Celiac disease 2015 update: new therapies.

Review

Celiac disease 2015 update: new therapies Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Osaka University on 04/23/15 For personal use only.

Expert Rev. Gastroenterol. Hepatol. Early online, 1–15 (2015)

Gopal Veeraraghavan, Daniel A Leffler, Dharmesh H Kaswala and Rupa Mukherjee* Department of Medicine, Celiac Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA *Author for correspondence: Tel.: +1 617 667 1272 Fax: +1 617 667 5826 [email protected]

Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by exposure to dietary gluten in genetically susceptible individuals. Currently, lifelong adherence to a gluten-free diet (GFD) is the only available treatment. However, GFD alone is not sufficient to relieve symptoms, control small intestinal inflammation and prevent long-term complications in many patients. The GFD has its challenges including issues related to adherence, lifestyle restrictions and cost. As a result, there is growing interest in and a need for non-dietary therapies to manage this condition. In recent years, different targets in the immune-mediated cascade of CD have been identified in clinical and pre-clinical trials for potential therapies. This review will discuss the latest non-dietary therapies in CD, including endopeptidases, modulators of enterocyte tight junctions and agents involved in gluten tolerization and immunomodulation. We will also discuss the potential implications of approved therapeutics on CD clinical practice. KEYWORDS: ALV003 . AT-1001 . CCR9 antagonist . celiac disease . drug therapy . gluten-free diet . larazotide acetate .

Necator americanus, Nexvax2 . tTG inhibitors

Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals resulting in malabsorption [1]. The estimated prevalence of this disease based on several epidemiological studies ranges from 1:70 to 1:200 [2–4]. Based on these studies, it is clear that CD has a worldwide prevalence and, in fact, is one of the most prevalent genetically based conditions [4]. CD can remain undiagnosed for many years. In fact, the average diagnostic delay in the US population is 11 years, with an average age of diagnosis around 44 years [5]. Data suggest that CD can present at any age, in any race or ethnic group, with a diverse clinical presentation ranging from asymptomatic disease to severe malabsorption [6]. The symptoms at initial presentation can range from full-blown classical features including diarrhea, bloating, abdominal pain and malabsorption to lack of any symptoms. Extraintestinal manifestations include skin rash (dermatitis herpetiformis), arthralgias, fatigue, headaches, ‘gluten fog’, peripheral neuropathies, osteoporosis, anemia due to iron or vitamin B12 deficiency and elevated liver enzymes [7]. Moreover, some of the gastrointestinal symptoms of CD can, initially, be mistaken for irritable bowel informahealthcare.com

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syndrome. In a screening study performed in Sweden in 1999, it was found that 8 out of 10 patients with CD had not been previously diagnosed with this condition. Therefore, CD remains a highly underdiagnosed condition [8]. Pathogenesis

The pathogenesis of CD is multifactorial and involves the interplay of genetic, immunological and environmental factors (see TABLE 1). Gluten peptides derived from wheat, rye and barley generate an inflammatory reaction that leads to damage of the small intestinal villi. These peptides contain distinct T-cell epitopes that are rich in proline and glutamine residues. The high proline content of gluten renders the peptides highly resistant to degradation by intestinal proteases. This leads to a pool of potentially immunogenic gluten epitopes in the small intestine [9]. The mode of entry of gluten into the lamina propria is not entirely clear. Some evidence suggests that gluten may enter the lamina propria via a paracellular route through disassembled tight junctions of the intestinal epithelial cells or epithelial transcytosis [10,11]. In the submucosa, intestinal tissue transglutaminase, also called tTG or TG2, targets the gluten peptides, cross-links and deamidates them

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Veeraraghavan, Leffler, Kaswala & Mukherjee

to negatively charged glutamic acid residues that are highly immunogenic. These residues are presented via HLA-DQ2 and HLA-DQ8 haplotypes by antigen-presenting cells to CD4+ T cells. Activation of the CD4+ T cells leads to production of pro-inflammatory cytokines and an increase in intraepithelial lymphocytes (IELs) with eventual mucosal remodeling characterized by crypt hyperplasia and villous atrophy. In addition, activation of B cells by the activated CD4+ T cells leads to production of autoantibodies to TG2 [12]. It is also postulated that gliadin peptides have a direct cytotoxic effect. This cytotoxicity is due to a direct stimulation by gliadin peptides of distinct mucosal cell populations to secrete IL-15 which, in turn, leads to increased proliferation of IELs. The IELs become activated via the interaction between MHC class I polypeptide-related sequence A (MICA) protein and Natural Killer Group 2D (NKG2D) receptor molecule expressed by cytotoxic cells and exert cytotoxic effects on epithelial cells with resultant increased epithelial permeability [13].

effective management of CD. Recently, there has been ongoing research to develop these alternative non-dietary therapies. Drug therapy

As our knowledge and understanding of the pathogenesis of CD continues to improve, numerous potential targets for drug therapies have emerged. FIGURE 1 illustrates the various potential sites of action of these drugs. Despite the promise of nondietary therapies for CD, only a few experimental therapies have been studied in randomized, controlled clinical trials. Currently, six agents have been studied in Phase I or II clinical trials. The goal of this article is to discuss the new advances in CD treatment with a focus on these therapeutic clinical trials (TABLE 1). This article will also include a discussion on some of the therapeutic strategies that have been studied in preclinical models of CD with a brief mention of therapies used to treat refractory CD (RCD). Finally, we will discuss how the availability of novel and effective therapeutics may change clinical care and practice surrounding CD in the coming years.

Need for alternative therapies

The cornerstone of treating CD is lifelong adherence to a gluten-free diet (GFD). In the past, CD was thought to be primarily a pediatric condition and children generally responded quite well to the GFD. Due to this rapid clinical response seen in children and because CD was not often re-evaluated in adulthood, the GFD was long thought of as a nearly ideal therapy. For this reason, little emphasis was placed on developing new therapies. However, in recent years, rapid expansion of the celiac population, especially into adulthood, has led to the recognition that the GFD alone is often associated with suboptimal outcomes in the older population. There are several reasons that can explain the suboptimal results seen with GFD therapy, especially in adults. First, it has been shown that there is ongoing small intestinal injury despite patients’ best efforts to comply with a GFD. This was confirmed in a population-based study in Sweden [14] in which 43% of the 7648 patients with CD had persistent villous atrophy despite being on a GFD [10]. The prevalence increased to 56% in patients who were above 70 years of age. Moreover, it is difficult to avoid gluten exposure. In a recent study from England, 40% of 287 patients reported intentional gluten exposure and only 29% reported that they had not been exposed to any gluten [15]. Patients also have a tendency to overestimate the degree of compliance with the GFD and may be exposed to gluten more often than they suspect. The most common cause of non-responsive CD was continued gluten exposure and was seen in 36% of patients with CD [16]. Additional factors that can affect adherence to a GFD include lack of palatability, lower nutritional content, higher costs and lack of availability. In addition, studies from both the US and Europe suggest that the burden of following the GFD is very high and that there is a high degree of patient dissatisfaction with current CD treatment [17,18]. Consequently, it is evident that there is an unmet need for alternative pharmacological therapeutic options, in addition to the GFD alone, for the doi: 10.1586/17474124.2015.1033399

