Review
Emerging drugs for celiac disease Hugh James Freeman
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
University of British Columbia, Department of Medicine (Gastroenterology), Vancouver, BC, Canada 1.
Background
2.
Medical need
3.
Existing treatment
4.
Market review
5.
Current research goals
6.
Scientific rationale
7.
Competitive environment
8.
Potential development issues
9.
Conclusion
10.
Expert opinion
Introduction: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. Areas covered: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. Expert opinion: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed. Keywords: celiac disease, celiac disease therapy, enzyme treatment, glutenase, gluten-free diet, gluten-sensitive enteropathy, larazotide Expert Opin. Emerging Drugs [Early Online]
1.
Background
Celiac disease is a life-long immune-mediated disorder primarily affecting the small intestinal mucosa [1]. The disorder is marked by clinical and pathological changes attributed to ingestion of dietary gluten and appears restricted to genetically susceptible individuals. Common features include diarrhea and weight loss, but celiac disease is now recognized to be very heterogeneous in its initial presentation, often first detected in those with other clinical disorders such as iron deficiency anemia, osteoporosis, ‘autoimmune’ conditions, like dermatitis herpetiformis or autoimmune thyroiditis, and some neurological disorders, including dementia. This variability in the initial clinical presentation appears largely related to genetic and immunological factors, age of onset, extent and degree of small intestinal mucosal inflammation, gender and familial nature. In recent years, celiac disease has appeared in ‘epidemics’ [2], possibly related to age of introduction of dietary gluten, specific infections, medication use and supplements [3]. Diagnosis requires an initial small intestinal biopsy showing pathological features of untreated celiac disease. As the disease is a gluten-dependent disorder, by definition, demonstration of improvement on a gluten-free diet is also crucial. Genetic markers, including human leukocyte antigen (HLA) markers, HLA-DQ2 and HLA-DQ8, as well as circulating antibodies to tissue transglutaminase antigen (tTG), are usually evident. Most also recognize that the single critical factor for persistent symptoms in celiacs is limited compliance to a strict diet, sometimes because gluten is ubiquitious, even in pill capsules. Others may have a different or superimposed disorder responsible for ongoing symptoms, including the irritable bowel syndrome. Finally, a complication of celiac disease may occasionally be responsible. 10.1517/14728214.2015.985204 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
1
H. J. Freeman
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
2.
Medical need
Historically, celiac disease was originally thought to be common only in Europe, specifically, the UK and some Scandanavian countries. The incidence of the disease was high in western Ireland [4], but believed to be low in the US [5]. Later, these estimates were revised, largely owing to serologically based studies that suggested ~ 1% or more of most populations in Europe and the Americas had celiac disease [6-8]. Standardization of these assays in different countries, however, has been limited [9,10]. Others have suggested that serological studies have overestimated sensitivity and underestimated specificity due to verification bias [11] as serologically negative subjects are rarely biopsied [12]. Regardless, these serological studies do indicate that rates of undiagnosed disease are probably quite significant, even in Europe and the US. Prevalence data in these countries has recently been summarized [13]. In children, rates reported from Sweden were 1:285 and 1:77, Finland, 1:99 and 1:67, and Italy, 1:230 and 1:106. Similar rates have been noted in New Zealand, Australia, Argentina and Israel [14-16]. In the US, overall prevalence rates for children and adults were recorded at 1:104 and 1:105, respectively [17]. Thus, the established medical need for treatment of celiac disease is substantial, estimated to be ~ 1% of most populations studied. 3.
Existing treatment
For > 70 years, a gluten-free diet has been recommended as treatment for celiac disease. The gluten-free diet usually leads to resolution of symptoms and improved nutrient absorption. Normalization of histopathological changes occurs and an improved nutritional state results. Evidence also suggests that long-term complications of celiac disease, such as bone disease, and risk of malignancy, particularly lymphoma, are reduced. However, gluten is ubiquitous and complete avoidance is very difficult. In recent decades, per capita consumption of wheat and other processed foods, which contain more gluten, have also both increased. The gluten-free diet is very expensive, rarely subsidized by government, even in many advanced nations, and not universally available. As a result, compliance for many with celiac disease is difficult. A clear need for other forms of therapies, even as added supplements, that might reduce sole reliance on a gluten-free diet is apparent. 4.
Market review
Some recent data have also suggested a change in celiac disease prevalence in recent decades. Celiac disease may be increasing, particularly in North America and Europe. In part, this may simply reflect increased physician recognition coupled with use of serologically based testing for screening and case finding. However, a true change in prevalence may have occurred, possibly related to other confounding environmental 2
factors [18]. In young male military recruits at Warren Air Force Base, a low prevalence of celiac disease was suggested, retrospectively, based on evaluation of stored frozen sera collected from 1948 to 1952, compared to more recent control cohorts from Olmstead Country in 2006 -- 2008 [19]. In an independent report, increasing sero-prevalence rates were also noted from 1974 to 1989 [20]. Endoscopic biopsy screening studies, rather than simple serological screening, has also been done. Routine duodenal biopsies obtained during endoscopic study over a 30-year period defined moderate-to-severe architectural changes typical of celiac disease in 2 -- 3% of adult Canadians referred for investigation of upper gastrointestinal symptoms [21]. Interestingly, in this study, environmental factors may have been important as a significant fall in new diagnoses of celiac disease occurred over two decades followed by a significant rise during the next decade. Other recent studies have indicated a change in risk in recent decades [22,23] including a recent report from Hangzhou in China suggesting increased detection, possibly because of serological screening [24]. Interestingly, Asian Canadians with biopsypositive celiac disease have also previously been noted, including a Chinese woman [25]. Celiac disease likely also occurs more often in China [26]. A particularly high allele frequency of DQB1*0201 or DQB1*0201/02 has been noted in Xinjiang in northwestern China, an area largely populated by Uygurs and Kazaks, rather than Han Chinese. Overall, calculated wheat consumption in China has also increased suggesting that the potential for gluten exposure is rapidly increasing. Wheat ingestion is greater north of the Yangtze River compared to rice consumption regions south of the Yangtze River. Rural Xinjiang seems especially susceptible, as wheat consumption there is relatively high. Although precise data are not available, these emerging data on rising risk of celiac disease, especially in China, indicate that the potential global market for treatment of celiac disease is likely to be very significant. 5.
Current research goals
The main goals of therapy are to reduce symptoms, improve nutrient absorption and obviate inflammatory changes persistent in the small intestine. Although the gluten-free diet has been universally effective as a treatment regimen, the approach is costly and compliance is difficult. Alternative forms of treatment based on a current understanding of the pathogenesis of celiac disease have been explored. Overall, current research goals include discovery and evaluation of measures aimed at either replacing entirely the need for a gluten-free diet, or more likely, supplementing its use. 6.
