Daclizumab has been marketed in the USA since 1997. A randomized, single-blind Phase I trial was directed to assess 3.2
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Immunoglobulin G 1 (human-mouse monoclonal clone 1H4 g-chain anti-human IL 2 receptor) Urea, N-(2-chloro-3-fluorophenyl)-N¢[4-chloro-2-hydroxy-3-(1-piperazinylsulfonyl) phenyl]-
Daclizumab
Expert Opin. Investig. Drugs (2015) 24(7)
CD: Crohn’s disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.
Alkaline phosphatase
NU-206
Recombinant, Blood fraction Haemostatic Recombinant, Radio/ chemoprotective Stomatological
Fusion protein
Abatacept
CNDO-201 ASP 1002 Catridecacog Blood-coagulation factor XIII [CAS]
mAb
mAb
mAb
Therapeutic class
Vatelizumab
1-25-oncostatin M (human precursor) fusion protein with CTLA-4 (antigen)
Immunoglobulin G, anti-(human IL 17 receptor A)
Brodalumab
Elubrixin
Chemical name
Drug name
II
a2b1 integrin antagonist
Alkaline phosphatase stimulant
Wnt pathway stimulant
Factor XIII stimulant
II
I
II
Immunostimulant II
CD80 antagonist III
II
II
II
Safety and efficacy
Tolerability, safety and efficacy Tolerability, safety and efficacy Safety and efficacy Tolerability, safety and efficacy Tolerability and safety
Tolerability, safety and efficacy Tolerability, safety and efficacy Safety and efficacy
Phase of Clinical end discontinuation point
IL-8 receptor antagonist
IL-2 receptor antagonist
IL-17 receptor antagonist
Mechanism of action
Table 1. Characteristics of discontinued drugs for the treatment of IBD.
CD, UC
CD, UC
CD, UC UC
CD, UC
UC
UC
UC
CD
Injectable
Injectable
Injectable
Oral
Injectable
Injectable
Oral
Injectable
Injectable
IBD Administration type Route
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Not determined
Not determined
Lack of efficacy
Lack of safety
Lack of efficacy
Lack of efficacy
Lack of efficacy
Lack of efficacy
Lack of efficacy
Reasons for discontinuation
Inflammatory bowel disease therapies discontinued between 2009 and 2014
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S. Mozaffari et al.
the pharmacokinetics of a single-dose daclizumab in healthy volunteers besides the tolerability and safety assessments [21]. A pilot open-label, uncontrolled study was conducted to investigate the efficacy and safety of daclizumab (1 mg/kg i.v.) in 10 patients with refractory UC. Daclizumab was associated with beneficial healing effects in decreasing clinical activity score and endoscopic scores in patients. It was accounted as a safe and tolerated medicine in patients. The most reported adverse event was nausea in patients that concomitantly used azathioprine [22]. A Phase II, randomized double-blind placebo-controlled test was acquitted in 159 patients with moderate to severely active UC in 20 weeks. Different doses (1, 2 mg/kg i.v.) of daclizumab were compared to placebo at different intervals. At the conclusion of the study, daclizumab was not associated with more significant reaction in the induction of remission versus placebo. Still, it was well supported and the most frequent adverse events were nasopharyngitis and pyrexia [23]. The drug faced diminishing market demand, according to the company and as of January 2009, its marketing authorization was taken away and the product completely discontinued because of commercial reasons. Elubrixin Elubrixin (SB-656933) is an IL-8 antagonist. It was under development for the treatment of UC [24]. It is demonstrated that elubrixin has an inhibitory effect on neutrophils in a dose-dependent fashion. The outcomes of randomized double-blind placebo-controlled Phase I trials in healthy subjects showed that elubrixin was tolerable and safe [25-27]. Phase I and II clinical trials have been conducted to examine the safety and efficacy of elubrixin in patients with UC [24]. Merely as the drug development was stopped, these tests were discontinued. 3.3
Vatelizumab Vatelizumab (SAR-39658) is also a mAb that antagonizes the integrin a 2 receptors. It was produced as an immune modulator for the treatment of inflammatory disorders such as multiple sclerosis and IBD. Integrins are involved in T-cellmediated signaling in the inflammation. Various pre-clinical studies prove the efficacy of vatelizumab in colitis models [28]. Phase I trials have been taken to evaluate the pharmacokinetics characteristics, safety and tolerability of the drug in healthy cases. Vatelizumab was well tolerated. In summary, there are two registered Phase II randomized double-blind placebocontrolled trials assessing the long-term safety and efficacy of vatelizumab in UC patients [29,30]. Still, tests have been ended and development operation is stopped. 3.4
Abatacept Abatacept is a fusion protein that regulates T-cell activation via binding to the CD80 and CD86 molecule. Abatacept is a selective co-stimulation modulator via preventing antigenpresenting cells. Its selective mechanism of action brings 3.5
4