Overview of the drug development process

Drug discovery and development is the process of bringing a new pharmaceutical drug to the market and it can take more than 5–15 years. For every 10,000 potential molecules identified, on average only 1–2 drugs make it through all the stages of drug development and eventually get approved for human use. This process begins with pre-clinical animal studies. A ‘no observable adverse effect level’ of the is determined to establish a safe dose for human trials. In the US, prior to human testing, an investigational new drug application is sent to the FDA for a review of drug safety. Subsequently, the drug undergoes various phases of human trials (from Phase I to Phase III) prior to its release in the market [19]. Phase I trials involve 20–80 healthy volunteers and the goal is to assess for safety, side effects and pharmacokinetics of the drug. Once deemed safe, the drug in question undergoes Phase II trials on patients in order to determine efficacy, dosing range and for further assessment of short-term side effects and safety. After this step, the drug then undergoes Phase III trials which are usually large multicenter trials typically involving thousands of patients in order to further assess its safety and efficacy in diverse populations. If the Phase III trials are successful, the drug is finally approved for release into the market. Phase IV trials involve post-marketing surveillance following release of the drug into the market. During these phases of drug development, various measures of clinical benefit and clinical endpoints have to be predetermined to assess efficacy. The drug also has to be monitored in these trials for various side effects to ensure safety. To aid in this endeavor, various clinical endpoints are used. An ideal drug for the treatment of CD should be able to achieve a complete resolution of inflammation on small intestinal biopsy despite significant gluten exposure. This endpoint would be the most objective and ‘the gold standard measure’ for efficacy of the drug [20]. However, endoscopies are invasive Expert Rev. Gastroenterol. Hepatol.

Review

Celiac disease 2015 update

Toxic or immunogenic gluten peptides (wheat, barley and rye)

2. Endopeptidases ALV003 AN-PEP STAN-1

4. Gluten sequestering polymer BL-7010

5. Gluten tolerization Nexvax2 , Hookworm

LUMEN

3. Probiotics

1. Tight junction modulator

Mucosal layer


(Larazotide acetate/AT-1001)

TJ

TJ

TJ

TJ

TJ

Apoptosis

Epithelium M U C O S A

(a)

Bifidobacterium infantis

TJ

Apoptosis

Matrix metalloproteinases

Lamina Propia

Myofibroblast Deaminated (b) Deamination gluten

TJ

IEL

Matrix degradation and mucosal remodeling (crypt hyperplasia and villous atrophy) (d) MMP-1, -3, -12 (c) 10. Anti IFN γ Anti TNFα

9. Anti –IL-15

DC

TG2 7. TG2 inhibitors cystamine

HLA DQ2/ DQ8

CD4 T cell

11. Anti-CD3 Anti-CD20

6. CC 6 CCR9 antagonist CC CCX282B (CCR9, α4β7)

8. DQ2/DQ8 blocking peptide analogues Plasma cell Antibodies to gluten and TG2

Figure 1. Celiac disease pathogenesis and potential therapeutic targets. Gluten is broken down by peptidases into smaller peptides that enter the lamina propria probably through tight junctions of the intestinal epithelial cells. These gluten peptides are cross-linked and deamidated by TG2. Antigen-presenting cells present these highly immunogenic peptides via HLA-DQ2 and HLA-DQ8 haplotypes to CD4+ T cells, triggering the immune response. Pro-inflammatory cytokines are released and IELs are activated resulting in crypt hyperplasia and villous atrophy. Gliadin may also directly stimulate distinct mucosal cells to secrete IL-15 causing proliferation of IELs that exert cytotoxic effects on intestinal epithelial cells. Based on our understanding of the pathogenesis of celiac disease, there are potential targets for drug therapy. These include: 1. Tight junction modulator larazotide acetate/AT-1001 reduces the paracellular transport of gluten into the lamina propria by inhibiting the opening of intestinal epithelial tight junctions and preventing gliadin entry; 2. Endopeptidases ALV003, AN-PEP and STAN-1 degrade gluten into non-immunogenic fragments, thereby mitigating gluten-induced mucosal injury; 3. Probiotic Bifidobacterium infantis reduces gliadin-induced intestinal permeability and downregulates the pro-inflammatory immune response; 4.Gluten-sequestering polymer BL-7010 binds to a-gliadin, preventing its degradation into immunogenic peptides; 5. Gluten tolerization and immunomodulation are seen with the vaccine Nexvax2 and inoculation with the hookworm Necator americanus; 6. CCR9 antagonist CCX282B blocks the chemokine receptor CCR9, thereby blocking lymphocyte homing; 7. TG2 inhibitor cystamine blocks T-cell proliferation of gluten-responsive T cells; 8. HLA-DQ2 and HLA-DQ8 blocking compounds prevent immune activation; 9. IL-15 is an essential growth factor for IELs and NK cells and IL-15 inhibitors may prevent immune-mediated tissue destruction; 10. Antibodies to IFN-g and TNF-a may prevent inflammation (the anti-TNF-a agent infliximab has been used to treat patients with refractory celiac disease); 11. Anti-CD3 antibodies suppress gluten-activated T cells and anti-CD20 antibodies suppress B cells. The role of these agents in the treatment of celiac disease has not yet been defined. AN-PEP: Prolyl endopeptidase derived from Aspergillus niger; HLA: Human leukocyte antigen; IEL: Intraepithelial lymphocyte; IL: Interleukin; INF: Interferon; MMP: Matrix metalloproteinase; TG2: Tissue transglutaminase; TNF: Tumor necrosis factor. Modified from [7].

and expensive, and it would be impractical to use resolution of inflammation in small intestinal biopsies as an endpoint in Phase III trials which involve large numbers of patients. Moreover, gluten challenge can potentially lead to severe symptoms in the study subjects and would not be practical in large informahealthcare.com

Phase III trials. Therefore, small intestinal biopsies and gluten challenge are more appropriate for ‘proof-of-concept’ Phase I and II studies, while serology and clinical rating scales could be used in later stages of drug development in larger Phase III ‘real-life study designs’ [20]. Various studies have used other doi: 10.1586/17474124.2015.1033399

doi: 10.1586/17474124.2015.1033399

Expert Rev. Gastroenterol. Hepatol.

