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Human genetic markers associated with response to treatments that target clostridium difficile toxin b

A Clostridium difficile, treatment-responsive technology, applied in the field of genetic markers, to solve problems such as inability to eliminate CDI

Pending Publication Date: 2019-08-02
MERCK & CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing therapies often fail to eliminate CDI or lead to recurrent disease; therefore, new approaches to preventive or curative treatment are needed
[0006] One of the biggest challenges in managing CDI is preventing relapse

Method used

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  • Human genetic markers associated with response to treatments that target clostridium difficile toxin b
  • Human genetic markers associated with response to treatments that target clostridium difficile toxin b
  • Human genetic markers associated with response to treatments that target clostridium difficile toxin b

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0233] Actoxumab / bezlotoxumab and belotoxumab in patients with CDI of subjects in clinical trials

[0234] To identify genetic contributions to treatment response, the inventors performed pharmacogenetic (PGx) analysis of C. difficile-infected subjects who had undergone clinical trials employing antibodies to C. difficile toxin B to use a genome-wide association study (GWAS) method to assess whether the mean treatment difference varies in subgroups of patients defined by genetic variation. The clinical study designs of the two clinical trials called MODIFYI (PN001) and MODIFY II (PN002) are as follows figure 1 shown.

[0235] PN001 is an adaptive design phase 3 trial in which subjects diagnosed with CDI and receiving standard-of-care treatment for CDI (metronidazole, vancomycin, or fidaxomicin) were randomly assigned in a 1:1:1:1 ratio to 4 One of the treatment groups (belotuzumab, aktokinumab, aktokinumab / belotuzumab, or placebo). In the prespecified interim analysis,...

Embodiment 2

[0241] Genome-wide association studies to identify SNPs associated with response to treatments comprising TcdB antibodies and antibiotics

[0242] Genome-wide association studies were performed to assess whether genetic variants in the human genome were associated with differences in treatment among patients randomly assigned to different groups of the study. Because the analysis of the clinical studies confirmed that the treatment benefit was primarily derived from belotomab rather than akinetizumab, it was determined that the benefit from the belotomab-containing treatment group (belokomab alone and belokumab alone Anti + Aktoximab) subjects were pooled and compared to placebo (no mAb administered, only 0.9% NaCl). The combined dataset for GWAS analysis was based on approximately 897 patients from both MODIFY I and II (PN001 and PN002, also referred to herein as the "PGx dataset"). Subjects from the Aktoximab alone group were not used for GWAS analysis. Only subjects wit...

Embodiment 3

[0246] statistical methods

[0247] Conducting two pivotal studies, MODIFY I and II (PN001 and PN002), to evaluate beloxomab (MK-6072), aktoximab (MK-3415), belotoximab and aktoximab Combination of mAbs (MK-3415A) and placebo for prevention of Clostridium difficile relapse (rCDI) in patients receiving standard-of-care antibiotics. The primary clinical endpoint of interest was rCDI, which was defined as a new episode of diarrhea associated with a positive local or central laboratory stool test for toxigenic C. difficile following clinical cure of the initial CDI episode (3 within 24 hours or less). occurrence of one or more loose stools). The primary efficacy endpoint was the proportion of patients with CDI recurrence assessed by Week 12. Initial efficacy results from two studies showed that beloxetumab was superior to placebo in reducing the rate of CDI recurrence (p<0.0001), while aktoximab alone showed no efficacy compared to placebo (p=0.3182 ).

[0248] Commercial Af...

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PUM

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Abstract

The present invention provides genetic markers on human chromosome 6 that are associated with a beneficial response to a treatment that targets Clostridium difficile (C. difficile) toxin B (TcdB), e.g. a TcdB antibody. These TcdB treatment response markers are useful, inter alia, to identify patients who are most likely to benefit from treatment with a treatment that 5 targets TcdB in methods of treating patients having a disease susceptible to treatment with a TcdB antibody, and in methods for selecting the most appropriate therapy for such patients. The invention also provides antibodies, drug products, and kits useful with the TcdB Treatment response markers of the invention.

Description

technical field [0001] The present invention relates to genetic markers on human chromosome 6 that predict a beneficial response to treatment with molecules targeting C. difficile toxin B in patients in need. The present invention also provides methods of diagnosing and / or treating such patients using genetic markers. [0002] CROSS-REFERENCE TO RELATED APPLICATIONS [0003] This application claims the benefit of currently pending US Provisional Application Serial No. 62 / 508,066, filed May 18, 2017, and currently pending International Application No. PCT / CN16 / 109900, filed December 14, 2016. Background technique [0004] C. difficile is an anaerobic, spore-forming, Gram-positive bacillus that is the most common cause of health care-acquired infections in the United States (U.S.) and Europe (Lessa et al., Burden of Clostridium difficile infection in the United States). States. N Engl J Med. 2015 372(9):825-34). The US Centers for Disease Control (CDC) has declared Clostri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6883
CPCC12Q1/6883C12Q2600/106C12Q2600/156A61P31/04A61P43/00C12Q1/689C12Q1/24C12Q1/6806
Inventor P·M·肖D·V·梅赫罗特拉R·L·布兰查德沈具东R·莫格M·B·多尔李俊桦徐讯
Owner MERCK & CO INC
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