Celiac disease: novel therapeutics CARLO CATASSI Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy
I have the following financial relationships to disclose: Dr Schär * Menarini Diagnostics
* Products or services produced by this company are relevant to my presentation.
Gluten-Free Diet (GFD) is the treatment of celiac disease (CeD) ASSOCIATED WITH
• Clinical benefit • Disappearance of serum antibodies • Small Intestinal mucosa improvement • Prevention of complications
the limitations of the GFD • PSYCHO-SOCIAL IMPACT • Gluten contamination
• Nutritional value • Cost
70% of Celiac Disease Subjects Have Gluten Exposure on GFD
Reported intentional and inadvertent gluten consumption (n=269) Hall NJ, Rubin GP, Charnock A, Intentional and Inadvertent Non Adherence in Adult Coeliac Disease. A Cross-Sectional Survey Appetite 68:56-62, 2013
Persistent mucosal damage in treated CeD Author
Setting
Sample size
Follow-up time Persistent Villous Atrophy
Collin
Finland, 2004
65
8 years 6-12 months
4% 67%
Lee
New York, 2003
39
8.5 years
79%
Lanzini
Italy, 2009
465
16 months
27%
Ciacci
Italy, 2002
390
6.9 years
24%
Selby
Australia,1999
89
8.3 years
43%
Hutchinson
UK, 2010
284
1.6 years
20%
Rubio-Tapia
Minnesota, 2010
241
2 years 5 years
66% 34%
Adapted from Alberto Rubio-Tapia
Khaleghi et al, 2016
The understanding of CeD mechanisms paved the way to interventions aimed to block specific pathophysiological steps
Therapeutic interventions in CeD
Kurada et al, 2016
Outline of CeD therapeutic development studies
PROBLEMS:
Wungjiranirun et al, AJG 2016
• A complete animal model of disease is not available • No biomarker established as a surrogate end-point for CeD: (a) CeD serological markers are poorly sensitive on GFD (b) Intestinal biopsy is invasive, technical artefects common, poorly specific on GFD • Lack of validated Patient-Reported Outcome (PRO)
CeD alternative treatments: I. luminal agents
Plugis and Koshla, 2015
Oral Proteases for Gluten Detoxification (Glutenases) • The stability and immunogenicity of gliadin peptides is largely attributable to their high Gln and Pro content • Both in people with and without CeD, the stability of gluten epitopes derives primarily from the inability of gastric, pancreatic and enterocyte endoproteases to cleave after Pro or Gln residues • Recombinant PEP from bacteria and fungi are able to proteolyze gliadin peptides • These enzyme maintain function in the pH ranges of the human GI tract
ALV003 • An orally administered mixture of PEP (from Sphingomonas capsulata) and Glnspecific EP-B2 (from barley seeds) • Combination therapy accelerates gluten detoxification in the stomach and gut lumen • Escalating dose clinical trials demonstrated that ALV003 is well tolerated over a wide range of doses with no observed serious adverse event
Intestinal morphometry at baseline and after 6-week gluten challenge (2 g/d)
Lahdeaho et al, 2014
CD alternative treatments: II. barrier agents
Plugis and Koshla, 2015
Larazotide acetate (AT-1001) • It is an octapeptide derived from ZOT from Vibrio cholarae • It antagonizes Zonulin action • It inhibits the opening of tight junctions in the epithelial cells in the small intestine • It prevents gliadin-induced permeability both ex vivo and in vivo • Safety: in almost 500 patients who received larazotide there was no concern about safety or severe adverse events
Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial
Leffler et al, Gastroenterology 2015
CD alternative treatments: III. mucosal agents
Plugis and Koshla, 2015
Gluten tolerization: Nexvax2 • Combines three proprietary peptides that elicit an immune response in celiac disease patients who carry HLA-DQ2 • Similarly to treatments for allergies, the “vaccine” is designed to reprogram gluten-specific T cells • Well tolerated in healthy, HLA-DQ2 positive celiac patients • A clinical trial to evaluate the Safety and Tolerability is currently recruiting patients • Open questions: (1) does the peptide vaccination tolerize gluten-reactive T cells in the intestinal mucosa, and (2) to what extent does this acquired immunity extend to less immunodominant epitopes?
The R & D pipeline for CD
modified from Gottlieb et al, 2015
Conclusions • The GFD remains the gold standard of CeD treatment • Possible applications of novel therapeutics in the near future: a) treatment of persisting symptoms in celiacs on the GFD b) to neutralize the effects of gluten contamination c) treatment of Non-Celiac Gluten Sensitivity (luminal agents only) d) treatment of refractory CeD • Phase IV studies will be required to monitor any negative relationship between use of novel therapeutics and the compliance to the GFD