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Methods of determining responsiveness to Anti-tnf alpha therapy in inflammatory bowel disease

Inactive Publication Date: 2011-09-22
CEDARS SINAI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]Various embodiments include a method of determining a high risk relative to a normal subject of non-responsiveness to treatment with an anti tumor necrosis actor alpha (TNFα) therapy in an individual, comprising obtaining a sample from the individual, assaying the sample for the presence or absence of one or more genetic and/or serological risk factors, and determining the high risk relative to a normal subject of non-responsiveness to the anti TNFα therapy based on the presence of one or more risk factors carried by the individual. In another embodiment, the presence of each genetic and/or serological risk factor has an additive effect on increasing the risk of non-responsiveness in the individual. In another embodiment, the individual is diagnosed with inflammatory bowel disease (IBD). In another embodiment, the individual is diagnosed with ulcerative colitis (UC). In another embodiment, the individual is a child. In another embodiment, the one or more genetic risk factors comprise genetic variants at the loci of tachykinin receptor 1 (TACR1), family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulato

Problems solved by technology

However, the clinical trial data for all anti-TNFα therapies among adult CD patients report that 40% of patients do not respond to the induction phase (primary non-responder) and that approximately 40% of those patients who do enter the maintenance phase of the trial lose response over time.
There are many differences in the patient population and outcome measures making a comparison across trials difficult and hard to interpret.
To date, however, it remains unknown whether these are independent of genetic variability.

Method used

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  • Methods of determining responsiveness to Anti-tnf alpha therapy in inflammatory bowel disease
  • Methods of determining responsiveness to Anti-tnf alpha therapy in inflammatory bowel disease
  • Methods of determining responsiveness to Anti-tnf alpha therapy in inflammatory bowel disease

Examples

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example 1

Generally

[0069]Genetics, immune responses and environmental factors for disease susceptibility and development, as well as their interactions, are important determinants of inflammatory bowel disease phenotype and disease progression. These factors may also interact in such a way that influences the outcome of therapies used to treat these heterogeneous phenotypes. Recent genomic discoveries from Genome Wide Association (GWA) studies in both Crohn's disease (CD) and ulcerative colitis (UC) have increased understanding of the genetic susceptibility to IBD. This novel genetic information provides important insight regarding the various mechanisms of inflammation involved in disease pathogenesis. Targeting these various pathways with effective therapies is the key to the successful management of the IBD patient. When introduced, the monoclonal antibodies targeting tumor necrosis factor alpha (TNFα) represented the largest advance in decades made in the realm of IBD therapeutics. Howeve...

example 2

Significance of Defining Predictors of Response to Anti-TNFα

[0070]Defining predictors of response to anti-TNFα will allow clinicians to choose the appropriate therapy for the appropriate IBD patient with the goal of maximizing efficacy and minimizing toxicity. Research described herein will allow the individualization of therapy based on who will or perhaps more importantly will not respond to different classes of therapeutic interventions currently available to IBD patients. The development of lymphoma, particularly a rare almost uniformly fatal sub-type of hepatosplenic T cell lymphoma in individuals receiving infliximab along with immunomodulators have resulted in clinicians wanting to carefully select those patients who are appropriate candidates for these therapies. The novel pharmacogenetic information described herein can not only improve the management of patients in the clinic with an existing anti-TNFα agent but also ultimately change the way large scale clinical trials ar...

example 3

Pharmacogenetic GWAS and Primary Non-Response

[0071]The inventors tested the association of the most significant CD susceptibility loci previously identified with infliximab responsiveness in pediatric IBD patients receiving infliximab from which there was complete clinical follow up. For these preliminary analyses, two (2) outcomes were evaluated:

[0072]1) primary non-response: patient did not respond to the induction regimen as defined by patient did not receive a clinical benefit from the first 3 infusions of infliximab and did not receive any further treatment doses. All significant associations are shown in Table 1 below. Remainder of analyses are detailed in Table 3.

[0073]2) secondary loss of response: patient responded to the induction regimen and despite dose escalation and / or frequency intensification of infliximab the drug was discontinued as of last follow up. Time to loss of response was also analyzed and data are shown in Table 3.

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Abstract

The present invention relates to methods of prognosing responsiveness to anti-TNFα therapy by determining the presence or absence of risk factors in the individual. In one embodiment, the risk factors are genetic markers, serological markers and / or clinical phenotypes associated with non-responsiveness to treatment with anti-TNFα therapy in an individual diagnosed with IBD.

Description

GOVERNMENT RIGHTS[0001]This invention was made with government support under Contract Nos. P01 DK046763, M01 RR00425 and DK063491 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0002]The invention relates generally to the field of inflammatory bowel disease and, more specifically, to genetic methods for diagnosing, prognosing, and treating inflammatory bowel disease.BACKGROUND[0003]All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.[0004]Natural history obs...

Claims

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Application Information

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IPC IPC(8): A61K39/395C12Q1/68A61P29/00
CPCC12Q1/6883C12Q2600/172C12Q2600/106C12Q2600/156A61P29/00
Inventor ROTTER, JEROME I.DUBINSKY, MARLATARGAN, STEPHAN R.TAYLOR, KENT D.
Owner CEDARS SINAI MEDICAL CENT
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