Scientific rationale
Table 1 lists some of the different treatment approaches that are currently being considered for exploration in celiac disease. Some remain in a discovery phase but some have now
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
Table 1. Possible alternative treatment approaches for celiac disease. Hypothetical mechanism
Hypothetical treatment
Reduced gluten exposure
Genetically modified grains Copolymer binders of gluten Proylendopeptidase (e.g., ALV003) Larazotide acetate (e.g., AT1001)
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
Gluten peptide hydrolysis* Tight junction blockade (zonulin)* Transglutaminase or HLA-DQ2/DQ8 blockers Immune tolerance induction
Potential developmental peptides Peptide vaccination (Nexvax)
*At or near full peer-review publication of advanced clinical trials.
reached the clinical trials stage. For more detailed information on immunopathogenetic mechanisms in celiac disease, outside the scope of this review, readers are directed to an extensively illustrated review elsewhere [1]. Genetic modification of grains It is believed that reduced dietary exposure to gluten components in novel modern grains that could be developed in future might be useful [27,28]. Modern types of wheat, currently in use, are believed to be more immunogenic, compared to ancient wild or diploid varieties of wheat. Engineered genetically modified grains completely lacking or with limited amounts of specific immunogenic peptides may be possible but are likely difficult to develop and cultivate. Gluten has different immunogenic peptide sequences and some, but not all, genes responsible are not known and may be anatomically located in different sites in the wheat genome. Critical baking features may be altered in the grains with the development of genetically modified varieties and there is a potential for contamination with wild wheat strains. 6.1
Co-polymeric binders Co-polymeric binders to cause luminal sequestration of gluten-containing substances in the diet might be used to reduce mucosal exposure. This approach was explored in vitro with epithelial cells [29] and in vivo with a rodent model [30]. One binding agent, hydroxyethylmethacrylate co-styrene sulfonate, appeared to reduce toxicity in these model systems, but human studies are still required. 6.2
Enzymatic gluten hydrolysis Another approach that is rapidly evolving and appears to be very promising has involved administration of dietary proteins that have already been hydrolyzed or ‘pre-digested’ before intestinal epithelial cell uptake. Ordinarily, initiation of protein hydrolysis begins in the lumen and involves gastric peptic and pancreatic proteolytic activities. Enterocyte peptidases further hydrolyze resultant peptide products into amino acids, dipeptides and tripeptides for enterocyte transport into the portal venous system. Proline- and glutamine-containing 6.3
peptides in gluten appear to be quite resistant to enzyme proteolysis. As a result, only limited gluten digestion occurs. Possibly, resulting peptides from this hydrolytic process could induce an immune response in genetically programmed individuals causing celiac disease [31,32]. Prolyl-endopeptidases derived from plants and specific bacterial agents (i.e., Flavobacterium, Sphingomonas) have the ability to hydrolyze internal proline-glutamine bonds in some proline-containing peptides [33]; however, gastric acid may cause enzyme inactivation or inhibition for some of these preparations. A combination of barley endoprotease and prolylendopeptidase in powder or tablet form appeared to be stable causing wheat gluten breakdown and reduced immunemediated effects [34-36]. As well, prolyl-endopeptidase from the microbiologic agent, Aspergillus niger, inhibited a gliadin-stimulated immune response by gluten-specific T cells [37]. Subsequent modeling suggested that most hydrolytic activity occurred in the gastric compartment with only limited activity required in small intestine [38]. A recently published pilot study of A. niger prolyl-endoprotease use in celiac patients demonstrated that the orally administered enzyme was well tolerated in biopsy-defined celiac patients; however, a difference from a placebo-treated group could not be demonstrated [39]. Enzymes from other microbial agents can operate in a gastric environment and these have been cloned and characterized [40-43]. Some Phase II clinical trials have been completed using ALV003, an oral combination glutenase recombinant agent (Alvine Pharmaceuticals, Inc., San Carlos CA; www.alvinepharma.com). This agent, however, is only stable at a pH range of 3.5 -- 5, reflecting the postprandial pH of the stomach without significant gastrointestinal absorption. Two trials (NCT00959114 and NCT01255696) were recently reported as a randomized, double-blind, placebocontrolled Phase II trial [44] showing that ALV003 reduced gluten-induced small bowel mucosal injury in patients with celiac disease on a ‘gluten-free’ diet daily. This diet was estimated to contain as much as 2 g gluten (equivalent to about ½ of a standard slice of bread). Currently, recruitment is ongoing for a further Phase II study (NCT01917630) on efficacy and safety of ALV-003 in symptomatic celiac disease patients. This is a double-blind placebo-controlled doseranging study with primary end points being intestinal mucosal morphometric measures, including change in villus height to crypt depth ratio from baseline to week 12. Estimated enrollment is 500 celiac patients with an estimated completion date of March 2015 (clinical trials.gov). A different ‘enzymatic’ approach examined gluten-free sourdough wheat treated with lactobacilli and fungal proteases. A resulting gluten content of < 8 p.p.m. appeared safe with no changes in hematological, serological or intestinal permeability end points [45]. A further study compared natural flour baked goods to two other hydrolyzed baked good groups. Most in the latter two hydrolyzed groups had no clinical, serological or histological worsening [46]. Others have
Expert Opin. Emerging Drugs (2014) 20(1)
3
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
H. J. Freeman
employed probiotic preparations, specifically VSL#3, a mixture of lactic acid and bifidobacteria, in preliminary studies showing effective hydrolysis of gliadin peptides [47] combined with evidence of an enhancement of mucosal tight junction markers in an animal model [48]. Initial studies, recently published [49], using an intriguing enzymatic approach have led to evaluation of Rothia mucilaginosa, a microbial inhabitant of the oral cavity that can enzymatically cleave gliadin at regions resistant to degradation by mammalian enzymes. These enzymes may eventually prove useful to neutralize T-cell immunogenic properties for celiac disease treatment but still require clinical trial evaluation in humans. Tight junction blockade Another approach has been to prohibit passage of immunologically active gluten peptides through the intracellular tight junctions as a paracellular transport route. In celiac disease, including its most early phases, the intestinal mucosa may be ‘leaky’ with increased paracellular permeability. Zonulin is a specific tight junction protein that functions together with other transmembrane proteins to regulate epithelial barrier permeability, highly expressed in celiac disease [50]. Gliadin may bind to a specific chemokine receptor, CXCR3, resulting in release of zonulin and increased intestinal permeability [51]. Larazotide acetate (AT1001) is a peptide that is believed to directly antagonize zonulin by receptor blockade [52] leading to possible impairment of paracellular transport from gliadin peptides and their resultant immunological effects. In initial clinical trials (Alba Therapeutics, Baltimore, MD; www.albatherapeutics.com), larazotide appeared to be safe with some symptomatic benefit compared to placebo but no significant change in intestinal permeability [53,54]. So far, these published studies seem disappointing. Some believe that there have been no true positive effects (apart from symptom benefit) and no clear dose response, suggesting a possible placebo effect. Recruitment for a late Phase II double-blind placebo-controlled dose-ranging study in 342 patients with biopsy-defined celiac disease as an adjunct to a gluten-free diet in celiac disease was completed in November 2013 (NCT0139613) and results should soon become available in published form. Once gluten peptides pass through tight junctions, another potential site of therapeutic intervention in the ‘immunopathogenic sequence’ of mucosal gliadin degradation has been considered, specifically, tTG-enzyme-induced deamidation. Normally, it is believed that deamidated peptides each assume negative charges resulting in enhanced affinity for the binding grooves on HLA-DQ2 and/or DQ8 molecules found the surface of antigen-presenting cells. As a result, T-lymphocyte activation and subsequent histopathologic mucosal effects occur. To counteract these effects, different hypothetical approaches have been considered. Blockade of tTG or the specific HLADQ2 and/or HLA-DQ8 molecules has been considered to prevent this peptide binding and resultant immune-related mucosal effects. Inhibition of in vitro tTG activity was shown 6.4
4
to inhibit gliadin-specific T-cell clones from patients with celiac disease along with gliadin-induced mucosal lymphocyte proliferation [54,55]. Alternatively, gluten peptide analogues might be used as HLA-blocking agents by prohibiting binding or access to the binding grooves on antigen-presenting cells. At this time, treatment focused on this specific step needs evaluation. It is conceivable that a number of deleterious short- and longterm immune-mediated side effects could also result from this form of immunological intervention. Immune tolerance induction Immune tolerance induction has also been examined. In theory, a peptide vaccine could result in development of tolerance in some immunologically active intestinal cells in celiac disease pathogenesis. NexVax vaccine employs three different gluten peptides that could hypothetically lead to tolerance in celiacs. Prior studies in transgenic mice with gluten-sensitive T cells demonstrated efficacy, while patients with celiac disease treated with this agent demonstrated acceptable shortterm safety with development of anti-gluten T cells [56]. Results of further studies to evaluate efficacy and long-term safety of these vaccines in celiac disease patients are still required. 6.5
7.