Larazotide acetate (AT-1001)

Tight junction modulators

Not available Not available Preventing intestinal permeability changes (measured by LAMA fractional excretion ratio) – outcome not met

The difference in average ontreatment CeD-GSRS score – outcome met for the 0.5 mg dose, but not for the 1 mg or 2 mg dose of larazotide acetate

NCT00889473 NCT00492960

NCT01396213

2. Preventing intestinal permeability changes (measured by LAMA fractional excretion ratio) – outcome not met

1. Safety and tolerability of multiple oral doses in celiacs on a gluten-free diet – outcome met

1. CeD-GSRS score change from baseline to end of treatment – Outcome met for the 0.5 mg dose, but not for the 1 mg or 2 mg dose of larazotide acetate 2. Average on-treatment score – CeD PRO Abdominal Domain – Outcome not met 3. Average on-treatment score – CeD PRO Gastrointestinal Domain - Outcome not met 4. Change from baseline to end of treatment – CeD PRO Abdominal Domain - Outcome not met 5. Change from baseline to end of treatment – CeD PRO Gastrointestinal Domain – Outcome not met

[24]

[21]

1. Prospectively validate a composite, weighed index of celiac disease activity – outcome met 2. Monitoring of AEs including signs and symptoms of gluten toxicity, physical exam and laboratory abnormalities – outcome met

[94]

[93]

[27,22]

[92]

[91]

Ref.

Not available

Not available

Gastrointestinal symptom severity, quality of life measures and antibodies to tTG – outcome met

Not available

Not available

Secondary outcomes

Results

NCT00620451

NCT00362856

Not available

NCT00386490 Phase II

Not available

NCT00386165

Phase I

Prevent opening of intestinal epithelial tight junctions

Primary outcomes

Clinical Trials.gov

Phase of development

Mechanism of action

AEs: Adverse events; CeD GSRS: Celiac Disease Gastrointestinal Symptom Rating Scale; CeD PRO: Celiac disease patient reported outcome; GSRS: Gastrointestinal Symptom Rating Scale; LAMA: Lactulose-to-mannitol; PEP: Prolyl endopeptidases; tTG; Tissue transglutaminase.

Therapeutic agent

Class of treatment

Table 1. An overview of the major therapeutic clinical trials for celiac disease.


Review Veeraraghavan, Leffler, Kaswala & Mukherjee

informahealthcare.com

PEP derived from Aspergillus niger

AN-PEP

Phase II

Phase I, Phase II

Not available No results available

NCT01560169 NCT01917630

Not available Not available

NCT01335503 NCT02060864

1. Histopathologic changes according to the modified Marsh criteria – outcome not met; 2. The presence of celiac diseasespecific antibodies (EMA, tTGA, gliadin) – outcome not met

1. Attenuation of small intestinal mucosal damage – outcome met; 2. Safety and tolerability of ALV003 – outcome met

NCT01255696

NCT00810654

1. Attenuation of small intestinal mucosal damage – outcome met; 2. Safety and tolerability of ALV003 – outcome met

NCT00959114

1. Safety and tolerability – outcome met; 2. Gastric pharmacokinetics and pharmacodynamics of ALV003 in the absence and presence of a meal – outcome met

NCT00626184

Phase II

1. Safety and tolerability – outcome met; 2. Gastric pharmacokinetics and pharmacodynamics of ALV003 in the absence and presence of a meal – outcome met

NCT00669825

Phase I

Primary outcomes

[33]

[33]

1. Changes in intraepithelial lymphocyte numbers – outcome met; 2. changes in serological markers – outcome not met 1. Changes in intraepithelial lymphocyte numbers – outcome met; 2. Changes in serological markers – outcome not met

Not available

[37]

[36]

[35]

1. Presence and activity of glutenreactive T cells isolated from biopsies and serum, immunophenotype of lymphocytes isolated from biopsies – outcome not met; 2. Clinical symptoms after gluten intake with and without AN-PEP – outcome not met Not available

[34]

Not available

[95]

[32]

Not available

Not available

[32]

Ref.

Not available

Secondary outcomes

Results

Clinical Trials.gov



Enzymatic degradation of gluten

ALV003

Endopeptidases

Mechanism of action

Therapeutic agent

Class of treatment

Table 1. An overview of the major therapeutic clinical trials for celiac disease (cont.).



Review

doi: 10.1586/17474124.2015.1033399

doi: 10.1586/17474124.2015.1033399

BL-7010

Gluten-binding polymer

Block the chemokine receptor CCR9 to prevent intestinal T-cell homing

CCX282B

Blocking intestinal homing – CCR9 antagonist

NCT01990885

Phase I/II underway

Phase II

Phase II

Not available

1. Duodenal histology (Marsh classification) – outcome not met; 2. Cell proliferation and cytokine INF-g profiles – outcome not met

NCT00671138

NCT00540657

1. Decrease in duodenal villus height:crypt depth – outcome met

1. Safety – outcome met

Not available

1. Intestinal permeability changes – outcome not met

Primary outcomes

[61]

1. Clinical response to wheat challenge – outcome not met; 2. Musocal inflammatory response – outcome not met

[65]

[62]

1. Quality of life improvement – outcome met; 2. Celiac symptom indices – outcome met; 3. Intraepithelial lymphocyte count – outcome not met; number of participants with 2 points increase in Marsh score – outcome not met; 4. Rise in tTG IgA – outcome not met

Not available

[54]

[49]

[44]

Ref.

Not available

Not available

1. GSRS – outcome met; 2. Fall in tTG IgA – outcome met; 3. Fall in anti-DGP – outcome not met

Secondary outcomes

Results

NCT01661933

NCT00879749

NCT01257620

Phase II

Phase I

Clinical Trials.gov



Inhibits Th1 immune response

Necator americanus

Desensitizing vaccine with three gluten peptides

Sequesters intraluminal gliadin and prevents its breakdown into immunogenic peptides

Downregulate proinflammatory immune response

Mechanism of action

Immune modulation with parasite

Nexvax2

Bifidobacterium infantis

Probiotics

Gluten vaccine

Therapeutic agent

Class of treatment

Table 1. An overview of the major therapeutic clinical trials for celiac disease (cont.).