about an anti-inflammatory effect [31]. Abatacept has got a license for RA treatment. It has been evaluated in IBD patients. Granting to the outcomes of four Phase III randomized double-blind clinical trials, abatacept did not show significant efficacy in comparison to the placebo in the installation and maintenance of remission of 451 and 490 adult patients with active CD and UC, respectively [32]. According to the efficacy and safety evaluations during 12 weeks of induction and 52 weeks of maintenance therapy, trials were terminated due to the lack of efficacy and safety in patients. Abatacept was associated with high risk of treatment failure and disease exacerbation with no acceptable safety profile compared to placebo [32,33]. CNDO-201 CNDO-201 is the embryonated egg of porcine whimpworm Trichuris Suis ova (TSO). It is demonstrated that helminthes may suppress the immune reactions of their hosts [34]. CNDO-201 was developed for the treatment of several autoimmune disorders such as IBD. In that respect are various observational and clinical trials measuring the potential efficacy of TSO in IBD treatment [35-38]. Several Phase I and II clinical trials have investigated the safety, tolerability and efficacy of TSO in UC and CD treatment. A randomized Phase I clinical trial evaluated the safety and tolerability of TSO in 36 CD patients and reported no adverse effects during treatment [35]. Administration of oral TSO in a randomized clinical trial was safe and effective in 54 UC patients. It induced significant remission and clinical improvement versus placebo. TSO decreased disease activity with no important adverse effects [36]. The effects of an open-label study in 29 CD patients reported TSO as an efficacious and safe treatment [37]. In another open-label trial in four CD and three UC patients, it was demonstrated that TSO decreased disease activity and no adverse event was accounted in the recruited patient [38]. Collectively, TSO administration in human showed beneficial efficacy in UC and CD patients and was safe [39]. Nevertheless, there was a demand for further clinical trial to conclude around the safety of TSO therapy in IBD patients. Therefore the development of this drug has been discontinued. 3.6
Catridecacog Catridecacog is a recombinant factor XIII, which produced for the handling of congenital, acquired factor XIII deficiency and UC. Factor XIII is known to have a role in fibrin clot stabilization and improvement of ulcers. Various studies have demonstrated the healing effect of unfractioned or low-molecular-weight heparin in UC and CD patients [40]. In an in vitro examination, factor XIII promoted the intestinal epithelial ulcer improvement when its effect on cultures of several cell lines was evaluated [41]. In an experimental induced colitis in rats, 10 days of intravenous administration of factor XIII resulted in lessening the severity of lesions in comparison to 3.7
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Inflammatory bowel disease therapies discontinued between 2009 and 2014
control [42]. The first favorable clinical outcomes in a UC case report led to further clinical trials in UC patients with acute disease status or UC patients with refractory and lack of responsiveness to treatment [43]. Several randomized, placebo-controlled, double-blind Phase I clinical trials has been dispatched to assess tolerability, safety and pharmacokinetic profile of catridecacog in healthy volunteers. The answers indicate that catridecacog is safe and well tolerated [44-47]. Some clinical investigations have described the beneficial therapeutic effects of factor XIII in IBD patients. To evaluate the efficacy of factor XIII in UC patients, a double-blind placebocontrolled study have been conducted in 28 patients, but no significant difference was observed between the effect of factor XIII and placebo on the intestinal bleeding [40]. A Phase IIa randomized double-blind placebo-controlled study investigated the efficacy of 35 IU/kg of intravenous factor XIII in UC patients [48]. Nevertheless, the work was terminated as the outcomes did not defend the hypothesis of efficacy of factor XIII in UC and a relation between low levels of this gene and disease activity was not mentioned. Therefore, the developer company discontinued the development of this drug in 2012. NU-206 NU-206 is a recombinant protein that stimulates GI epithelial cells. It can induce repair and curing the injury in animal IBD models. This molecule was developed to assess its efficacy in various diseases including IBD. There are a few data on its evaluation and development process. In an experimentally induced colitis model, NU206 improved the inflammation. It cuts the inflammatory cytokines in the intestine significantly [49]. One double-blind, placebo-controlled Phase I trial in 32 healthy volunteers was carried on to assess the safety and pharmacokinetics of NU206. The outcomes indicated that it was safe and tolerable with no severe adverse effects [50]. Another Phase Ib trial was directed in 80 healthy volunteers, to evaluate safety, tolerability and pharmacokinetics of single and multiple doses of NU-206 [51]. Although this drug was safe, there is no clear cause for its discontinuation of evaluation in randomized trials. 3.8
Alkaline phosphatase Alkaline phosphatase is an enzyme that is demonstrated to have a role in the improvement of inflamed GI mucosa. In experimental models of induced colitis in rats, inflammation and oxidative stress resulted in activation and up-regulation of alkaline phosphatase [52]. It reduced colonic inflammation and TNF-a levels [53]. In several conducted Phase I and II trials, alkaline phosphatase was safe and significantly diminished the inflammatory cytokine and biomarkers compared to placebo [54]. Two Phase IIa trials have been enrolled with 21 patients suffering from UC and CD. Oral administration of alkaline phosphatase was efficacious in the induction of remission in patients. No severe adverse effect was described during these trials [55]. The final results have not been 3.9
published, but the development of this medicine was discontinued. 4.
