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


Sample size

Follow-up time Persistent Villous Atrophy


Finland, 2004


8 years 6-12 months

4% 67%


New York, 2003


8.5 years



Italy, 2009


16 months



Italy, 2002


6.9 years





8.3 years



UK, 2010


1.6 years



Minnesota, 2010


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


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