Review Veeraraghavan, Leffler, Kaswala & Mukherjee




‘surrogate’ endpoints such as non-invasive biomarkers including tTG-IgA and anti-deamidated gliadin peptide (DGP) antibodies, as well as validated scales such as the Gastrointestinal Symptom Rating Scale (GSRS) and the CD GSRS and the Psychological General Well-Being Index scales for evaluating the resolution of clinical symptoms [21–24]. Various drugs with unique mechanisms of action have been studied in Phase I and Phase II trials using different endpoints, in order to evaluate their efficacy in the treatment of CD [25]. These studies are further discussed in detail below. Modulation of enterocyte tight junctions Larazotide acetate (AT-1001 )

Tight junctions between intestinal epithelial cells are highly dynamic structures that control paracellular permeability by cytoskeletal reorganization. They regulate the passage of fluids, macromolecules and bacterial components through the paracellular space. Patients with CD manifest a defect in these tight junctions and demonstrate increased paracellular permeability when exposed to gluten. These gluten peptides enter the lamina propria where they initiate a T-cell–mediated inflammatory response [26]. Larazotide acetate or AT-1001 (Alba Therapeutics, Baltimore, MD, USA) is a novel octapeptide derived from the zonula occludens toxin secreted by Vibrio cholerae. Larazotide acetate is believed to reduce the paracellular transport of gluten into the lamina propria by inhibiting the opening of tight junctions and preventing the entry of gliadin into the submucosa and limiting inflammation. Several clinical trials conducted to assess the efficacy of larazotide acetate have been completed (TABLE 1). A recent Phase II, double-blinded gluten challenge study was performed on 86 patients with CD on a GFD and in remission with no symptoms or detectable autoantibodies [22]. These patients were randomly assigned to 0.25, 1, 4 and 8 mg doses of larazotide acetate or placebo three-times daily and were simultaneously exposed to 2.4 mg of gluten per day for 14 days. The primary outcome was intestinal permeability measured by the urinary lactulose-to-mannitol (LAMA) fractional excretion ratio. In this study, the primary endpoint of reduction in intestinal permeability was not met – there was no difference in the LAMA ratio between the patients who received larazotide acetate versus the placebo group despite the gluten challenge. Also, 50% of the patients in the placebo group experienced symptoms secondary to gluten exposure, compared to 20.8% of patients who were either not exposed to gluten or were on larazotide acetate. All doses aside from the 8 mg dose appeared to protect against gluten-induced symptoms as measured by the GSRS, although the 0.25 mg dose was numerically the most effective. Overall, larazotide acetate appeared to significantly mitigate gastrointestinal symptoms triggered by a 2-week gluten challenge, but with no measurable difference in intestinal permeability. This agent was well tolerated at all doses and the safety profile was similar to that of placebo. In a follow-up study, 184 patients with CD maintained on a GFD were randomized to varying doses of larazotide (1, 4, informahealthcare.com

Review

8 mg) or placebo three-times daily along with 2.7 g of gluten per day for 6 weeks [21]. Outcomes included the LAMA fractional excretion ratio, anti-transglutaminase (anti-tTG) antibody levels and rating of gastrointestinal symptoms assessed by the GSRS. In this study, again there was no significant difference in the LAMA ratio between the larazotide acetate group and the placebo group. The GSRS scores in the placebo group increased in the first 3 weeks and then plateaued in the last 3 weeks of the study. In the group receiving 1 mg of larazotide acetate, there was significant protection from gluten-induced gastrointestinal symptoms measured by the GSRS. The GSRS scores in the patients who received 4 and 8 mg of larazotide acetate were in the intermediate range and were not statistically different from those of placebo, similar to what was seen in an earlier study by Paterson et al. [27]. Also, 58% of the patients who received larazotide acetate reported gastrointestinal adverse events, which was similar to or lower than that of the placebo group. There was a reduction in the anti-tTG levels across all larazotide dose groups, suggesting some efficacy in reduction of the autoimmune response to gluten. In the latest multicenter randomized, double-blinded, placebo-controlled Phase IIb trial on larazotide acetate, 342 patients with CD who had been on a GFD for ‡12 months were studied [24]. While maintaining a GFD, patients were exposed to placebo for the first 4 weeks and were subsequently treated for 12 weeks with 0.5, 1 or 2 mg of larazotide acetate three-times daily. This was followed by a 4-week run-out phase. The primary endpoint was the mean difference in the GSRS score, which was met with the 0.5 mg dose of larazotide acetate. With the 0.5 mg dose of larazotide acetate, there was a statistically significant 26% decrease in CD Patient Reported Outcome Symptomatic Days (p = 0.017); 31% increase in Improved Symptom Days (p = 0.034); ‡50% reduction from baseline of weekly average Abdominal Pain Score for ‡6 out of 12 weeks of treatment (p = 0.022); and a decrease in non-gastrointestinal symptoms of headache and tiredness (p = 0.010). Among the patients treated with larazotide acetate 0.5 mg, a subset of patients reporting the highest number of Gastrointestinal Symptomatic Days scores (5–7) per week at baseline experienced approximately 30 fewer Gastrointestinal Symptomatic Days compared to 10 more Gastrointestinal Symptomatic Days noted in the placebo group. There was no difference in any endpoint for the 1 or 2 mg dose of larazotide acetate compared to placebo. The safety profile of larazotide acetate was comparable to placebo. This study showed that larazotide acetate dosed at 0.5 mg threetimes daily caused a better reduction in the signs and symptoms in patients with CD already on a GFD treated with this dose of the drug than those patients with CD on a GFD alone [24]. It is important to note that this study did not measure histologic endpoints and that larazotide had no significant effect on serologic titers. Therefore, an important drawback of this study is the lack of information on the effect of larazotide acetate on small intestinal histology. doi: 10.1586/17474124.2015.1033399

Review


Enzyme therapy: endopeptidases

Gluten proteins have a high glutamine and proline content, which makes them resistant to proteolysis by mammalian digestive enzymes [28]. A number of therapeutic enzymes designed to degrade gluten into non-immunogenic fragments are currently being studied.


ALV003

ALV003 (Alvine Pharmaceuticals, San Carlos, CA, USA) is a 1:1 combination of ALV001, which is an EP-B2 cysteine endopeptidase derived from the endosperm of germinating barely, and ALV002, which is a prolyl endopeptidase (PEP) from the bacterium Sphingomonas capsulata [29]. Both endopeptidases are synthesized by recombinant engineering. The amplified genes encoding for proEP-B2 and PEP genes are cloned into plasmids (pMTB1 and apET28b) and introduced into Escherichia coli BL21(DE3) cells via transformation [30,31]. Both endopeptidases are active and stable at gastric pH [30]. EP-B2 exhibits activity against a2 gliadin and the 33mer wheat gliadin peptide [30]. The resulting oligopeptides are still immunogenic and further degraded by ALV002, which renders them non-toxic [29]. The combination of ALV001 and ALV002 acts synergistically and has been shown to be more efficacious than either of the endopeptidases alone [29]. Based on these findings, the safety, tolerability and activity of ALV003 were assessed in two Phase I, single, escalating dose clinical trials [32]. Study 1 enrolled 24 healthy volunteers and 4 patients with CD, and all of them received ALV003 in the fasting state. In study 2, 52 healthy volunteers and 1 patient with CD received the drug with a 1 g gluten-containing meal. Both studies were designed as single-dose, single-blinded, placebo-controlled, cross-over trials. ALV003 was administered in escalating doses of 100, 300, 900 and 1800 mg. Gastric samples were obtained through nasogastric aspiration and assessed for ALV003 enzymatic activity and gluten degradation. All doses of ALV003 were well tolerated with no serious adverse events. In study 2, analysis of gastric aspirates obtained 30 min after a meal showed that the 100 and 300 mg doses of ALV003 were able to degrade gluten in the human stomach as effectively as it was able to do in vitro (100 mg: 75% in vivo vs 77% in vitro and 300 mg: 88% in vivo vs 93% in vitro). In a recently published Phase IIa trial, the efficacy of ALV003 was compared with placebo in 41 patients with biopsy-proven CD undergoing a 6-week-long gluten challenge of 2 g/day [33]. Upper endoscopies were performed at baseline and at the end of gluten exposure at 6 weeks. Primary endpoints included the villus height to crypt depth ratio (VH: CrD) and CD3+ IEL density. Serologic markers and symptoms were also assessed. In patients who received ALV003, there was no change in histological measures while in the placebo group, VH:CrD deteriorated from a mean of 2.8 before gluten challenge to 2.0 at study conclusion. Similarly, the IEL count increased from 61 cells/mm to 91 cells/mm in the placebo group. In contrast, no difference was seen in symptoms in the treatment and placebo groups. There was also no significant doi: 10.1586/17474124.2015.1033399