Conclusion
Taken collectively, nine molecules for the treatment of IBD were discontinued during the survey period. The major goal in the treatment of IBD is to target several involved receptors and cytokines. Some potential targets are ILs. Two of discontinued drugs for the treatment of UC and CD were mAbs, which antagonize IL receptors (brodalumab and daclizumab). Elubrixin has been also designed to block IL-8 receptors. Brodalumab, daclizumab and elubrixin are IL-17, IL-2 and IL-8 receptor antagonists, respectively. Stimulating the IL-23 receptor increases the secretion of IL-17, TNF-a and IL-6 from T-cells. Granting to the known role of IL-17 pathway signaling in the intestinal inflammation, IL-17-deficient mouse as an observational model of IBD has been used and several approaches for inhibition of IL-17 are developing [14]. As significant high levels of IL-17 is observed in the inflamed tissues of the intestine in UC and CD patients, inhibiting the expression of IL-17 or blocking its receptor may be of clinical importance to bring off the inflammation [15]. Other current molecules are being developed as IL-17 vaccine or antibody [14]. Via suppression of IL-17 production, an anti-inflammatory effect with less suppressive impact on the host defense system can be observed [17]. In addition, in experimental colitis models, anti-IL-17 therapy ameliorated the inflammation and decreased the disease activity [15]. However, brodalumab worsened the disease condition in CD patients and thus the developer discontinued the assessment of Phase II trials. Daclizumab is an inhibitor of IL-2, the same as basiliximab, the approved drug for the prevention of graft rejection. Daclizumab is thought to possess a crucial effect on T-cell activation. It was linked with low frequencies of adverse issues in UC patients, including nausea, nasopharyngitis and pyrexia. The same as brodalumab, daclizumab did not demonstrate good effects in UC patients when compared to placebo in a Phase II clinical trial [23]. Elubrixin as an IL-8 antagonist was thought to be efficacious in ameliorating the inflammation. It was first designed in 2004 and later, after chemical structure changes; its growth was carried on in 2009. Nevertheless, no development was reported in 2012 and its clinical trial at Phase II in UC patients was given up. Vatelizumab was designed to prevent or lessen the aggregation of inflammatory cells in 2006. It was evaluated in UC patients in Phase II trials but in 2014, the news of its discontinuation of development for UC was reported. Abatacept as a human immunosuppressant antibody blocks T-cell activation by antagonizing the CD80. Abatacept at the doses higher than those approved for the treatment of RA was well tolerated, but was not significantly superior to the placebo in the rate of remission and therefore its Phase III safety and efficacy trials was discontinued [32].
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Some other therapeutic options are to modulate some associated factors, which are altered in the inflammation. It is observed that helminthes can induce T helper 2 immune responses that results in bringing down the Th1 responsiveness. In animalinduced IBD models, helminthes exerts protective effects and changes the bacterial flora of the bowel. The observational subjects showed that helminthes may prevent or improve colitis by induction of T-cells and modulatory cytokines. This event results in decreasing the immune responsiveness and inflammation reduction [56,57]. CNDO-201 immunotherapy raised safety concerns besides the efficacy in diminishing the inflammation. Consequently, its development for UC and CD treatment was ceased in 2013. Forasmuch as the pathophysiology of IBD is demonstrated to have an association with large wounds and homeostatic imbalance and change in the small vessels of the intestinal wall, and considering the low plasma levels of factor XIII in IBD patients than normal levels [40,58-60], several surveys have been carried on to discover the beneficial efficacy of factor XIII in IBD patients [43]. The hypothesis was about the probable relation between low levels of this gene and disease severity and injury healing. It was considered that increasing the levels of factor XIII may promote the wound healing in UC patients. Nevertheless, the results of Phase II clinical trials did not confirm this theory when investigating the effects of catridecacog as a recombinant factor XIII [48]. It is thought that the intestinal level of alkaline phosphatase in children with IBD is more depressed than normal [61]. Thus, it can be presented as a therapeutic option in IBD. Alkaline phosphatase was administrated in UC and CD patients in Phase I and II clinical trials to assess its safety and efficacy, but as its discontinuation of development was reported in 2011, the trials were ended. 5.
Expert opinion
Advances in the knowledge of IBD pathophysiology determine new biological targets that can be followed by pharmaceutical companies to find a better treatment by focusing on key receptors and molecules involved in the inflammation pathway [62]. To run the development process to get an approved medication, one molecule should pass through preclinical and then several clinical tests. The results of these tests must confirm the efficacy and safety of each molecule before
6
permission to enter the market. This review focused on several new molecules that were evaluated in clinical stages for management of IBD, but their process was discontinued because of issues of safety or efficacy. In the present review, all information about the molecules designed for the treatment of UC or CD between 2009 and 2014, which their development has been ceased, were gathered and evaluated. Except for abatacept, all drugs were discontinued within Phase I and II clinical trial when the first evaluations of safety and efficacy were conducted. Abatacept reached in the Phase III clinical trial, but the outcomes of tests in UC and CD patients did not confirm clinical efficacy and safety. Some drugs such as brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from a Phase II trial due to the lack of significant efficacy versus placebo. The CNDO-210 has the safety concerns and thus its development was given up. Catridecacog was also broken off when lack of efficacy in Phase IIa trial was confirmed in UC patients. The other potential examined drug was NU-206 that was stopped from developing in a Phase I trial. Alkaline phosphatase was not effective in UC and CD patients and has been laid off by the developer in the Phase IIa trial. Although most of the trials were registered trials, the outcomes of the surveys have not been clearly described. Data suggest that more or less anti-inflammatory cytokines such as IL-10 and IL-11 could be of more attention. Abatacept showed no significant benefit in patients suggesting that non-specific T-cell inhibition is not enough to maintain the IBD patients in remission. In CD, activation of Th1 and Th17 through IL-12, IL-18 and IL-23 results in the secretion of IL-2, IL-17, INF-g and TNF-a. In UC, colon inflammation is associated with Th2 immune responses mediated by IL-4, IL-5 and IL-13 increment that can be targeted and tested more precisely in future.
