TY - CHAP
T1 - Phase III Placebocontrolled, Randomized Clinical Trial with Synthetic Crohn's Disease Patients to Evaluate Treatment Response
AU - Abedi, V.
AU - Lu, P.
AU - Hontecillas, R.
AU - Verma, M.
AU - Vess, G. A.
AU - Philipson, C. W.
AU - Carbo, A.
AU - Leber, A.
AU - Juni, N. T.
AU - Hoops, S.
AU - Bassaganya-Riera, J.
N1 - Funding Information:
This work was supported by funds from the Nutritional Immunology and Molecular Medicine Laboratory ( https://www.nimml.org ).
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/3/22
Y1 - 2016/3/22
N2 - Crohn's disease (CD) is one of the two most prevailing clinical manifestations of inflammatory bowel disease (IBD), a disease that afflicts 1.4 million Americans and 4 million people worldwide. The current treatment paradigm for IBD includes medications with limited efficacy and significant side effects. Thus, there is an unmet clinical need for safer and more effective CD therapeutics. Drug discovery and development is a lengthy and costly process, especially in clinical trial stages requiring billions of dollars to advance new products to market. To accelerate the path to cures, we have developed a novel integrated approach for creating a synthetic patient population and testing the efficacy of novel therapeutics for CD in large clinical cohorts in silico. By using supervised machine learning methods, thousands of virtual patients were created based on clinical and immunological data of CD patients. A nutritional intervention, conjugated linoleic acid, a Phase IIa therapeutic targeting mothers against decapentaplegic homolog 7 (SMAD7), GED-0301, a novel preclinical stage lanthionine synthetase cyclase-like 2 (LANCL2) therapeutic, and a placebo were administered to 10,000 virtual patients in silico. Efficacy of these treatments on CD was evaluated by analyzing predicted changes of Crohn's Disease Activity Index (CDAI) scores and correlations with immunological variables. Our study shows that targeting LANCL2, a novel therapeutic target for inflammation and diabetes, significantly ameliorates disease activity of CD patients with an average drop of 126 points of CDAI for severe cases. This is the first study to design and implement an in silico Phase III clinical trial for CD to investigate response to treatment in terms of changes in pharmacodynamic immunological marker profiles (ie, TNF-α and IFN-γ) and health outcomes.
AB - Crohn's disease (CD) is one of the two most prevailing clinical manifestations of inflammatory bowel disease (IBD), a disease that afflicts 1.4 million Americans and 4 million people worldwide. The current treatment paradigm for IBD includes medications with limited efficacy and significant side effects. Thus, there is an unmet clinical need for safer and more effective CD therapeutics. Drug discovery and development is a lengthy and costly process, especially in clinical trial stages requiring billions of dollars to advance new products to market. To accelerate the path to cures, we have developed a novel integrated approach for creating a synthetic patient population and testing the efficacy of novel therapeutics for CD in large clinical cohorts in silico. By using supervised machine learning methods, thousands of virtual patients were created based on clinical and immunological data of CD patients. A nutritional intervention, conjugated linoleic acid, a Phase IIa therapeutic targeting mothers against decapentaplegic homolog 7 (SMAD7), GED-0301, a novel preclinical stage lanthionine synthetase cyclase-like 2 (LANCL2) therapeutic, and a placebo were administered to 10,000 virtual patients in silico. Efficacy of these treatments on CD was evaluated by analyzing predicted changes of Crohn's Disease Activity Index (CDAI) scores and correlations with immunological variables. Our study shows that targeting LANCL2, a novel therapeutic target for inflammation and diabetes, significantly ameliorates disease activity of CD patients with an average drop of 126 points of CDAI for severe cases. This is the first study to design and implement an in silico Phase III clinical trial for CD to investigate response to treatment in terms of changes in pharmacodynamic immunological marker profiles (ie, TNF-α and IFN-γ) and health outcomes.
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U2 - 10.1016/B978-0-12-804203-8.00028-6
DO - 10.1016/B978-0-12-804203-8.00028-6
M3 - Chapter
AN - SCOPUS:84969610554
SN - 9780128042038
SP - 411
EP - 427
BT - Emerging Trends in Applications and Infrastructures for Computational Biology, Bioinformatics, and Systems Biology
PB - Elsevier Inc.
ER -