difference in tTG-IgA and anti-DGP antibody titers between the placebo and the treatment groups. All patients were endomyseal antibody (EMA) negative at study onset; however, one patient each in the placebo and treatment groups developed positive EMA titers above 1:5. These findings suggest that ALV003 can prevent gluten-induced mucosal injury in patients with CD consuming a moderate amount of gluten [33]. A Phase IIb trial enrolling 500 patients in North America and Europe is currently underway [34]. In contrast to the previous study, this study is being undertaken in patients with CD who have continued symptoms and biopsy-proven mucosal inflammation despite a GFD. This study does not involve a gluten challenge. Aspergillus niger endopeptidase – AN-PEP

A second PEP derived from Aspergillus niger (AN-PEP; DSM, Heerlen, The Netherlands) has been developed. In one published study, 16 adult patients with CD on a GFD were enrolled in a three-phase, randomized, double-blinded, placebo-controlled study [35]. In the safety phase, all participants consumed a daily dose of 7 g of gluten along with ANPEP for 2 weeks and underwent a baseline and end-of-challenge biopsy. This was followed by the second phase which was a 2 week washout of AN-PEP while on a GFD. In the third phase, the 14 patients without significant histologic deterioration during the first phase were randomized to 7 g of gluten per day with either AN-PEP or placebo for 2 more weeks. The primary endpoint was a change in histology at the end of the third phase. Other secondary endpoints included celiac antibody titers and CD quality of life indices. AN-PEP was well tolerated and the CD quality of life indices scores remained relatively high during the 2-week safety phase. There were no major adverse events. However, histological deterioration as evidenced by an increase in Marsh grade was noted in two patients in the first phase. No significant change in serology was noted in this phase. Following the third phase, in the placebo arm, two patients had a demonstrated worsening of 2 Marsh grades and 5 patients demonstrated worsening by 1 Marsh grade. In the treatment group, one patient improved by 1 Marsh grade and another worsened by 1 Marsh grade. The patients in this study were challenged with a relatively high dose of gluten, compared to the ALV003 and larazotide acetate studies. Moreover, serological titers were checked at 2 weeks, which is a duration that is unlikely to yield gluten challenge induced serologic changes. Interpretation of study data was further limited by the fact that the actual level of titers was not reported. Overall, the findings in this study suggest that AN-PEP is not effective in preventing gluten-induced mucosal damage at 7 g of gluten per day, but it remains to be seen whether AN-PEP may be more effective with lower doses of gluten or in the pre-treatment of foods with trace amounts of gluten. Two additional studies are investigating the efficacy of AN-PEP to degrade gluten in healthy subjects ([36], completed) and in subjects with non-celiac gluten sensitivity ([37], currently Expert Rev. Gastroenterol. Hepatol.


recruiting). Both trials have been sponsored by DSM Food Specialties and are exploring the role of AN-PEP as a dietary supplement or food additive, rather than as a drug. Hence, the potential role of AN-PEP as a therapeutic agent for CD remains unclear.


STAN-1

STAN-1 is a cocktail of microbial enzymes commonly used in food supplements; it was also found to have gluten-degrading properties in the laboratory. This agent was studied in a randomized, double-blinded, placebo-controlled trial in 35 patients with CD on a GFD for at least 1 year with persistent seropositivity for tTG-IgA [38]. Patients were randomized to enzyme or placebo for 12 weeks, along with 1 g of daily gluten. The authors studied tTG-IgA titers as an endpoint and found no significant difference in serology between the two groups. A second arm of this Phase II study is evaluating the role of STAN-1 in patients with dermatitis herpetiformis; the results are pending. Probiotics

The enteric microbiota plays a key role in maintaining health status. As a result, dysbiosis has been implicated in various autoimmune, inflammatory disorders including CD. Collado et al. found reduced concentrations of Bifidobacterium species in fecal samples and duodenal biopsies from patients with both active and non-active CD compared to controls [39]. Moreover, in a molecular study of the microbiota of children with CD, it was confirmed that bifidobacteria were not present in the duodenum and were found in lower fecal concentrations in patients compared to healthy controls; 2 years on a GFD did not restore the microbiota [40]. Based on these findings, several studies have investigated the role of Bifidobacterium in CD pathogenesis in in vitro and in vivo models [41–43]. These studies have shown that Bifidobacterium infantis and Bifidobacterium lantis can reduce gliadin-induced increases in epithelial permeability and, overall, downregulate the pro-inflammatory immune response in patients with CD. These findings raise the possibility of developing a therapy based on bifidobacteria for patients with CD. In the only published clinical trial assessing probiotics in CD, 22 adult patients with untreated CD were enrolled in a placebo-controlled, double-blinded, randomized study [44]. The primary endpoint was intestinal permeability as measured by the mean LAMA fractional urinary ratio. Secondary endpoints included inflammatory and immunological markers, celiac serology concentration and clinical assessment of gastrointestinal symptoms using the GSRS. Patients were randomized to receive 2 capsules of B. infantis NLS super strain (Lifestart 2; Natren, Inc., Westlake Village, CA, USA) before meals or placebo for 3 weeks, while consuming 12 g of gluten daily. The authors found no significant change in intestinal permeability as measured by LAMA in either the treatment or placebo group. However, patients randomized to the probiotic experienced significant improvement in their gastrointestinal informahealthcare.com

Review

symptoms based on GSRS scores. In addition, there was a trend toward lower tTG-IgA and anti-DGP titers in the treatment arm. It is unclear whether the reduction in the antibody titers after 3 weeks of treatment represents a true therapeutic effect. Overall, this study suggests that the probiotic B. infantis NLS may alleviate some gastrointestinal symptoms in patients with untreated CD. However, the role of probiotics in clinical care of patients with CD remains unproven. Gluten-sequestering polymers: BL-7010

