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      Identifying a subpopulation with higher likelihoods of early response to treatment in a heterogeneous rare disease: a post hoc study of response to teduglutide for short bowel syndrome

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          Teduglutide, a glucagon-like peptide-2 analog, has demonstrated efficacy in reducing parenteral support (PS) among patients with short bowel syndrome with intestinal failure (SBS–IF). This study aims to identify a subpopulation of SBS–IF patients for whom teduglutide has an especially pronounced effect.

          Patients and methods

          Data were from a 24-week, Phase III trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent SBS Subjects; NCT00798967) that randomized SBS–IF patients with PS dependency to receive teduglutide (n=43) or placebo (n=43). Two prediction models (1 for each arm) were developed for response, defined as 20% reduction in weekly PS at Weeks 20 and 24. Potential predictors included demographics, disease characteristics, and concomitant medications. Patients were then ranked based on the effect score, an individualized predicted response rate difference with teduglutide versus placebo. A subpopulation of patients with a pronounced benefit from teduglutide versus placebo was identified. Baseline characteristics and clinical outcomes were compared between patients included versus those not included in the subpopulation.


          Six predictors of response to teduglutide were selected: older age, volvulus as the cause of major intestinal resection, baseline PS volume >6 L per week, longer time since start of PS dependency, absence of ileocecal valve, and lower percentage of colon remaining. Higher percentage of colon remaining and volvulus were the selected predictors for response to placebo. A subpopulation of patients more likely to respond to teduglutide was identified as those with the top 60% effect scores. The difference in response rate between teduglutide and placebo was 62% in the subpopulation, which was substantially higher than the difference of 33% in the overall population. Mean PS day reduction was also significantly higher for teduglutide compared to placebo in the subpopulation.


          Pretreatment characteristics as predictors of response to teduglutide versus placebo within 24 weeks were identifiable in the clinical trial population of SBS–IF patients.

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          Most cited references 25

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          The path to personalized medicine.

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            Regression shrinkage and selection via the lasso

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              Genomic and personalized medicine: foundations and applications.

              The last decade has witnessed a steady embrace of genomic and personalized medicine by senior government officials, industry leadership, health care providers, and the public. Genomic medicine, which is the use of information from genomes and their derivatives (RNA, proteins, and metabolites) to guide medical decision making-is a key component of personalized medicine, which is a rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. As medicine begins to embrace genomic tools that enable more precise prediction and treatment disease, which include "whole genome" interrogation of sequence variation, transcription, proteins, and metabolites, the fundamentals of genomic and personalized medicine will require the development, standardization, and integration of several important tools into health systems and clinical workflows. These tools include health risk assessment, family health history, and clinical decision support for complex risk and predictive information. Together with genomic information, these tools will enable a paradigm shift to a comprehensive approach that will identify individual risks and guide clinical management and decision making, all of which form the basis for a more informed and effective approach to patient care. DNA-based risk assessment for common complex disease, molecular signatures for cancer diagnosis and prognosis, and genome-guided therapy and dose selection are just among the few important examples for which genome information has already enabled personalized health care along the continuum from health to disease. In addition, information from individual genomes, which is a fast-moving area of technological development, is spawning a social and information revolution among consumers that will undoubtedly affect health care decision making. Although these and other scientific findings are making their way from the genome to the clinic, the full application of genomic and personalized medicine in health care will require dramatic changes in regulatory and reimbursement policies as well as legislative protections for privacy for system-wide adoption. Thus, there are challenges from both a scientific and a policy perspective to personalized health care; however, they will be confronted and solved with the certainty that the science behind genomic medicine is sound and the practice of medicine that it informs is evidence based.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                25 July 2018
                : 14
                : 1267-1277
                [1 ]Outcomes Research and Epidemiology, Shire Human Genetic Therapies, Inc., Cambridge, MA, USA, krchen@ 123456shire.com
                [2 ]Analysis Group, Inc., Los Angeles, CA, USA
                [3 ]Analysis Group, Inc., New York, NY, USA
                [4 ]Analysis Group, Inc., Boston, MA, USA
                [5 ]Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark
                Author notes
                Correspondence: Kristina S Chen, Shire Human Genetic Therapies, Inc., 650 E Kendall Street, Boston, MA 02142, USA, Tel +1 617 588 8741, Email krchen@ 123456shire.com
                © 2018 Chen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research


                subpopulation, sbs, teduglutide, intestinal failure


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