Competitive environment
Based on this scientific rationale, some drugs have already surfaced in this emerging competitive environment for management of celiac disease. Table 2 summarizes two agents that have already entered late Phase II clinical trials and may show some promise. To date, published results suggest some positive, but only limited, results. Positive results with ALV003 in a Finnish population are encouraging, particularly since the end points evaluated were morphological. In this setting, histopathological end points to assess actual effects on the inflammatory response would have been useful. Some positive clinical (not morphological) results were also achieved with larazotide, but functional studies were not consistent. Perhaps, these will be clarified by the already completed study, not yet published. Neither of these approaches, however, was meant to completely substitute for a gluten-free diet in celiac disease. Perhaps, some, but not all celiacs, could utilize a broader based diet with small amounts of gluten, combined with one of these agents. As a result, better compliance might also be encouraged. As well, if only a limited effect appeared with either agent alone, it is possible that both could be used in combination because their mechanism of action differs. 8.
Potential development issues
A number of difficult issues need to be addressed that may prohibit potential development, especially during clinical evaluation. First, end points of each treatment regimen being
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
Table 2. Competitive environment. Compound Company Structure Stage
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
ALV003 AT1001
Mechanism
Phase IIa, IIb Glutenase Alvine [57] Enzyme Larazotide Phase IIa, IIb Zonulin Alba [58] blockade
evaluated need to be precisely documented. The most critical element is normalization of mucosal biopsies following a course of treatment. Only a single study on enzyme therapy with ALV003 had demonstrated any morphological effects, while the other study on larazotide did not report any morphological effects based on small bowel biopsies after therapy. Other end points of the treatment response may include the degree and quality of the response, including improved symptoms and measures of absorptive function. Even if these are improved, the presence of an ongoing immune response as reflected by the presence of antibodies to tTG and persistent mucosal inflammatory changes, not only in the small intestine but also in the oral mucosa [56], may be important. Indeed, these findings may not signal a real treatment advance because the long-term risks of only partially treated celiac disease may continue. Second, use of the standard therapy, specifically, the gluten-free diet, may be needed in all clinical treatment trials because the gluten-free diet is an already established and effective treatment. Third, and finally, the long-term of each agent should be evaluated. The long-term background risk of other superimposed diseases, including lymphoma, could be altered, especially over an extended period. 9.
Conclusion
Celiac disease is an immune-mediated disorder mainly affecting the small intestine. Current treatment with a gluten-free diet is generally effective, but the diet is expensive and compliance is difficult. An alternative to the gluten-free diet, or at least, a treatment to supplement the gluten-free diet would be useful, particularly for reduction of any persistent inflammatory changes that might be associated with ongoing symptoms or lead to long-term complications, including malignant disorders. Celiac disease is recognized in ~ 1% of most populations evaluated. The disease appears to be increasing, possibly due to other, as yet unidentified, factors in the environment.
Recent studies also suggest that the disease is becoming widely recognized on a global scale, particularly in genetically predisposed individuals living in areas that depend on wheat cultivation. Based on current hypotheses related to the pathogenesis of celiac disease, a wide array of potential treatment options have been explored ‘at the bench’ in the laboratory and some have been initially assessed ‘at the bedside’ in clinical trials. 10.
Expert opinion
At this time, a number of agents have reached the initial stages of clinical trials, but the most promising clinical studies published to date utilize enzymes that have been cloned and characterized for hydrolysis of dietary gluten after oral administration. So far, studies with ALV003, a novel recombinant glutenase, have been most intriguing. A randomized double-blind, placebo-controlled Phase II trial has shown attenuation of gluten-induced small intestinal mucosal injury in patients with celiac disease. In the most recent studies, symptoms and histopathological changes were reduced in celiacs treated with 2 g added gluten daily and ALV003, compared to the placebo. Serologic changes were not observed, in spite of histopathological changes, suggesting a persistent immune response. Although the dose of added gluten was very limited and the population studied was quite homogeneous, replication in other populations would be valuable. These initial studies, however, emphasize that this form of enzyme therapy is not meant to replace, but supplement the current gold standard of treatment, the gluten-free diet. Although both an improved clinical state and improved laboratory parameters were evident in this clinical trial, persistent inflammatory changes were still present, so the long-term risks of celiac disease may not be significantly altered and may require added years to define.
Declaration of interest The author has 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. Emerging Drugs (2014) 20(1)
5
H. J. Freeman
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
2.
3.
4.
Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol 2012;18:6036--59 Ivarsson A, Persson LA, Nystrom L, et al. Epidemic of celiac disease in Swedish children. Acta Paediatr 2000;89:165--71 Lebwohl B, Ludvigsson JF, Green PH. The unfolding story of celiac disease risk factors. Clin Gastroenterol Hepatol 2014;12:632--5
Kowlessar OD, Phillips LD. Celiac disease. Med Clin North Am 1970;54:647--56
6.
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286--92
7.
Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517--24
9.
10.
11.
12.
6
Cook HB, Burt MJ, Collett JA, et al. Adult celiac disease: prevalence and clinical significance. J Gastroenterol Hepatol 2000;15:1032--6
14.
Hovell CJ, Collett JA, Vautier G, et al. High prevalence of celiac disease in a population-based study from Western Australia: a case for screening? Med J Aust 2001;175:247--50
15.
West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected celiac disease in England. Gut 2003;52:960--5 Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? Gastroenterology 2005;128:S47--51 Cavell B, Stenhammar L, Ascher H, et al. Increasing incidence of childhood celiac disease in Sweden. Results of a national study. Acta Paediatr 1992;81:589--92 Carlsson AK, Axelsson IE, Borulf SK, et al. Serological screening for celiac disease in healthy 2.5-year-old children in Sweden. Pediatrics 2001;107:42--5 Catassi C, Ratsch IM, Fabiani E, et al. High prevalence of undiagnosed celiac disease in 5280 Italian students screened by antigliadin antibodies. Acta Paediatr 1995;84:672--6
Gomez JC, Selvaggio GS, Viola M, et al. Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. Am J Gastroenterol 2001;96:2700--4
16.