BL-7010 is a copolymer of styrene sulfonate with hydroxyethylmethacrylate (manufactured by BioLineRx Ltd. under a worldwide license agreement with Univalor) [45]. This polymer has been reported to bind with high efficiency to a-gliadin in pH environments similar to those found in both the stomach and duodenum [46]. The proposed mechanism of action of BL-7010 is to sequester gluten and prevent the degradation of a-gliadin into immunogenic particles with subsequent uptake into the intestinal submucosa [47]. The efficacy of this polymer in binding gliadin has been demonstrated in in vitro and in vivo mouse models [47]. In a recently published study, McCarville et al. used a NOD-DQ8 mouse model exposed to gluten to establish the safety of this copolymer [48]. BL-7010 was not absorbed systemically and prevented gluteninduced decreases in VH:CrD, increase in IELs and worsening intestinal epithelial permeability [48]. In addition, no interaction was noted with either pepsin or pancreatin or various vitamins [48]. A combined Phase I/Phase II, double-blinded, placebo-controlled, dose escalation study is underway in 40 patients with CD [49]. The primary objective of the study is to assess the safety of BL-7010. The secondary objective is to assess the systemic effects of the polymer in patients with well-controlled CD. Gluten tolerization & immunomodulation

In autoimmune disorders, various environmental factors in conjunction with genetic predisposition lead to breakdown of the regulatory mechanisms responsible for the normal balance between inflammation and tolerance. Tregs including the CD4, CD25, FOXP3 subtypes play a role in maintaining tolerance to dietary proteins [50]. In CD, these T cells including Tregs, both directly and indirectly, modulate the immune responses through various inflammatory cytokines such as IL-10, IL-15, IFN-g and TNF-a. An ideal therapy for CD and other autoimmune disorders is to ‘reset’ the immune system by restoring the balance between inflammation and tolerance. While this area remains in its infancy, advancements in our understanding of immune function have led to work on novel therapeutic approaches. Gluten vaccination

A desensitizing or therapeutic vaccine called Nexvax2 is currently in development for patients with CD (ImmusanT, Cambridge, MA, USA). The aim of the vaccine is to use doi: 10.1586/17474124.2015.1033399


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peptide-based immunotherapy to shift the T-cell response from pro-inflammatory to regulatory, in order to restore immune tolerance to gluten and allow resumption of a regular, glutencontaining diet. Murine models are limited in their ability to recapitulate the entire human phenotype of CD and are only able to recapitulate some of the components of the complex immune mechanisms involved [51,52]. Based on studies in a transgenic HLA-DQ2 murine model, three immunogenic 16-mer peptides that account for 60% of the overall gluten T-cell response in HLA-DQ2–positive individuals have been identified [53]. These three peptides were injected via subcutaneous route in these HLA-DQ2 transgenic mice. Gluten vaccination elicited enhanced tolerance through suppression of CD4+ T-cell proliferation, diminished IL-2 and IFN-g production, and increased expression of Tregs. Nexvax2 has been studied in a Phase I, double-blinded, randomized clinical trial. The results of this study have been presented in abstract form only [54]. In this study, 34 HLA-DQ2 +/DQ8 patients with well-controlled CD on a GFD were randomized to receive 9, 30, 60 or 90 mg of Nexvax2 or placebo subcutaneously on a weekly basis for 3 weeks. Patients who received the 60 and 90 mg doses of the vaccine experienced gluten-like gastrointestinal side effects, and their symptoms were more pronounced with higher doses. Seven out of nineteen subjects who received 30, 60 or 90 mg of Nexvax2 reported symptoms of nausea. Two subjects required anti-emetic therapy, and two subjects had vomiting at 2 and 5.5 h, after the initial dose. In the 90 mg dose group, one subject withdrew from the study due to severe gastrointestinal symptoms. The incidence of abdominal pain, diarrhea and abnormal feces was similar in the placebo and Nexvax2 groups. Gluten-specific T cells were detected by IFN-g enzyme-linked immunoSpot assay (ELISpot) and positive responses were seen after at least one dose of the vaccine, most commonly on day 6 of administration of the vaccine. The authors suggest that these findings possibly reflect intestinal immune activation similar to oral gluten exposure and support the mechanism of action of Nexvax2. Overall, the safety profile of the vaccine was deemed to be acceptable. Hookworm infection

According to the ‘Hygiene Hypothesis’, chronic infections including intestinal parasitic infections help regulate the immune system and prevent autoimmune and allergic diseases [55,56]. Studies have been performed on the potential utility of helminths on autoimmune illnesses including inflammatory bowel disease (IBD) and CD [57–60]. A Phase Ib/IIa study that involved experimental infection with the hookworm Necator americanus was performed in patients with CD in remission on a GFD, in order to determine the safety, tolerability and immunologic effects of hookworm infection on a GFD and during gluten challenge [61]. In this prospective, randomized, double-blinded, placebocontrolled study, 20 patients with CD well controlled on a GFD underwent cutaneous inoculation with hookworm larvae doi: 10.1586/17474124.2015.1033399

or placebo at weeks 0 and 12. At week 20, the patients received a 5-day challenge with 16 g of gluten daily. The primary outcomes in this study were changes in duodenal histology Marsh score and IFN-g levels pre- and post-gluten challenge. Five out of the 10 patients inoculated with the hookworm developed transient abdominal pain that resolved spontaneously, but no other serious adverse events were reported. Gluten challenge resulted in similar degrees of intestinal inflammation and gluten-related gastrointestinal symptoms in the treatment and placebo groups. A follow-up study published in 2014 investigated the ability of hookworm infection to prevent intestinal damage and symptoms using a protocol of slowly escalating doses of gluten to promote tolerance [62]. During the 52-week study, 12 adults with CD on a GFD were inoculated with N. americanus larvae and given 10–50 mg of gluten per day for 12 weeks, then 1 g of gluten per day for 12 weeks, and finally 3 g of gluten per day for 2 weeks. The 3 g gluten challenge for 2 weeks was deemed sufficient to induce significant serological and histological changes in >75% patients with CD [63]. Immunologic markers including Tregs and inflammatory T-cell populations were studied in peripheral blood samples and duodenal mucosa. Celiac antibody titers and symptom response were also documented. The primary outcome was duodenal VH:CrD after the 1 g gluten challenge. While this study lacked a control group, no change was seen in VH:CrD or IEL count. The authors also noted that there was an expansion of the Treg population and a reduction in IFN-g expressing T cells. Interestingly, the mean tTG-IgA titers declined despite increasing doses of gluten exposure, while the quality of life indices improved. Based on these findings, the authors suggested that infection with N. americanus during a gluten dose escalation challenge can promote immune regulation with tolerance to gluten in patients with CD. Larger placebo-controlled studies are expected. CCR9 antagonist