Declaration of interest The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Inflammatory bowel disease therapies discontinued between 2009 and 2014
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Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol 2003;98:2034-41 Fiasse R, Latinne D. Intestinal helminths: a clue explaining the low incidence of inflammatory bowel diseases in Subsaharan Africa? Potential benefits and hazards of helminth therapy. Acta Gastroenterol Belg 2006;69:418-22 Bregenzer N, Caesar I, Andus T, et al. Lack of clinical efficacy of additional factor XIII treatment in patients with steroid refractory colitis. The Factor XIII Study Group. Z Gastroenterol 1999;37:999-1004
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Novo Nordisk A/S. Safety and Pharmacokinetics of Recombinant Factor XIII Administration in Healthy Volunteers. 2013. Available from: http://clinicaltrials.gov/ct2/show/ NCT01848002 Novo Nordisk A/S. Safety and Pharmacokinetics of Recombinant Factor XIII in Healthy Volunteers. 2013. Available from: http://clinicaltrials. gov/ct2/show/NCT01847989 Novo Nordisk A/S. Safety of Recombinant Factor XIII (rFXIII) in Healthy Japanese Volunteers. 2010. Available from: http://clinicaltrials. gov/ct2/show/NCT01153997 Novo Nordisk A/S. Comparison of a Blood Clotting Drug (Recombinant Factor XIII) Produced by Two Different Manufacturers in Healthy Male Subjects. 2010. Available from: http://clinicaltrials. gov/ct2/show/NCT01082406 Novo Nordisk A/S. A Placebo-controlled Trial With rFXIII Administered to Subjects With Mild to Moderate Active Ulcerative Colitis. 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01706159 Zhao J, de Vera J, Narushima S, et al. R-spondin1, A Novel Intestinotrophic Mitogen, Ameliorates Experimental Colitis in Mice. Gastroenterology 2007;132:1331-43
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Press releases, Nuvelo, 10 Dec 2008 & KHK, 28 Apr 2009
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Form 10-Q, Nuvelo, 8 Nov 2006; Press releases, Nuvelo, 17 Mar & 23 Jul 2008
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Cario E, Goebell H, Dignass AU. Factor XIII modulates intestinal epithelial wound healing in vitro. Scand J Gastroenterol 1999;34:485-90
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D’Argenio G, Grossman A, Cosenza V, et al. Recombinant factor XIII improves established experimental colitis in rats. Dig Dis Sci 2000;45:987-97
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Tuin A, Poelstra K, de Jager-Krikken A, et al. Role of alkaline phosphatase in colitis in man and rats. Gut 2009;58:379-87
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Affiliation Shilan Mozaffari1, Shekoufeh Nikfar2 & Mohammad Abdollahi†1 † Author for correspondence 1 Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology, Tehran, Iran E-mail: [email protected]; [email protected] 2 Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Pharmacoeconomics and Pharmaceutical Administration, Tehran, Iran
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Inflammatory bowel disease therapies discontinued between 2009 and 2014 1.
Introduction
2.
Search strategy
3.
Results
4.
Conclusion
5.
Expert opinion
Shilan Mozaffari, Shekoufeh Nikfar & Mohammad Abdollahi† †
Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology, Tehran, Iran
Introduction: New therapeutic approaches are currently under development, which consider the fundamental mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). The disease is associated with inflamed intestinal and colonic mucosa in response to the dysregulated immune system. Areas covered: The aim of this article is to review drugs that have been designed for the treatment of IBD and discontinued between 2009 and 2014. Herein, nine molecules with different mechanisms of action are under review. Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from the Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. Finally, NU-206 and alkaline phosphatase also ceased in development during Phase I and II tests. Expert opinion: The development in our knowledge and understanding of the pathophysiology of IBD and the identification of key objectives for the future play significant roles in IBD therapeutic development. Furthermore, well-planned clinical trials with concise measures of efficacy and safety are required to better decide whether to extend or terminate the development process. Some anti-inflammatory cytokines such as IL-2, IL-12, IL-17, IL-18, IL-23 and INF-g could garner more attention in the future. Keywords: Crohn’s disease, discontinued treatment, inflammatory bowel disease, ulcerative colitis Expert Opin. Investig. Drugs [Early Online]
1.
Introduction
Ulcerative colitis (UC) and Crohn’s disease (CD) as two inflammatory conditions of the gastrointestinal (GI) tract are generally recognized as inflammatory bowel disease (IBD). The disease is associated with consequent symptoms of the inflamed intestinal and colonic mucosa in response to the dysregulated immune system [1]. Referable to the debilitating effect of disease in affected patients, there are several molecules designed by the pharmaceutical companies that undergo several stages of clinical tests. However, available approved medicines are 5-aminosalicylate (mesalamine and sulfasalazine), corticosteroids, antibiotics, anti-TNF and immunosuppressive drugs (azathioprine, mercaptoprine and methotreaxate) [2-9]. It is suggested that in addition to genetic backgrounds, a recent intestinal infection or alteration of GI microflora, immune dysregulation and some environmental agents such as oxidative stress are involved in the pathophysiology of IBD [10,11]. Regarding the underlying mechanisms involved in the pathogenesis of IBD, there are developing therapeutic options assessed for the treatment or ameliorating the condition. In that respect are several biologic drugs such as adalimumab, 10.1517/13543784.2015.1035432 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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S. Mozaffari et al.
