Home > Gastroenterology > ECCO 2019 > Genetics > Gene expression signature predicts non-response

Gene expression signature predicts non-response

Conference
ECCO 2019
Trial
ACT1, PURSUIT-SC, PROgECT, PURSUIT-J, UNITI
The molecular profile score (MPS) consistently predicted non-responders to therapy in 4 independent trials of TNF-antagonists in inflammatory bowel disease (IBD) and an anti-IL-12/23 trial in Crohn’s disease [1]. This ability was regardless of ethnicity or whether the therapy targeted TNF or IL-12/23 pathways. Clinical parameters and inflammatory markers by themselves lack the granularity to identify this subset of non-responder patients.

The MPS consisted of a colonic 13-gene expression panel. It accurately predicted non-responders, as defined by lack of mucosal improvement, to TNF-antagonist therapy in UC in all 4 independent clinical trials. There was a high negative predictive value of 0.78 in the ACT1 trial, 0.79 in PURSUIT-SC, 0.89 in PROgECT, and 0.73 in PURSUIT-J. In addition, the MPS could predict non-responders, as defined by lack of endoscopic response, to anti-IL-12/23 therapy in the UNITI trial, with a negative predictive value of 0.85. Non-responders, as predicted by MPS, did not differ from predicted responders in baseline disease severity, nor in baseline inflammatory markers including C-reactive protein, faecal calprotectin, or faecal lactoferrin levels. Transcriptomics and microbiome analysis revealed potential ways to treat these predicted non-responders, as they had 268 differentially expressed genes enriched in inflammatory pathways and demonstrated significant microbial dysbiosis. The MPS is now the first prospectively validated predictive biomarker that can accurately identify a discrete subset of non-responder patients to 2 different anti-inflammatory therapies. It may be valuable in identifying subsets of patients in need of treatment with alternative therapies or for patient stratification in clinical trials.


    1. Sato T, et al. ECCO 2019, OP36.




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