Effector and memory T lymphocytes use the chemokine receptor CCR9 and integrin a4b7 to localize to the small intestine [9]. Studies have shown that the number of T cells expressing CCR9 is increased in the peripheral blood of patients with CD. Based on these findings, it was postulated that blocking lymphocyte homing might represent a therapeutic target in CD. CCX282-B (ChemoCentryx, Mountain View, CA, USA, GlaxoSmithKline, Middlesex, United Kingdom), which blocks the chemokine receptor CCR9, was studied as a treatment option for both CD and IBD. CCX282-B was studied in a randomized, placebo-controlled trial for its safety and efficacy in 436 patients with Crohn’s disease. CCX282-B was well tolerated in this study and initially thought to be safe [64]. However, a subsequent Phase III study conducted in patients with IBD had to be discontinued due to lack of efficacy and increased incidence of adverse events. The only trial involving CCX282-B that has been performed in 90 patients with CD studied the effects of this drug on the VH:CrD of small Expert Rev. Gastroenterol. Hepatol.



intestinal biopsy specimens before and after gluten exposure [65]. This study was completed in July 2008, but the results have not yet been published. Concerns have also been raised regarding the risk of gastrointestinal infections seen in patients treated with this class of drugs, since the lymphocyte homing mechanism involving CCR9 is not antigen-specific. A new CCR9 antagonist called CCX507 that has greater specificity for the receptor is being studied. Therapeutic agents in pre-clinical testing Inhibitors of TG2

As discussed earlier, tissue TG2 plays a central role in the pathogenesis of CD through modification of gluten peptides allowing for high-affinity binding to HLA-DQ2 and HLA-DQ8. It has long been theorized that inhibition of TG2 may prevent presentation of gluten peptides by HLA-DQ2 and HLA-DQ8, thereby mitigating the T-cell inflammatory response [66,67]. A few pre-clinical proof-of-concept studies have tested several non-selective TG2 inhibitors in vitro. These agents can function as reversible, irreversible or competitive inhibitors of the TG enzyme. Cystamine is a competitive inhibitor that was found to block T-cell proliferation of gluten-responsive T cells in ex vivo cultures of duodenal tissue from patients with Another irreversible inhibitor called KCC009 that has increased affinity for human TG2 was tested in healthy mice [69]. This agent showed good oral bioavailability, efficient TG2 inhibition in small intestinal tissue, a short serum half-life and a low toxicity profile. Overall, these studies have shown that TG2 inhibition can prevent gliadin-induced adaptive and innate immune responses in vitro and ex vivo [68,70,71]. Despite the promising results obtained in pre-clinical testing, TG2 plays important roles in inflammation and wound healing in the intestine, and TG isoenzymes are found throughout the body, raising the possibility of safety issues [72]. A new generation of TG2 inhibitors engineered with a high-affinity thiol-binding group has been developed with 70- to 225-fold increased specificity for intestinal TG2 versus other TGs based on in vitro testing [53]. Overall, it remains to be seen whether TG2 inhibitors can be safe and effective therapeutic agents in CD.

Review

mediated immune responses. In another study, Ju¨se et al. designed high-affinity binders to HLA-DQ2 by using a positional scanning nonapeptide library to determine optimal amino acid substitution leading to enhanced binding [77]. They developed a decapeptide that has 50-fold enhanced binding affinity compared to the immunodominant gluten epitope, DQ2a-I-gliadin. Siegel et al. used the HLA-DQ2 crystalline structure to design gluten peptide analogs modified with an aldehyde group [78]. These modified peptides serve as both tight-binding HLA-DQ2 ligands and high-affinity, reversible TG2 inhibitors [79]. No data are currently available on the in vivo efficacy and safety of such an approach. It is important to note that this therapeutic strategy poses a number of challenges. In particular, it is unclear how the modified peptides would reach their target in the lamina propria while competing with the luminal, immunogenic gluten peptides. Moreover, there are safety concerns, since this approach can lead to immunosuppression and hypersensitivity reactions. Immune cell–targeted therapies and their role in immune suppression, especially in RCD

Strategies to suppress the inflammatory T-cell response have been investigated as treatment options for CD. Given that CD is characterized by a robust cytokine response, agents that either suppress inflammatory cytokines or amplify regulatory ones are potential therapeutic targets. Some patients with CD can develop RCD (RCD I and II) and are at risk of severe complications including ulcerative jejunitis and enteropathy-associated T-cell lymphoma. Treatments for RCD I and II include steroids such as prednisone and budesonide, antiinflammatory medications such as mesalamine, immunosuppressive therapy, chemotherapeutic agents like cladribine, as well as stem cell and mesenchymal stem cell transplantation for patients with enteropathy-associated T-cell lymphoma. Some of these agents are being investigated for use in CD, although they have been tested in clinical trials in several inflammatory, autoimmune diseases such as IBD and rheumatoid arthritis. A few of the immune cell-targeted therapies are discussed in more detail below. IL-15 antagonists

HLA-DQ2 or HLA-DQ8 blockers

The presentation of gliadin peptides on HLA-DQ2 and HLADQ8 haplotypes by antigen-presenting cells drives the adaptive immune response in patients with CD. Therefore, the use of HLA-blocking compounds is a potential therapeutic target to prevent immune activation [67,73–75]. This strategy remains in the discovery/pre-clinical phase. Currently, efforts have focused on designing blockers for HLA-DQ2, the more frequent haplotype, in addition to developing gluten peptide analogs. Kapoerchan et al. designed a series of gluten peptides in which the proline residue was replaced by azidoprolines [75,76]. They found that these modified gluten peptides have a 100- to 200-fold higher binding affinity for HLA-DQ2, compared to the natural gluten peptide. Moreover, some of the compounds were found to be non-immunogenic and minimize gluteninformahealthcare.com

IL-15 is an essential growth factor for intraepithelial T lymphocytes and NK cells and is responsible for their activation and proliferation. Enhanced expression of IL-15 via the innate immune response induces increased production of IELs, a characteristic finding in CD. IL-15 also upregulates the expression of MICA in epithelial cells. The activation and stimulation of lymphocytes through the binding of MICA to the NKG2D receptor leads to cytotoxicity toward epithelial cells. This may play a role in compromising epithelial barrier function in CD. IL-15 is also believed to orchestrate tissue destruction and inflammation through a complex signaling process mediated by JAK 1 and 3 [80]. Therefore, blocking the action of this cytokine could represent a therapeutic target in CD. Tofacitinib is a non-specific inhibitor of JAK that has been recently approved by the FDA for the treatment of rheumatoid doi: 10.1586/17474124.2015.1033399


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arthritis. The efficacy of this drug was demonstrated in a transgenic celiac mouse model [80]. Transgenic mice with CD that overexpress IL-15 develop villous atrophy in the small intestine. Mice treated with tofacitinib showed lasting reversal of intestinal inflammation, suggesting that this agent might reverse the pathologic manifestations of IL-15 overactivity. If similar effects are observed in human studies, tofacitinib may have a role in the treatment of severe cases of RCD where blocking IL-15 may induce apoptosis of malignant cells, preventing their transformation into lymphoma. A recent mouse model has shown that neutralizing IL-15 with a mouse anti-mouse monoclonal antibody (mAb) to IL-15 depletes NK cells in vitro [81]. A human mAb to IL-15, called AMG 714 has been developed. However, human subjects treated with this mAb did not show depletion in NK cells; the role of AMG 714 in patients with inflammatory disorders such as CD remains unclear [81]. A humanized Mik-b-1 mAb that blocks IL-15 is currently undergoing Phase I testing in patients with RCD [82].