Article highlights. .
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.
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Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from a Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and thus its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. NU-206 and alkaline phosphatase were stopped from developing within Phase I and II trials. As significant high levels of IL-17 have been discovered in the inflamed tissues of the intestine in ulcerative colitis (UC) and Crohn’s disease (CD) patients, inhibiting the expression of IL-17 or blocking its receptor was of clinical importance to bring off the inflammation; however this therapeutic target was not successful. Abatacept did not demonstrate any significant any more beneficial effects in CD patients than placebo and this may indicate that non-specific T-cell inhibition is not enough to keep remission in inflammatory bowel disease (IBD) patients. Increasing the knowledge on the pathophysiology of IBD and identifying the key objectives are role-playing factors in the treatment of IBD. In CD, activation of Th1 and Th17 through IL-12, IL-18 and IL-23 increases the secretion of IL-2, IL-17, INF-g and TNF-a. With UC, inflammation of the colon is associated with Th2 immune responses elicited by an increase of IL-4, IL-5 and IL-13. Well-designed clinical trials with concise measures of efficacy and safety are needed to better decide whether to extend or terminate the development procedure.
This box summarizes key points contained in the article.
certolizumab pegol, etanercept and golimumab that are approved as anti-TNF drugs. In addition, rituximab and abatacept are approved as anti-CD20 and T-cell inhibitors, respectively. Natalizumab and vedolizumab are new medicines with the mechanism of a4 integrin inhibition [12,13]. The lack of either response or maintaining the remission, and initiation of serious adverse events with currently available medicines, make the pharmaceutical companies to continue to look for novel therapies. New designed molecules are being looked into various pre-clinical to Phase III of clinical tests to get the license, but there is forever a possibility for each medication to be taken away in each phase of study. The present review focused on the recently designed molecules for the treatment of UC and CD, which their development has been stopped due to lack of efficacy, presence of adverse events or because of market issues. 2.
Search strategy
Electronic databases, including PubMed, Clinical Trial.gov, Google Scholar and Cochrane Central Register of Controlled trials, were sought for all pre-clinical and clinical trials, which assessed the efficacy and safety of novel drugs for IBD 2
(CD, UC) up to 2014 September. The applied key words were efficacy, safety, UC, CD and IBD. All titles, abstracts and reference sections were studied to find relevant articles evaluating new therapeutics for IBD. The articles in which the investigated drug is approved or is in process were omitted. The included studies were on the efficacy and safety of molecules that their clinical trials have been stopped or failed and pulled back from the development process from 2009 to 2014. The collected available data were summed up in a table according to the drug therapeutic class, mechanism of action, chemical name, administration route and the type of IBD in patients (Table 1). 3.
Results
Brodalumab Brodalumab is a human mAb for IL-17 receptors. It is under development for the treatment of rheumatoid arthritis (RA), psoriasis and CD. Its mechanism of action is via blocking the IL-17, and IL-25 (IL-17E) signaling to control the associated inflammatory pathways. These cytokines can induce NF-kB activation and stimulate the production of other inflammatory cytokins [14,15]. Phase I and II clinical trials in healthy volunteers and patients with psoriasis have been conducted to determine the pharmacokinetics of brodalumab [16]. The results demonstrate the influence of body weight on some pharmacokinetic variations of the drug. The age or disease status did not clinically affect the pharmacokinetics of drug [16]. As brodalumab is being assessed for the treatment of psoriasis, in the major part of studies, its safety and efficacy were evaluated in psoriasis patients [17]. Consequently, at that place are few available data for its efficacy in CD patients. In that location were two registered clinical trials assessing efficacy and safety of brodalumab in CD. A randomized double-blind placebo-controlled Phase II clinical trial has been conducted to assess the efficacy and safety of brodalumab (700 mg intravenous [i.v.]) in 130 CD patients. The work however has been terminated [18]. Another open-label Phase II study evaluated the safety and efficacy of the drug (350 mg i.v. q 4 weeks for 30 months) in 67 CD patients and was also terminated [19]. Brodalumab has not been examined in Phase III trials for CD and then its development has been discontinued for RA and CD. Due to non-published results, no reasons have been noted for termination of studies. 3.1
Daclizumab Daclizumab is a humanized mAb that blocks the receptor of IL-2 (CD25) on T-cells. This contributes to the inhibition of lymphocyte proliferation and differentiation [20]. Daclizumab is approved for the prevention of rejection in organ transplantation. It has been also evaluated for the management of autoimmune disorders, including UC [20]. Daclizumab has been marketed in the USA since 1997. A randomized, single-blind Phase I trial was directed to assess 3.2
Expert Opin. Investig. Drugs (2015) 24(7)
Immunoglobulin G 1 (human-mouse monoclonal clone 1H4 g-chain anti-human IL 2 receptor) Urea, N-(2-chloro-3-fluorophenyl)-N¢[4-chloro-2-hydroxy-3-(1-piperazinylsulfonyl) phenyl]-
Daclizumab
Expert Opin. Investig. Drugs (2015) 24(7)
CD: Crohn’s disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.