Shamir R, Lerner A, Shinar E, et al. The use of a single serological marker underestimates the prevalence of celiac disease in Israel: a study of blood donors. Am J Gastroenterol 2002;97:2589--94
17.
Hoffenberg EJ, Mackenzie T, Barriga KJ, et al. A prospective study of the incidence of childhood celiac disease. J Pediatr 2003;143:308--14
18.
Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of celiac disease over time. Aliment Pharmacol Ther 2007;26:1217--25
19.
Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 2009;137:88--93 Interesting serologically based study suggesting an increase prevalence of disease over time using stored sera.
Mylotte M, Egan-Mitchell B, McCarthy CF, McNicholl B. Incidence of celiac disease in the West of Ireland. Br Med J 1973;1:703--5
5.
8.
13.
over two decades: population-based study. Am J Gastroenterol 2014;109:757--68 24.
Jiang LL, Zhang BL, Liu YS. Is adult celiac disease really uncommon in Chinese? J Zhejiang Univ Sci B 2009;10:168--71
25.
Freeman HJ. Biopsy-defined celiac disease in Asian-Canadians. Can J Gastroenterol 2003;17:433--6
26.
Yuan J, Gao J, Li X, et al. The tip of the “celiac iceberg” in China: a systematic review and meta-analysis. PLoS One 2013;8:e81151 Interesting study collating serological studies with urban and rural consumption of wheat and rice in Chinese provinces.
.
27.
Carroccio A, Di Prima L, Noto D, et al. Searching for wheat plants with low toxicity in celiac disease: between direct toxicity and immunologic activation. Dig Liver Dis 2011;43:34--9
28.
Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, et al. Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology 2005;129:797--806
29.
Pinier M, Verdu EF, Nasser-Eddine M, et al. Polymeric binders suppress gliadininduced toxicity in the intestinal epithelium. Gastroenterology 2009;136:288--98
Catassi C, Kryszak D, Bhatti B, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med 2010;42:530--8 Long-term study on natural history of celiac disease in an American cohort.
30.
Pinier M, Fuhrmann G, Galipeau HJ, et al. The copolymer P (HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology 2012;142:316--25
Freeman HJ. Detection of adult celiac disease with duodenal screening biopsies over a 30-year period. Can J Gastroenterol 2013;27:405--8 Biopsy-based study over three decades showing temporal variation in rates of diagnosis of celiac disease.
31.
Sollid LM, Qiao SW, Anderson RP, et al. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 2012;64:455--60
32.
Gass J, Khosla C. Prolyl endopeptidases. Cell Mol Life Sci 2007;64:345--55
22.
Namatovu F, Sandstrom O, Olsson C, et al. Celiac disease risk varies between birth cohorts, generating hypotheses about causality: evidence from 36 years of population-based follow-up. BMC Gastroenterol 2014;14:59
33.
Garcia-Horsman JA, Venalainen JI, Lohi O, et al. Deficient activity of mammalian prolyl oligopeptidases on the immunoreactive peptide digestion in celiac disease. Scand J Gastroenterol 2007;42:562--71
23.
West J, Fleming KM, Tata LJ, et al. Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK
34.
Piper JL, Gray GM, Khosla C. High selectivity of human tissue transglutaminase for immunoreactive
.
20.
.
21.
.
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
gliadin peptides: implications for celiac sprue. Biochemistry 2002;41:386--93 35.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
36.
Khosla C, Gray CM, Sollid LM. Putative efficacy and dosage of prolyl endopeptidase for digesting and detoxifying gliadin peptides. Gastroenterology 2005;129:1362--3 Gass J, Vora H, Bethune MT, et al. Effect of barley endoprotease EP-B2 on gluten digestion in the intact rat. J Pharmacol Exp Ther 2006;318:1178--86
44.
..
Lahdeaho M-L, Kaukinen K, Laurila K, et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 2014;146:1649--58 Important study showing positive effects of oral glutenase therapy and its current limitations.
45.
Di Cagno R, Barbato M, Di Camillo C, et al. Gluten-free sourdough wheat baked goods appear safe for young celiac patients: a pilot study. J Pediatr Gastroenterol Nutr 2010;51:777--83
46.
Greco L, Gobbetti M, Auricchio R, et al. Safety for patients with celiac disease of baked goods made of wheat flour hydrolyzed during food processing. Clin Gastroenterol Hepatol 2011;9:24--9
Mitea C, Havenaar R, Drijfhout JW, et al. Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for celiac disease. Gut 2008;57:25--32
47.
De Angelis M, Rizzello CG, Fasano A, et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for celiac sprue. Biochim Biophys Acta 2006;1762:80--93
39.
Tack GJ, van de Water JM, Bruins MJ, et al. Consumption of gluten with gluten-containing enzyme by celiac patients: a pilot-study. World J Gastroenterol 2013;19:5837--47
48.
40.
Siegel M, Bethune MT, Gass J, et al. Rational design of combination enzyme therapy for celiac sprue. Chem Biol 2006;13:649--58
37.
38.
41.
42.
43.
Stepniak D, Spaenjij-Dekking L, Mitea C, et al. Highly efficient gluten degradation with a newly identified prolyl endopeptidase: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol 2006;291:G621--9
Siegel M, Garber M, Spencer A, et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci 2012;57:440--50 Tye-Din JA, Anderson RP, French RA, et al. The effects of ALV003 predigestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol 2010;134:289--95 Gass J, Bethune MT, Siegel M, et al. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology 2007;133:472--80
Tian N, Wei G, Schuppan D, Helmerhorst EJ. Effect of Rothia mucilaginosa enzymes on gliadin (gluten) structure, deamidation and immunogenic isotopes relevant to celiac disease. Am J Physiol Gastrointest Liver Physiol 2014;307(8):G769--76
49.
Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001;121:580--91
50.
Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in celiac disease. Lancet 2000;355:1519--19
51.
Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008;135:194--204
Expert Opin. Emerging Drugs (2014) 20(1)
52.
Paterson BM, Lammers KM, Arrieta MC, et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of a single dose of AT-1001 in celiac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007;26:757--66
53.
Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 2012;107:1554--62
54.
Kelly CP, Green PH, Murray JA, Larazotide Acetate Celiac Disease Study Group. Larazotide acetate in patients with celiac disease undergoing a gluten challenge: a randomized placebocontrolled study. Aliment Pharmacol Ther 2013;37:252--62 Important study with larazotide in celiac disease patients with a gluten challenge.
.
55.
Molberg O, McAdam S, Lundin KE, et al. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 2001;31:1317--23
56.
Maiuri L, Ciacci C, Ricciardelli I, et al. Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 2005;129:1400--13
57.
Alvine Pharmaceuticals. San Carlos, California Available from: www. alvinepharma.com
58.
Alba Therapeutics. Baltimore, Maryland Available from: www.albatherapeutics. com
Affiliation Hugh James Freeman MD CM FRCPC FACP University of British Columbia, Department of Medicine (Gastroenterology), Vancouver, BC, Canada E-mail: [email protected]
7
Emerging drugs for celiac disease Hugh James Freeman
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
University of British Columbia, Department of Medicine (Gastroenterology), Vancouver, BC, Canada 1.