important to note that effector T cells may become autonomous and no longer responsive to suppression by Tregs, thereby raising important concerns regarding the overall efficacy of anti-CD3 therapy as well as its safety profile [50]. Anti-CD20

In addition to T cells, B cells also play a key role in the pathogenesis of CD through the production of disease-specific autoantibodies. The B-cell marker CD20 has been targeted for therapy in B-cell malignancies and autoimmune disorders including multiple sclerosis and rheumatoid arthritis [88,89]. However, anti-CD20 therapy does not eliminate mucosal IgA-producing plasmablasts [90]. Therefore, its ability to eliminate TG2 autoantibodies in CD is not certain. Although several CD-20 antagonists have been approved and are on the market, their role in the treatment of CD has not yet been defined. Conclusion

IL-10 agonists

IL-10 suppresses the secretion of pro-inflammatory cytokines from gliadin-activated T cells. Therefore, IL-10 agonists have been considered in the list of potential drug candidates for the treatment of CD. An ex vivo study using cultured intestinal biopsy specimens from patients with CD showed that IL-10 suppressed T-cell activation. However, this finding was not replicated in a pilot study conducted in 10 patients with RCD who received 8 mg/kg of recombinant IL-10 subcutaneously three-times a week for 3 months [83]. The primary end point was mucosal histopathology at 3 months. Only one patient had complete regression of villous atrophy. Moreover, upon discontinuation of the drug, patients had recurrence of symptoms. Based on these findings, IL-10 does not hold promise as a therapeutic agent in RCD. Anti-IFN-g & anti-TNF-a

IFN-g and TNF-a both play important roles in the immunopathogenesis of CD. mAb-based therapy against both of these inflammatory cytokines has been proposed as potential treatment for CD. However, published data are lacking to support the use of these agents in CD, except for isolated case reports on the use of the anti-TNF-a agent infliximab for RCD [84–86]. Although data for the use of anti-TNF-a agents in IBD have been well established, these findings cannot be extended to the celiac population at this time. Moreover, there remain safety and cost concerns with this class of therapeutics. Anti-CD3

The CD3 molecule is a co-receptor of the T-cell receptor. Therefore, antibodies against CD3 could theoretically suppress gluten-activated T cells and reduce inflammation in CD. AntiCD3 therapy has been evaluated in type I diabetes and murine models of transplant rejection. Studies have shown that Tregs can be induced in vitro by anti-CD3 antibodies and may promote immune tolerance to gluten in CD [87]. However, it is doi: 10.1586/17474124.2015.1033399

Ongoing advances in drug development have led to alternative, non-dietary treatments for CD. This review has focused on the six treatments that are currently in clinical trials, although none are in Phase III testing. Most agents currently being studied are intended to serve as an adjunct to the gluten-free diet. However, immune tolerance inducing therapies have the potential to allow resumption of a fully normal diet. Expert commentary & five year view

The only available treatment for CD is a GFD. However, the GFD is not ideal and there is a growing appreciation for the unmet need for alternative therapies in CD. Currently, glutendegrading enzymes and modulators of intestinal permeability have been evaluated in Phase II testing and are yet to enter Phase III clinical trials. These agents hold the possibility of becoming available within the next 5 years. However, they are not meant to completely replace a GFD. The initial goal of these non-dietary therapies is to serve as adjunctive agents in conjunction with a GFD and to mitigate the effects of low doses of gluten ingested inadvertently or intentionally. Other drugs with novel mechanisms of action including immunebased therapies are also being studied, although largely in developmental stages. In addition, novel biologics such as IL-15 antagonists, though unlikely to be safe enough for routine use in CD, may be effective in RCD. Several novel treatment options at various stages of development are in the pipeline. When safe and effective therapeutic agents for CD are available, it is likely that there will be a dramatic increase in requests for clinical care by patients with CD, analogous to what has been seen with other diverse medical conditions from irritable bowel syndrome to erectile dysfunction. Clinicians should be prepared for this influx of patients, many of whom have not been seen for their CD in years, to return for evaluation and discussion of therapeutic options. We expect that this will eventually result in the growth of CD as a specialty similar to IBD currently. Expert Rev. Gastroenterol. Hepatol.


Financial & competing interests disclosure

D Leffler has served as a consultant for and/or received research support from the following: Alba Therapeutics, Alvine Pharmaceuticals, Shire Therapeutics, Ironwood Pharmaceuticals, Genzyme, Glenmark Pharmaceuticals, GI Supply, Pfizer, Coronado Biosciences, Bioline Rx, Inova

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Diagnostics and Prometheus Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues


.

It is currently accepted that there is a significant unmet medical need in celiac disease (CD) due to ongoing symptoms, high treatment burden and incomplete intestinal healing.

.

Two groups of agents, tight junction inhibitors and endopeptidases, have been studied extensively and are nearing Phase III trials, while multiple other agents are in earlier stages of development.

.

Multiple heterogeneous CD clinical trials of adjunctive therapies to the gluten-free diet (GFD) have been reported in the last 5 years. However, there is growing consensus regarding efficient clinical trial design. Although gluten challenge can be used to study drug development in the initial phases for proof of principle, real-life studies are more appropriate in the later phases of drug development. As drug development for CD progresses in the future, it is expected that there will be increasing uniformity in studies including a combination of gluten challenge and ‘real-life’ trials aimed at improving disease in persistently symptomatic individuals.

.

Adjunctive therapies to the GFD and immune therapies aimed at full restoration of tolerance may need to be studied differently; optimal trial design for immunotherapies is not well established.

.

While multiple regulatory hurdles remain for CD that has no US FDA- or EMA-approved therapy, there has been remarkable progress in the last 5 years and an approved therapy is likely in the coming years. This is expected to dramatically change the CD clinical landscape.

.

Ultimately, new drugs for CD should be safe, effective and a convenient alternative to the GFD. The availability of novel treatment alternatives may lead to a paradigm shift in the management of CD in the coming years.

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Celiac disease: the search for adjunctive or alternative therapies.

Celiac disease and overweight in children: an update.

Celiac disease and endocrine autoimmune disorders in children: an update.

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[Mitral regurgitation: update 2015].

June 2015 update.

Ochsner Research Update, 2014-2015.

HMMER web server: 2015 update.

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Potential new clinical therapies for Chagas disease.

Wilson's disease: Prospective developments towards new therapies.

Therapies from Fucoidan: An Update.

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Update in Lung Cancer 2015.

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