Alkaline phosphatase
NU-206
Recombinant, Blood fraction Haemostatic Recombinant, Radio/ chemoprotective Stomatological
Fusion protein
Abatacept
CNDO-201 ASP 1002 Catridecacog Blood-coagulation factor XIII [CAS]
mAb
mAb
mAb
Therapeutic class
Vatelizumab
1-25-oncostatin M (human precursor) fusion protein with CTLA-4 (antigen)
Immunoglobulin G, anti-(human IL 17 receptor A)
Brodalumab
Elubrixin
Chemical name
Drug name
II
a2b1 integrin antagonist
Alkaline phosphatase stimulant
Wnt pathway stimulant
Factor XIII stimulant
II
I
II
Immunostimulant II
CD80 antagonist III
II
II
II
Safety and efficacy
Tolerability, safety and efficacy Tolerability, safety and efficacy Safety and efficacy Tolerability, safety and efficacy Tolerability and safety
Tolerability, safety and efficacy Tolerability, safety and efficacy Safety and efficacy
Phase of Clinical end discontinuation point
IL-8 receptor antagonist
IL-2 receptor antagonist
IL-17 receptor antagonist
Mechanism of action
Table 1. Characteristics of discontinued drugs for the treatment of IBD.
CD, UC
CD, UC
CD, UC UC
CD, UC
UC
UC
UC
CD
Injectable
Injectable
Injectable
Oral
Injectable
Injectable
Oral
Injectable
Injectable
IBD Administration type Route
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Not determined
Not determined
Lack of efficacy
Lack of safety
Lack of efficacy
Lack of efficacy
Lack of efficacy
Lack of efficacy
Lack of efficacy
Reasons for discontinuation
Inflammatory bowel disease therapies discontinued between 2009 and 2014
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S. Mozaffari et al.
the pharmacokinetics of a single-dose daclizumab in healthy volunteers besides the tolerability and safety assessments [21]. A pilot open-label, uncontrolled study was conducted to investigate the efficacy and safety of daclizumab (1 mg/kg i.v.) in 10 patients with refractory UC. Daclizumab was associated with beneficial healing effects in decreasing clinical activity score and endoscopic scores in patients. It was accounted as a safe and tolerated medicine in patients. The most reported adverse event was nausea in patients that concomitantly used azathioprine [22]. A Phase II, randomized double-blind placebo-controlled test was acquitted in 159 patients with moderate to severely active UC in 20 weeks. Different doses (1, 2 mg/kg i.v.) of daclizumab were compared to placebo at different intervals. At the conclusion of the study, daclizumab was not associated with more significant reaction in the induction of remission versus placebo. Still, it was well supported and the most frequent adverse events were nasopharyngitis and pyrexia [23]. The drug faced diminishing market demand, according to the company and as of January 2009, its marketing authorization was taken away and the product completely discontinued because of commercial reasons. Elubrixin Elubrixin (SB-656933) is an IL-8 antagonist. It was under development for the treatment of UC [24]. It is demonstrated that elubrixin has an inhibitory effect on neutrophils in a dose-dependent fashion. The outcomes of randomized double-blind placebo-controlled Phase I trials in healthy subjects showed that elubrixin was tolerable and safe [25-27]. Phase I and II clinical trials have been conducted to examine the safety and efficacy of elubrixin in patients with UC [24]. Merely as the drug development was stopped, these tests were discontinued. 3.3
Vatelizumab Vatelizumab (SAR-39658) is also a mAb that antagonizes the integrin a 2 receptors. It was produced as an immune modulator for the treatment of inflammatory disorders such as multiple sclerosis and IBD. Integrins are involved in T-cellmediated signaling in the inflammation. Various pre-clinical studies prove the efficacy of vatelizumab in colitis models [28]. Phase I trials have been taken to evaluate the pharmacokinetics characteristics, safety and tolerability of the drug in healthy cases. Vatelizumab was well tolerated. In summary, there are two registered Phase II randomized double-blind placebocontrolled trials assessing the long-term safety and efficacy of vatelizumab in UC patients [29,30]. Still, tests have been ended and development operation is stopped. 3.4
Abatacept Abatacept is a fusion protein that regulates T-cell activation via binding to the CD80 and CD86 molecule. Abatacept is a selective co-stimulation modulator via preventing antigenpresenting cells. Its selective mechanism of action brings 3.5
4
about an anti-inflammatory effect [31]. Abatacept has got a license for RA treatment. It has been evaluated in IBD patients. Granting to the outcomes of four Phase III randomized double-blind clinical trials, abatacept did not show significant efficacy in comparison to the placebo in the installation and maintenance of remission of 451 and 490 adult patients with active CD and UC, respectively [32]. According to the efficacy and safety evaluations during 12 weeks of induction and 52 weeks of maintenance therapy, trials were terminated due to the lack of efficacy and safety in patients. Abatacept was associated with high risk of treatment failure and disease exacerbation with no acceptable safety profile compared to placebo [32,33]. CNDO-201 CNDO-201 is the embryonated egg of porcine whimpworm Trichuris Suis ova (TSO). It is demonstrated that helminthes may