Background
2.
Medical need
3.
Existing treatment
4.
Market review
5.
Current research goals
6.
Scientific rationale
7.
Competitive environment
8.
Potential development issues
9.
Conclusion
10.
Expert opinion
Introduction: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. Areas covered: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. Expert opinion: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed. Keywords: celiac disease, celiac disease therapy, enzyme treatment, glutenase, gluten-free diet, gluten-sensitive enteropathy, larazotide Expert Opin. Emerging Drugs [Early Online]
1.
Background
Celiac disease is a life-long immune-mediated disorder primarily affecting the small intestinal mucosa [1]. The disorder is marked by clinical and pathological changes attributed to ingestion of dietary gluten and appears restricted to genetically susceptible individuals. Common features include diarrhea and weight loss, but celiac disease is now recognized to be very heterogeneous in its initial presentation, often first detected in those with other clinical disorders such as iron deficiency anemia, osteoporosis, ‘autoimmune’ conditions, like dermatitis herpetiformis or autoimmune thyroiditis, and some neurological disorders, including dementia. This variability in the initial clinical presentation appears largely related to genetic and immunological factors, age of onset, extent and degree of small intestinal mucosal inflammation, gender and familial nature. In recent years, celiac disease has appeared in ‘epidemics’ [2], possibly related to age of introduction of dietary gluten, specific infections, medication use and supplements [3]. Diagnosis requires an initial small intestinal biopsy showing pathological features of untreated celiac disease. As the disease is a gluten-dependent disorder, by definition, demonstration of improvement on a gluten-free diet is also crucial. Genetic markers, including human leukocyte antigen (HLA) markers, HLA-DQ2 and HLA-DQ8, as well as circulating antibodies to tissue transglutaminase antigen (tTG), are usually evident. Most also recognize that the single critical factor for persistent symptoms in celiacs is limited compliance to a strict diet, sometimes because gluten is ubiquitious, even in pill capsules. Others may have a different or superimposed disorder responsible for ongoing symptoms, including the irritable bowel syndrome. Finally, a complication of celiac disease may occasionally be responsible. 10.1517/14728214.2015.985204 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
1
H. J. Freeman
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
2.
Medical need
Historically, celiac disease was originally thought to be common only in Europe, specifically, the UK and some Scandanavian countries. The incidence of the disease was high in western Ireland [4], but believed to be low in the US [5]. Later, these estimates were revised, largely owing to serologically based studies that suggested ~ 1% or more of most populations in Europe and the Americas had celiac disease [6-8]. Standardization of these assays in different countries, however, has been limited [9,10]. Others have suggested that serological studies have overestimated sensitivity and underestimated specificity due to verification bias [11] as serologically negative subjects are rarely biopsied [12]. Regardless, these serological studies do indicate that rates of undiagnosed disease are probably quite significant, even in Europe and the US. Prevalence data in these countries has recently been summarized [13]. In children, rates reported from Sweden were 1:285 and 1:77, Finland, 1:99 and 1:67, and Italy, 1:230 and 1:106. Similar rates have been noted in New Zealand, Australia, Argentina and Israel [14-16]. In the US, overall prevalence rates for children and adults were recorded at 1:104 and 1:105, respectively [17]. Thus, the established medical need for treatment of celiac disease is substantial, estimated to be ~ 1% of most populations studied. 3.
Existing treatment
For > 70 years, a gluten-free diet has been recommended as treatment for celiac disease. The gluten-free diet usually leads to resolution of symptoms and improved nutrient absorption. Normalization of histopathological changes occurs and an improved nutritional state results. Evidence also suggests that long-term complications of celiac disease, such as bone disease, and risk of malignancy, particularly lymphoma, are reduced. However, gluten is ubiquitous and complete avoidance is very difficult. In recent decades, per capita consumption of wheat and other processed foods, which contain more gluten, have also both increased. The gluten-free diet is very expensive, rarely subsidized by government, even in many advanced nations, and not universally available. As a result, compliance for many with celiac disease is difficult. A clear need for other forms of therapies, even as added supplements, that might reduce sole reliance on a gluten-free diet is apparent. 4.
Market review
Some recent data have also suggested a change in celiac disease prevalence in recent decades. Celiac disease may be increasing, particularly in North America and Europe. In part, this may simply reflect increased physician recognition coupled with use of serologically based testing for screening and case finding. However, a true change in prevalence may have occurred, possibly related to other confounding environmental 2
factors [18]. In young male military recruits at Warren Air Force Base, a low prevalence of celiac disease was suggested, retrospectively, based on evaluation of stored frozen sera collected from 1948 to 1952, compared to more recent control cohorts from Olmstead Country in 2006 -- 2008 [19]. In an independent report, increasing sero-prevalence rates were also noted from 1974 to 1989 [20]. Endoscopic biopsy screening studies, rather than simple serological screening, has also been done. Routine duodenal biopsies obtained during endoscopic study over a 30-year period defined moderate-to-severe architectural changes typical of celiac disease in 2 -- 3% of adult Canadians referred for investigation of upper gastrointestinal symptoms [21]. Interestingly, in this study, environmental factors may have been important as a significant fall in new diagnoses of celiac disease occurred over two decades followed by a significant rise during the next decade. Other recent studies have indicated a change in risk in recent decades [22,23] including a recent report from Hangzhou in China suggesting increased detection, possibly because of serological screening [24]. Interestingly, Asian Canadians with biopsypositive celiac disease have also previously been noted, including a Chinese woman [25]. Celiac disease likely also occurs more often in China [26]. A particularly high allele frequency of DQB1*0201 or DQB1*0201/02 has been noted in Xinjiang in northwestern China, an area largely populated by Uygurs and Kazaks, rather than Han Chinese. Overall, calculated wheat consumption in China has also increased suggesting that the potential for gluten exposure is rapidly increasing. Wheat ingestion is greater north of the Yangtze River compared to rice consumption regions south of the Yangtze River. Rural Xinjiang seems especially susceptible, as wheat consumption there is relatively high. Although precise data are not available, these emerging data on rising risk of celiac disease, especially in China, indicate that the potential global market for treatment of celiac disease is likely to be very significant. 5.
Current research goals
The main goals of therapy are to reduce symptoms, improve nutrient absorption and obviate inflammatory changes persistent in the small intestine. Although the gluten-free diet has been universally effective as a treatment regimen, the approach is costly and compliance is difficult. Alternative forms of treatment based on a current understanding of the pathogenesis of celiac disease have been explored. Overall, current research goals include discovery and evaluation of measures aimed at either replacing entirely the need for a gluten-free diet, or more likely, supplementing its use. 6.
