Combination therapy for nonalcoholic steatohepatitis (NASH) and liver fibrosis

一种纤维化疾病、是非的技术，应用在杂环化合物有效成分、消化系统、药物组合等方向，能够解决减少纤维化等问题，达到减少肝脏炎症评分、副作用减少、减少副作用的效果

Inactive Publication Date: 2019-10-18
CHAOYI BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preclinical and human data suggest that targeting CCR5 or CCR2 / 5 with CCR5 or CCR2 / 5 antagonists is effective in reducing fibrosis, but much less so in NAS score or steatosis (2)

Method used

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  • Combination therapy for nonalcoholic steatohepatitis (NASH) and liver fibrosis
  • Combination therapy for nonalcoholic steatohepatitis (NASH) and liver fibrosis
  • Combination therapy for nonalcoholic steatohepatitis (NASH) and liver fibrosis

Examples

Experimental program
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Embodiment

[0046] We have used a well-validated mouse model in which NASH and fibrosis are induced by sequential induction of diabetes and a high-fat diet (14). On day 2, C59BL / 6J mice were injected with streptozotocin and then treated with a high-fat diet from weeks 4 to 9. Intervention treatment started from week 5 to week 9. At week 9, these mice were euthanized. Intervention of NASH and its subsequent disease process was performed by administering the CCR5 antagonist maraviroc (dose 45 mg / kg po once daily) and OCA (30 mg / kg once daily) alone or in combination for 4 weeks.

[0047] Such as Figure 1A As shown, the CCR5 antagonist maraviroc alone had a limited effect on NAS scores, and OCA alone caused only a slight decrease in NAS scores. Combination of CCR5 antagonists with OCA resulted in significantly lower NAS scores and was more effective in reducing NAS scores than any single agent alone. The NAS score was determined according to the consensus of the Nonalcoholic Steatohepati...

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Abstract

The innovation is directed to a method for treating a CCR5 and / or CCR2 mediated disease such as nonalcoholic steatohepatitis (NASH) comprising administering an effective amount of a C-C Chemokine receptor 5 (CCR5) antagonist (e.g., maraviroc or vicriviroc or cenicriviroc) and / or an effective amount of a C-C Chemokine receptor 2 (GGR2) antagonist, or a CCR5 / CCR2 antagonist together with an effective amount of farnesoid X receptor (FXR) agonist (e.g., obeticholic acid (OCA)). An effective amount can be a regular clinical dose of either agent alone or a reduced dose of the FXR receptor agonist and / or the CCR5 / CCR2 antagonist. The combination is effective to treat NASH with (1) enhanced efficacy and (2) substantial reduction of side effects, particularly those associated with administration ofOCA or its analogues, namely less effect on liver enzyme elevation, and less severity and frequency of pruritus (3). The fixed dose combination provides for better efficacy and safety profile.

Description

technical field [0001] This application claims the benefit of US Provisional Application Serial No. 62 / 439,666, filed December 28, 2016, the entire teachings of which are incorporated herein by reference. Background technique [0002] Nonalcoholic steatohepatitis (NASH) is an insidious and slowly progressive disease with a marked impact on quality of life. It can eventually lead to cirrhosis, decompensated liver disease and / or hepatocellular carcinoma. It is essentially characterized by ongoing damage from steatosis, release of inflammatory chemokines, inflammation, and fibrosis. Fibrosis associated with inflammation is a key driver of disease progression. Multiple drugs with different mechanisms have been tested in clinical trials, but no effective treatments have been approved. [0003] There are now many new molecules in various stages of clinical development for NASH, but only marginal / minor effects have been reported (1, 2). [0004] CCR5 antagonists were originally...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/575A61K31/46A61K31/4375A61K31/4178A61K31/506A61P1/16A61P11/00A61P13/12
CPCA61K31/4178A61K31/4375A61K31/46A61K31/506A61K31/575A61P1/16A61P11/00A61P13/12A61K2300/00A61K31/5545A61P43/00
Inventor 刘华涛克里斯多福·王庄昭南
Owner CHAOYI BIOPHARMACEUTICAL CO LTD
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