suppress the immune reactions of their hosts [34]. CNDO-201 was developed for the treatment of several autoimmune disorders such as IBD. In that respect are various observational and clinical trials measuring the potential efficacy of TSO in IBD treatment [35-38]. Several Phase I and II clinical trials have investigated the safety, tolerability and efficacy of TSO in UC and CD treatment. A randomized Phase I clinical trial evaluated the safety and tolerability of TSO in 36 CD patients and reported no adverse effects during treatment [35]. Administration of oral TSO in a randomized clinical trial was safe and effective in 54 UC patients. It induced significant remission and clinical improvement versus placebo. TSO decreased disease activity with no important adverse effects [36]. The effects of an open-label study in 29 CD patients reported TSO as an efficacious and safe treatment [37]. In another open-label trial in four CD and three UC patients, it was demonstrated that TSO decreased disease activity and no adverse event was accounted in the recruited patient [38]. Collectively, TSO administration in human showed beneficial efficacy in UC and CD patients and was safe [39]. Nevertheless, there was a demand for further clinical trial to conclude around the safety of TSO therapy in IBD patients. Therefore the development of this drug has been discontinued. 3.6
Catridecacog Catridecacog is a recombinant factor XIII, which produced for the handling of congenital, acquired factor XIII deficiency and UC. Factor XIII is known to have a role in fibrin clot stabilization and improvement of ulcers. Various studies have demonstrated the healing effect of unfractioned or low-molecular-weight heparin in UC and CD patients [40]. In an in vitro examination, factor XIII promoted the intestinal epithelial ulcer improvement when its effect on cultures of several cell lines was evaluated [41]. In an experimental induced colitis in rats, 10 days of intravenous administration of factor XIII resulted in lessening the severity of lesions in comparison to 3.7
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Inflammatory bowel disease therapies discontinued between 2009 and 2014
control [42]. The first favorable clinical outcomes in a UC case report led to further clinical trials in UC patients with acute disease status or UC patients with refractory and lack of responsiveness to treatment [43]. Several randomized, placebo-controlled, double-blind Phase I clinical trials has been dispatched to assess tolerability, safety and pharmacokinetic profile of catridecacog in healthy volunteers. The answers indicate that catridecacog is safe and well tolerated [44-47]. Some clinical investigations have described the beneficial therapeutic effects of factor XIII in IBD patients. To evaluate the efficacy of factor XIII in UC patients, a double-blind placebocontrolled study have been conducted in 28 patients, but no significant difference was observed between the effect of factor XIII and placebo on the intestinal bleeding [40]. A Phase IIa randomized double-blind placebo-controlled study investigated the efficacy of 35 IU/kg of intravenous factor XIII in UC patients [48]. Nevertheless, the work was terminated as the outcomes did not defend the hypothesis of efficacy of factor XIII in UC and a relation between low levels of this gene and disease activity was not mentioned. Therefore, the developer company discontinued the development of this drug in 2012. NU-206 NU-206 is a recombinant protein that stimulates GI epithelial cells. It can induce repair and curing the injury in animal IBD models. This molecule was developed to assess its efficacy in various diseases including IBD. There are a few data on its evaluation and development process. In an experimentally induced colitis model, NU206 improved the inflammation. It cuts the inflammatory cytokines in the intestine significantly [49]. One double-blind, placebo-controlled Phase I trial in 32 healthy volunteers was carried on to assess the safety and pharmacokinetics of NU206. The outcomes indicated that it was safe and tolerable with no severe adverse effects [50]. Another Phase Ib trial was directed in 80 healthy volunteers, to evaluate safety, tolerability and pharmacokinetics of single and multiple doses of NU-206 [51]. Although this drug was safe, there is no clear cause for its discontinuation of evaluation in randomized trials. 3.8
Alkaline phosphatase Alkaline phosphatase is an enzyme that is demonstrated to have a role in the improvement of inflamed GI mucosa. In experimental models of induced colitis in rats, inflammation and oxidative stress resulted in activation and up-regulation of alkaline phosphatase [52]. It reduced colonic inflammation and TNF-a levels [53]. In several conducted Phase I and II trials, alkaline phosphatase was safe and significantly diminished the inflammatory cytokine and biomarkers compared to placebo [54]. Two Phase IIa trials have been enrolled with 21 patients suffering from UC and CD. Oral administration of alkaline phosphatase was efficacious in the induction of remission in patients. No severe adverse effect was described during these trials [55]. The final results have not been 3.9
published, but the development of this medicine was discontinued. 4.