Scientific rationale
Table 1 lists some of the different treatment approaches that are currently being considered for exploration in celiac disease. Some remain in a discovery phase but some have now
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
Table 1. Possible alternative treatment approaches for celiac disease. Hypothetical mechanism
Hypothetical treatment
Reduced gluten exposure
Genetically modified grains Copolymer binders of gluten Proylendopeptidase (e.g., ALV003) Larazotide acetate (e.g., AT1001)
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
Gluten peptide hydrolysis* Tight junction blockade (zonulin)* Transglutaminase or HLA-DQ2/DQ8 blockers Immune tolerance induction
Potential developmental peptides Peptide vaccination (Nexvax)
*At or near full peer-review publication of advanced clinical trials.
reached the clinical trials stage. For more detailed information on immunopathogenetic mechanisms in celiac disease, outside the scope of this review, readers are directed to an extensively illustrated review elsewhere [1]. Genetic modification of grains It is believed that reduced dietary exposure to gluten components in novel modern grains that could be developed in future might be useful [27,28]. Modern types of wheat, currently in use, are believed to be more immunogenic, compared to ancient wild or diploid varieties of wheat. Engineered genetically modified grains completely lacking or with limited amounts of specific immunogenic peptides may be possible but are likely difficult to develop and cultivate. Gluten has different immunogenic peptide sequences and some, but not all, genes responsible are not known and may be anatomically located in different sites in the wheat genome. Critical baking features may be altered in the grains with the development of genetically modified varieties and there is a potential for contamination with wild wheat strains. 6.1
Co-polymeric binders Co-polymeric binders to cause luminal sequestration of gluten-containing substances in the diet might be used to reduce mucosal exposure. This approach was explored in vitro with epithelial cells [29] and in vivo with a rodent model [30]. One binding agent, hydroxyethylmethacrylate co-styrene sulfonate, appeared to reduce toxicity in these model systems, but human studies are still required. 6.2
Enzymatic gluten hydrolysis Another approach that is rapidly evolving and appears to be very promising has involved administration of dietary proteins that have already been hydrolyzed or ‘pre-digested’ before intestinal epithelial cell uptake. Ordinarily, initiation of protein hydrolysis begins in the lumen and involves gastric peptic and pancreatic proteolytic activities. Enterocyte peptidases further hydrolyze resultant peptide products into amino acids, dipeptides and tripeptides for enterocyte transport into the portal venous system. Proline- and glutamine-containing 6.3
peptides in gluten appear to be quite resistant to enzyme proteolysis. As a result, only limited gluten digestion occurs. Possibly, resulting peptides from this hydrolytic process could induce an immune response in genetically programmed individuals causing celiac disease [31,32]. Prolyl-endopeptidases derived from plants and specific bacterial agents (i.e., Flavobacterium, Sphingomonas) have the ability to hydrolyze internal proline-glutamine bonds in some proline-containing peptides [33]; however, gastric acid may cause enzyme inactivation or inhibition for some of these preparations. A combination of barley endoprotease and prolylendopeptidase in powder or tablet form appeared to be stable causing wheat gluten breakdown and reduced immunemediated effects [34-36]. As well, prolyl-endopeptidase from the microbiologic agent, Aspergillus niger, inhibited a gliadin-stimulated immune response by gluten-specific T cells [37]. Subsequent modeling suggested that most hydrolytic activity occurred in the gastric compartment with only limited activity required in small intestine [38]. A recently published pilot study of A. niger prolyl-endoprotease use in celiac patients demonstrated that the orally administered enzyme was well tolerated in biopsy-defined celiac patients; however, a difference from a placebo-treated group could not be demonstrated [39]. Enzymes from other microbial agents can operate in a gastric environment and these have been cloned and characterized [40-43]. Some Phase II clinical trials have been completed using ALV003, an oral combination glutenase recombinant agent (Alvine Pharmaceuticals, Inc., San Carlos CA; www.alvinepharma.com). This agent, however, is only stable at a pH range of 3.5 -- 5, reflecting the postprandial pH of the stomach without significant gastrointestinal absorption. Two trials (NCT00959114 and NCT01255696) were recently reported as a randomized, double-blind, placebocontrolled Phase II trial [44] showing that ALV003 reduced gluten-induced small bowel mucosal injury in patients with celiac disease on a ‘gluten-free’ diet daily. This diet was estimated to contain as much as 2 g gluten (equivalent to about ½ of a standard slice of bread). Currently, recruitment is ongoing for a further Phase II study (NCT01917630) on efficacy and safety of ALV-003 in symptomatic celiac disease patients. This is a double-blind placebo-controlled doseranging study with primary end points being intestinal mucosal morphometric measures, including change in villus height to crypt depth ratio from baseline to week 12. Estimated enrollment is 500 celiac patients with an estimated completion date of March 2015 (clinical trials.gov). A different ‘enzymatic’ approach examined gluten-free sourdough wheat treated with lactobacilli and fungal proteases. A resulting gluten content of < 8 p.p.m. appeared safe with no changes in hematological, serological or intestinal permeability end points [45]. A further study compared natural flour baked goods to two other hydrolyzed baked good groups. Most in the latter two hydrolyzed groups had no clinical, serological or histological worsening [46]. Others have
Expert Opin. Emerging Drugs (2014) 20(1)
3
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
H. J. Freeman
employed probiotic preparations, specifically VSL#3, a mixture of lactic acid and bifidobacteria, in preliminary studies showing effective hydrolysis of gliadin peptides [47] combined with evidence of an enhancement of mucosal tight junction markers in an animal model [48]. Initial studies, recently published [49], using an intriguing enzymatic approach have led to evaluation of Rothia mucilaginosa, a microbial inhabitant of the oral cavity that can enzymatically cleave gliadin at regions resistant to degradation by mammalian enzymes. These enzymes may eventually prove useful to neutralize T-cell immunogenic properties for celiac disease treatment but still require clinical trial evaluation in humans. Tight junction blockade Another approach has been to prohibit passage of immunologically active gluten peptides through the intracellular tight junctions as a paracellular transport route. In celiac disease, including its most early phases, the intestinal mucosa may be ‘leaky’ with increased paracellular permeability. Zonulin is a specific tight junction protein that functions together with other transmembrane proteins to regulate epithelial barrier permeability, highly expressed in celiac disease [50]. Gliadin may bind to a specific chemokine receptor, CXCR3, resulting in release of zonulin and increased intestinal permeability [51]. Larazotide acetate (AT1001) is a peptide that is believed to directly antagonize zonulin by receptor blockade [52] leading to possible impairment of paracellular transport from gliadin peptides and their resultant immunological effects. In initial clinical trials (Alba Therapeutics, Baltimore, MD; www.albatherapeutics.com), larazotide appeared to be safe with some symptomatic benefit compared to placebo but no significant change in intestinal permeability [53,54]. So far, these published studies seem disappointing. Some believe that there have been no true positive effects (apart from symptom benefit) and no clear dose response, suggesting a possible placebo effect. Recruitment for a late Phase II double-blind placebo-controlled dose-ranging study in 342 patients with biopsy-defined celiac disease as an adjunct to a gluten-free diet in celiac disease was completed in November 2013 (NCT0139613) and results should soon become available in published form. Once gluten peptides pass through tight junctions, another potential site of therapeutic intervention in the ‘immunopathogenic sequence’ of mucosal gliadin degradation has been considered, specifically, tTG-enzyme-induced deamidation. Normally, it is believed that deamidated peptides each assume negative charges resulting in enhanced affinity for the binding grooves on HLA-DQ2 and/or DQ8 molecules found the surface of antigen-presenting cells. As a result, T-lymphocyte activation and subsequent histopathologic mucosal effects occur. To counteract these effects, different hypothetical approaches have been considered. Blockade of tTG or the specific HLADQ2 and/or HLA-DQ8 molecules has been considered to prevent this peptide binding and resultant immune-related mucosal effects. Inhibition of in vitro tTG activity was shown 6.4
4
to inhibit gliadin-specific T-cell clones from patients with celiac disease along with gliadin-induced mucosal lymphocyte proliferation [54,55]. Alternatively, gluten peptide analogues might be used as HLA-blocking agents by prohibiting binding or access to the binding grooves on antigen-presenting cells. At this time, treatment focused on this specific step needs evaluation. It is conceivable that a number of deleterious short- and longterm immune-mediated side effects could also result from this form of immunological intervention. Immune tolerance induction Immune tolerance induction has also been examined. In theory, a peptide vaccine could result in development of tolerance in some immunologically active intestinal cells in celiac disease pathogenesis. NexVax vaccine employs three different gluten peptides that could hypothetically lead to tolerance in celiacs. Prior studies in transgenic mice with gluten-sensitive T cells demonstrated efficacy, while patients with celiac disease treated with this agent demonstrated acceptable shortterm safety with development of anti-gluten T cells [56]. Results of further studies to evaluate efficacy and long-term safety of these vaccines in celiac disease patients are still required. 6.5
7.
