A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease
Abstract Celiac disease is a chronic, immune‐mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten‐free diet. This randomized, double‐blind, placebo‐controlled, paralle...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13901 |
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| author | Darren Bentley Marie Mannino Marianne Manchester Priscila Camillo Teixeira Bernhard Reis Malcolm Boyce Sandra Nagel |
| author_facet | Darren Bentley Marie Mannino Marianne Manchester Priscila Camillo Teixeira Bernhard Reis Malcolm Boyce Sandra Nagel |
| author_sort | Darren Bentley |
| collection | DOAJ |
| description | Abstract Celiac disease is a chronic, immune‐mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten‐free diet. This randomized, double‐blind, placebo‐controlled, parallel‐group, single‐center study tested the effects of the cathepsin S inhibitor RO5459072 on the immune response to a 13‐day gluten challenge in 19 participants with celiac disease (ClinicalTrials.gov: NCT02679014). Nine participants in the RO5459072 arm received 100 mg study drug b.i.d. (200 mg daily); 10 received a placebo. The primary end point was the number of responders to the gluten challenge (defined as individuals with an increase in the number of gliadin‐specific, IFNγ‐secreting T cells detected using an ELISPOT assay). However, there was a weak response to the gluten challenge across both arms. Few participants had an increase in gliadin‐specific, IFNγ‐secreting T cells, and the antigen‐specific responses (anti‐tTG and anti‐DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered to detect a treatment effect under these circumstances. Pharmacodynamic findings suggested that RO5459072 had some beneficial effects. Fewer participants in the RO5459072 arm exhibited gliadin‐specific IFNγ‐secreting T cells after 6 days' gluten intake. Participants in the RO5459072 arm also showed decreased intestinal permeability, and a decrease in the number of circulating B cells, CD4+ and CD8+ T cells compared to baseline. Nevertheless, the absence of clear effects on the response to a gluten challenge indicates that inhibition of cathepsin S may not be an effective treatment strategy for celiac disease. |
| format | Article |
| id | doaj-art-4e82533cd14f4c14872ef82ac0d81365 |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj-art-4e82533cd14f4c14872ef82ac0d813652025-01-24T08:17:46ZengWileyClinical and Translational Science1752-80541752-80622025-01-01181n/an/a10.1111/cts.13901A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac diseaseDarren Bentley0Marie Mannino1Marianne Manchester2Priscila Camillo Teixeira3Bernhard Reis4Malcolm Boyce5Sandra Nagel6Certara UK Ltd. Sheffield UKBristol Myers Squibb Lawrence Township New Jersey USAF. Hoffmann‐La Roche Basel SwitzerlandF. Hoffmann‐La Roche Basel SwitzerlandF. Hoffmann‐La Roche Basel SwitzerlandHammersmith Medicines Research London UKF. Hoffmann‐La Roche Basel SwitzerlandAbstract Celiac disease is a chronic, immune‐mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten‐free diet. This randomized, double‐blind, placebo‐controlled, parallel‐group, single‐center study tested the effects of the cathepsin S inhibitor RO5459072 on the immune response to a 13‐day gluten challenge in 19 participants with celiac disease (ClinicalTrials.gov: NCT02679014). Nine participants in the RO5459072 arm received 100 mg study drug b.i.d. (200 mg daily); 10 received a placebo. The primary end point was the number of responders to the gluten challenge (defined as individuals with an increase in the number of gliadin‐specific, IFNγ‐secreting T cells detected using an ELISPOT assay). However, there was a weak response to the gluten challenge across both arms. Few participants had an increase in gliadin‐specific, IFNγ‐secreting T cells, and the antigen‐specific responses (anti‐tTG and anti‐DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered to detect a treatment effect under these circumstances. Pharmacodynamic findings suggested that RO5459072 had some beneficial effects. Fewer participants in the RO5459072 arm exhibited gliadin‐specific IFNγ‐secreting T cells after 6 days' gluten intake. Participants in the RO5459072 arm also showed decreased intestinal permeability, and a decrease in the number of circulating B cells, CD4+ and CD8+ T cells compared to baseline. Nevertheless, the absence of clear effects on the response to a gluten challenge indicates that inhibition of cathepsin S may not be an effective treatment strategy for celiac disease.https://doi.org/10.1111/cts.13901 |
| spellingShingle | Darren Bentley Marie Mannino Marianne Manchester Priscila Camillo Teixeira Bernhard Reis Malcolm Boyce Sandra Nagel A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease Clinical and Translational Science |
| title | A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease |
| title_full | A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease |
| title_fullStr | A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease |
| title_full_unstemmed | A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease |
| title_short | A randomized, double‐blind, placebo‐controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease |
| title_sort | randomized double blind placebo controlled multiple dose parallel study to investigate the effects of a cathepsin s inhibitor in celiac disease |
| url | https://doi.org/10.1111/cts.13901 |
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