Conclusion
Taken collectively, nine molecules for the treatment of IBD were discontinued during the survey period. The major goal in the treatment of IBD is to target several involved receptors and cytokines. Some potential targets are ILs. Two of discontinued drugs for the treatment of UC and CD were mAbs, which antagonize IL receptors (brodalumab and daclizumab). Elubrixin has been also designed to block IL-8 receptors. Brodalumab, daclizumab and elubrixin are IL-17, IL-2 and IL-8 receptor antagonists, respectively. Stimulating the IL-23 receptor increases the secretion of IL-17, TNF-a and IL-6 from T-cells. Granting to the known role of IL-17 pathway signaling in the intestinal inflammation, IL-17-deficient mouse as an observational model of IBD has been used and several approaches for inhibition of IL-17 are developing [14]. As significant high levels of IL-17 is observed in the inflamed tissues of the intestine in UC and CD patients, inhibiting the expression of IL-17 or blocking its receptor may be of clinical importance to bring off the inflammation [15]. Other current molecules are being developed as IL-17 vaccine or antibody [14]. Via suppression of IL-17 production, an anti-inflammatory effect with less suppressive impact on the host defense system can be observed [17]. In addition, in experimental colitis models, anti-IL-17 therapy ameliorated the inflammation and decreased the disease activity [15]. However, brodalumab worsened the disease condition in CD patients and thus the developer discontinued the assessment of Phase II trials. Daclizumab is an inhibitor of IL-2, the same as basiliximab, the approved drug for the prevention of graft rejection. Daclizumab is thought to possess a crucial effect on T-cell activation. It was linked with low frequencies of adverse issues in UC patients, including nausea, nasopharyngitis and pyrexia. The same as brodalumab, daclizumab did not demonstrate good effects in UC patients when compared to placebo in a Phase II clinical trial [23]. Elubrixin as an IL-8 antagonist was thought to be efficacious in ameliorating the inflammation. It was first designed in 2004 and later, after chemical structure changes; its growth was carried on in 2009. Nevertheless, no development was reported in 2012 and its clinical trial at Phase II in UC patients was given up. Vatelizumab was designed to prevent or lessen the aggregation of inflammatory cells in 2006. It was evaluated in UC patients in Phase II trials but in 2014, the news of its discontinuation of development for UC was reported. Abatacept as a human immunosuppressant antibody blocks T-cell activation by antagonizing the CD80. Abatacept at the doses higher than those approved for the treatment of RA was well tolerated, but was not significantly superior to the placebo in the rate of remission and therefore its Phase III safety and efficacy trials was discontinued [32].
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Some other therapeutic options are to modulate some associated factors, which are altered in the inflammation. It is observed that helminthes can induce T helper 2 immune responses that results in bringing down the Th1 responsiveness. In animalinduced IBD models, helminthes exerts protective effects and changes the bacterial flora of the bowel. The observational subjects showed that helminthes may prevent or improve colitis by induction of T-cells and modulatory cytokines. This event results in decreasing the immune responsiveness and inflammation reduction [56,57]. CNDO-201 immunotherapy raised safety concerns besides the efficacy in diminishing the inflammation. Consequently, its development for UC and CD treatment was ceased in 2013. Forasmuch as the pathophysiology of IBD is demonstrated to have an association with large wounds and homeostatic imbalance and change in the small vessels of the intestinal wall, and considering the low plasma levels of factor XIII in IBD patients than normal levels [40,58-60], several surveys have been carried on to discover the beneficial efficacy of factor XIII in IBD patients [43]. The hypothesis was about the probable relation between low levels of this gene and disease severity and injury healing. It was considered that increasing the levels of factor XIII may promote the wound healing in UC patients. Nevertheless, the results of Phase II clinical trials did not confirm this theory when investigating the effects of catridecacog as a recombinant factor XIII [48]. It is thought that the intestinal level of alkaline phosphatase in children with IBD is more depressed than normal [61]. Thus, it can be presented as a therapeutic option in IBD. Alkaline phosphatase was administrated in UC and CD patients in Phase I and II clinical trials to assess its safety and efficacy, but as its discontinuation of development was reported in 2011, the trials were ended. 5.
Expert opinion
Advances in the knowledge of IBD pathophysiology determine new biological targets that can be followed by pharmaceutical companies to find a better treatment by focusing on key receptors and molecules involved in the inflammation pathway [62]. To run the development process to get an approved medication, one molecule should pass through preclinical and then several clinical tests. The results of these tests must confirm the efficacy and safety of each molecule before
6
permission to enter the market. This review focused on several new molecules that were evaluated in clinical stages for management of IBD, but their process was discontinued because of issues of safety or efficacy. In the present review, all information about the molecules designed for the treatment of UC or CD between 2009 and 2014, which their development has been ceased, were gathered and evaluated. Except for abatacept, all drugs were discontinued within Phase I and II clinical trial when the first evaluations of safety and efficacy were conducted. Abatacept reached in the Phase III clinical trial, but the outcomes of tests in UC and CD patients did not confirm clinical efficacy and safety. Some drugs such as brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from a Phase II trial due to the lack of significant efficacy versus placebo. The CNDO-210 has the safety concerns and thus its development was given up. Catridecacog was also broken off when lack of efficacy in Phase IIa trial was confirmed in UC patients. The other potential examined drug was NU-206 that was stopped from developing in a Phase I trial. Alkaline phosphatase was not effective in UC and CD patients and has been laid off by the developer in the Phase IIa trial. Although most of the trials were registered trials, the outcomes of the surveys have not been clearly described. Data suggest that more or less anti-inflammatory cytokines such as IL-10 and IL-11 could be of more attention. Abatacept showed no significant benefit in patients suggesting that non-specific T-cell inhibition is not enough to maintain the IBD patients in remission. In CD, activation of Th1 and Th17 through IL-12, IL-18 and IL-23 results in the secretion of IL-2, IL-17, INF-g and TNF-a. In UC, colon inflammation is associated with Th2 immune responses mediated by IL-4, IL-5 and IL-13 increment that can be targeted and tested more precisely in future.
Declaration of interest The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Expert Opin. Investig. Drugs (2015) 24(7)
Inflammatory bowel disease therapies discontinued between 2009 and 2014
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Affiliation Shilan Mozaffari1, Shekoufeh Nikfar2 & Mohammad Abdollahi†1 † Author for correspondence 1 Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Toxicology and Pharmacology, Tehran, Iran E-mail: [email protected]; [email protected] 2 Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Department of Pharmacoeconomics and Pharmaceutical Administration, Tehran, Iran