Competitive environment
Based on this scientific rationale, some drugs have already surfaced in this emerging competitive environment for management of celiac disease. Table 2 summarizes two agents that have already entered late Phase II clinical trials and may show some promise. To date, published results suggest some positive, but only limited, results. Positive results with ALV003 in a Finnish population are encouraging, particularly since the end points evaluated were morphological. In this setting, histopathological end points to assess actual effects on the inflammatory response would have been useful. Some positive clinical (not morphological) results were also achieved with larazotide, but functional studies were not consistent. Perhaps, these will be clarified by the already completed study, not yet published. Neither of these approaches, however, was meant to completely substitute for a gluten-free diet in celiac disease. Perhaps, some, but not all celiacs, could utilize a broader based diet with small amounts of gluten, combined with one of these agents. As a result, better compliance might also be encouraged. As well, if only a limited effect appeared with either agent alone, it is possible that both could be used in combination because their mechanism of action differs. 8.
Potential development issues
A number of difficult issues need to be addressed that may prohibit potential development, especially during clinical evaluation. First, end points of each treatment regimen being
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
Table 2. Competitive environment. Compound Company Structure Stage
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
ALV003 AT1001
Mechanism
Phase IIa, IIb Glutenase Alvine [57] Enzyme Larazotide Phase IIa, IIb Zonulin Alba [58] blockade
evaluated need to be precisely documented. The most critical element is normalization of mucosal biopsies following a course of treatment. Only a single study on enzyme therapy with ALV003 had demonstrated any morphological effects, while the other study on larazotide did not report any morphological effects based on small bowel biopsies after therapy. Other end points of the treatment response may include the degree and quality of the response, including improved symptoms and measures of absorptive function. Even if these are improved, the presence of an ongoing immune response as reflected by the presence of antibodies to tTG and persistent mucosal inflammatory changes, not only in the small intestine but also in the oral mucosa [56], may be important. Indeed, these findings may not signal a real treatment advance because the long-term risks of only partially treated celiac disease may continue. Second, use of the standard therapy, specifically, the gluten-free diet, may be needed in all clinical treatment trials because the gluten-free diet is an already established and effective treatment. Third, and finally, the long-term of each agent should be evaluated. The long-term background risk of other superimposed diseases, including lymphoma, could be altered, especially over an extended period. 9.
Conclusion
Celiac disease is an immune-mediated disorder mainly affecting the small intestine. Current treatment with a gluten-free diet is generally effective, but the diet is expensive and compliance is difficult. An alternative to the gluten-free diet, or at least, a treatment to supplement the gluten-free diet would be useful, particularly for reduction of any persistent inflammatory changes that might be associated with ongoing symptoms or lead to long-term complications, including malignant disorders. Celiac disease is recognized in ~ 1% of most populations evaluated. The disease appears to be increasing, possibly due to other, as yet unidentified, factors in the environment.
Recent studies also suggest that the disease is becoming widely recognized on a global scale, particularly in genetically predisposed individuals living in areas that depend on wheat cultivation. Based on current hypotheses related to the pathogenesis of celiac disease, a wide array of potential treatment options have been explored ‘at the bench’ in the laboratory and some have been initially assessed ‘at the bedside’ in clinical trials. 10.
Expert opinion
At this time, a number of agents have reached the initial stages of clinical trials, but the most promising clinical studies published to date utilize enzymes that have been cloned and characterized for hydrolysis of dietary gluten after oral administration. So far, studies with ALV003, a novel recombinant glutenase, have been most intriguing. A randomized double-blind, placebo-controlled Phase II trial has shown attenuation of gluten-induced small intestinal mucosal injury in patients with celiac disease. In the most recent studies, symptoms and histopathological changes were reduced in celiacs treated with 2 g added gluten daily and ALV003, compared to the placebo. Serologic changes were not observed, in spite of histopathological changes, suggesting a persistent immune response. Although the dose of added gluten was very limited and the population studied was quite homogeneous, replication in other populations would be valuable. These initial studies, however, emphasize that this form of enzyme therapy is not meant to replace, but supplement the current gold standard of treatment, the gluten-free diet. Although both an improved clinical state and improved laboratory parameters were evident in this clinical trial, persistent inflammatory changes were still present, so the long-term risks of celiac disease may not be significantly altered and may require added years to define.
Declaration of interest The author has 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. Emerging Drugs (2014) 20(1)
5
H. J. Freeman
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
2.
3.
4.
Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol 2012;18:6036--59 Ivarsson A, Persson LA, Nystrom L, et al. Epidemic of celiac disease in Swedish children. Acta Paediatr 2000;89:165--71 Lebwohl B, Ludvigsson JF, Green PH. The unfolding story of celiac disease risk factors. Clin Gastroenterol Hepatol 2014;12:632--5
Kowlessar OD, Phillips LD. Celiac disease. Med Clin North Am 1970;54:647--56
6.
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003;163:286--92
7.
Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517--24
9.
10.
11.
12.
6
Cook HB, Burt MJ, Collett JA, et al. Adult celiac disease: prevalence and clinical significance. J Gastroenterol Hepatol 2000;15:1032--6
14.
Hovell CJ, Collett JA, Vautier G, et al. High prevalence of celiac disease in a population-based study from Western Australia: a case for screening? Med J Aust 2001;175:247--50
15.
West J, Logan RF, Hill PG, et al. Seroprevalence, correlates, and characteristics of undetected celiac disease in England. Gut 2003;52:960--5 Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? Gastroenterology 2005;128:S47--51 Cavell B, Stenhammar L, Ascher H, et al. Increasing incidence of childhood celiac disease in Sweden. Results of a national study. Acta Paediatr 1992;81:589--92 Carlsson AK, Axelsson IE, Borulf SK, et al. Serological screening for celiac disease in healthy 2.5-year-old children in Sweden. Pediatrics 2001;107:42--5 Catassi C, Ratsch IM, Fabiani E, et al. High prevalence of undiagnosed celiac disease in 5280 Italian students screened by antigliadin antibodies. Acta Paediatr 1995;84:672--6
Gomez JC, Selvaggio GS, Viola M, et al. Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. Am J Gastroenterol 2001;96:2700--4
16.
Shamir R, Lerner A, Shinar E, et al. The use of a single serological marker underestimates the prevalence of celiac disease in Israel: a study of blood donors. Am J Gastroenterol 2002;97:2589--94
17.
Hoffenberg EJ, Mackenzie T, Barriga KJ, et al. A prospective study of the incidence of childhood celiac disease. J Pediatr 2003;143:308--14
18.
Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of celiac disease over time. Aliment Pharmacol Ther 2007;26:1217--25
19.
Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 2009;137:88--93 Interesting serologically based study suggesting an increase prevalence of disease over time using stored sera.
Mylotte M, Egan-Mitchell B, McCarthy CF, McNicholl B. Incidence of celiac disease in the West of Ireland. Br Med J 1973;1:703--5
5.
8.
13.
over two decades: population-based study. Am J Gastroenterol 2014;109:757--68 24.
Jiang LL, Zhang BL, Liu YS. Is adult celiac disease really uncommon in Chinese? J Zhejiang Univ Sci B 2009;10:168--71
25.
Freeman HJ. Biopsy-defined celiac disease in Asian-Canadians. Can J Gastroenterol 2003;17:433--6
26.
Yuan J, Gao J, Li X, et al. The tip of the “celiac iceberg” in China: a systematic review and meta-analysis. PLoS One 2013;8:e81151 Interesting study collating serological studies with urban and rural consumption of wheat and rice in Chinese provinces.
.
27.
Carroccio A, Di Prima L, Noto D, et al. Searching for wheat plants with low toxicity in celiac disease: between direct toxicity and immunologic activation. Dig Liver Dis 2011;43:34--9
28.
Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, et al. Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology 2005;129:797--806
29.
Pinier M, Verdu EF, Nasser-Eddine M, et al. Polymeric binders suppress gliadininduced toxicity in the intestinal epithelium. Gastroenterology 2009;136:288--98
Catassi C, Kryszak D, Bhatti B, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med 2010;42:530--8 Long-term study on natural history of celiac disease in an American cohort.
30.
Pinier M, Fuhrmann G, Galipeau HJ, et al. The copolymer P (HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology 2012;142:316--25
Freeman HJ. Detection of adult celiac disease with duodenal screening biopsies over a 30-year period. Can J Gastroenterol 2013;27:405--8 Biopsy-based study over three decades showing temporal variation in rates of diagnosis of celiac disease.
31.
Sollid LM, Qiao SW, Anderson RP, et al. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 2012;64:455--60
32.
Gass J, Khosla C. Prolyl endopeptidases. Cell Mol Life Sci 2007;64:345--55
22.
Namatovu F, Sandstrom O, Olsson C, et al. Celiac disease risk varies between birth cohorts, generating hypotheses about causality: evidence from 36 years of population-based follow-up. BMC Gastroenterol 2014;14:59
33.
Garcia-Horsman JA, Venalainen JI, Lohi O, et al. Deficient activity of mammalian prolyl oligopeptidases on the immunoreactive peptide digestion in celiac disease. Scand J Gastroenterol 2007;42:562--71
23.
West J, Fleming KM, Tata LJ, et al. Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK
34.
Piper JL, Gray GM, Khosla C. High selectivity of human tissue transglutaminase for immunoreactive
.
20.
.
21.
.
Expert Opin. Emerging Drugs (2014) 20(1)
Emerging drugs for celiac disease
gliadin peptides: implications for celiac sprue. Biochemistry 2002;41:386--93 35.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Washington on 01/31/15 For personal use only.
36.
Khosla C, Gray CM, Sollid LM. Putative efficacy and dosage of prolyl endopeptidase for digesting and detoxifying gliadin peptides. Gastroenterology 2005;129:1362--3 Gass J, Vora H, Bethune MT, et al. Effect of barley endoprotease EP-B2 on gluten digestion in the intact rat. J Pharmacol Exp Ther 2006;318:1178--86
44.
..
Lahdeaho M-L, Kaukinen K, Laurila K, et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 2014;146:1649--58 Important study showing positive effects of oral glutenase therapy and its current limitations.
45.
Di Cagno R, Barbato M, Di Camillo C, et al. Gluten-free sourdough wheat baked goods appear safe for young celiac patients: a pilot study. J Pediatr Gastroenterol Nutr 2010;51:777--83
46.
Greco L, Gobbetti M, Auricchio R, et al. Safety for patients with celiac disease of baked goods made of wheat flour hydrolyzed during food processing. Clin Gastroenterol Hepatol 2011;9:24--9
Mitea C, Havenaar R, Drijfhout JW, et al. Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for celiac disease. Gut 2008;57:25--32
47.
De Angelis M, Rizzello CG, Fasano A, et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for celiac sprue. Biochim Biophys Acta 2006;1762:80--93
39.
Tack GJ, van de Water JM, Bruins MJ, et al. Consumption of gluten with gluten-containing enzyme by celiac patients: a pilot-study. World J Gastroenterol 2013;19:5837--47
48.
40.
Siegel M, Bethune MT, Gass J, et al. Rational design of combination enzyme therapy for celiac sprue. Chem Biol 2006;13:649--58
37.
38.
41.
42.
43.
Stepniak D, Spaenjij-Dekking L, Mitea C, et al. Highly efficient gluten degradation with a newly identified prolyl endopeptidase: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol 2006;291:G621--9
Siegel M, Garber M, Spencer A, et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci 2012;57:440--50 Tye-Din JA, Anderson RP, French RA, et al. The effects of ALV003 predigestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol 2010;134:289--95 Gass J, Bethune MT, Siegel M, et al. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology 2007;133:472--80
Tian N, Wei G, Schuppan D, Helmerhorst EJ. Effect of Rothia mucilaginosa enzymes on gliadin (gluten) structure, deamidation and immunogenic isotopes relevant to celiac disease. Am J Physiol Gastrointest Liver Physiol 2014;307(8):G769--76
49.
Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001;121:580--91
50.
Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in celiac disease. Lancet 2000;355:1519--19
51.
Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008;135:194--204
Expert Opin. Emerging Drugs (2014) 20(1)
52.
Paterson BM, Lammers KM, Arrieta MC, et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of a single dose of AT-1001 in celiac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007;26:757--66
53.
Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 2012;107:1554--62
54.
Kelly CP, Green PH, Murray JA, Larazotide Acetate Celiac Disease Study Group. Larazotide acetate in patients with celiac disease undergoing a gluten challenge: a randomized placebocontrolled study. Aliment Pharmacol Ther 2013;37:252--62 Important study with larazotide in celiac disease patients with a gluten challenge.
.
55.
Molberg O, McAdam S, Lundin KE, et al. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 2001;31:1317--23
56.
Maiuri L, Ciacci C, Ricciardelli I, et al. Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology 2005;129:1400--13
57.
Alvine Pharmaceuticals. San Carlos, California Available from: www. alvinepharma.com
58.
Alba Therapeutics. Baltimore, Maryland Available from: www.albatherapeutics. com
Affiliation Hugh James Freeman MD CM FRCPC FACP University of British Columbia, Department of Medicine (Gastroenterology), Vancouver, BC, Canada E-mail: [email protected]
7
