Combination Therapy for Cholestasis Reducing Bile Acid Pool
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Solution Overview
Problem
Current therapies for cholestasis are limited in effectively reducing the bile acid pool in the liver, leading to inadequate treatment for patients with genetic and acquired forms of the condition, as they trigger compensatory mechanisms that limit the magnitude of bile acid reduction.
Innovation Solution
A combination therapy involving an apical sodium-dependent bile acid transporter (ASBT) inhibitor and a fibroblast growth factor 15 (FGF15) analogue or analogue, which simultaneously inhibits hepatic bile acid synthesis and intestinal bile acid re-uptake, thereby achieving a more significant reduction in the bile acid pool.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If FXR agonists or FGF19 analogues are used to inhibit de novo bile acid synthesis, then bile acid pool reduction is achieved, but compensatory mechanisms induce bile acid synthesis and limit the magnitude of reduction
Solution Approach 1:
The invention divides the bile acid reduction strategy into two separate targets: hepatic synthesis (via FXR/FGF19 pathway) and intestinal re-uptake (via ASBT). By segmenting the intervention points, the patent overcomes the compensatory mechanism where blocking one pathway triggers upregulation of the other, thereby achieving more reliable and sustained bile acid pool reduction.
Solution Approach 2:
The patent combines two therapeutic agents: an FXR agonist or FGF19 analogue (to inhibit hepatic synthesis) with an ASBT inhibitor (to block intestinal re-uptake). This combination therapy merges the actions on both major bile acid handling pathways, preventing compensatory induction and achieving greater magnitude of bile acid pool reduction than either single agent alone.
2Quantity of substance
If ASBT inhibitors are used to block intestinal bile acid re-uptake, then fecal bile acid loss increases, but compensatory induction of de novo bile acid synthesis limits the magnitude of bile acid pool reduction
Solution Approach 1:
The invention utilizes the natural feedback regulation of bile acid metabolism by combining ASBT inhibition with FXR agonism or FGF19 analoguing. The FXR/FGF19 pathway provides negative feedback to suppress compensatory de novo synthesis that would otherwise occur in response to ASBT inhibition, thereby maintaining efficient bile acid excretion without triggering compensatory synthesis that would limit pool reduction.
3Ease of operation
If single-agent therapies are used to treat cholestasis, then treatment simplicity is maintained, but therapeutic efficacy is insufficient for patients who do not adequately respond
Solution Approach 1:
The patent changes the therapeutic parameter from monotherapy to combination therapy, thereby improving efficacy for refractory cholestasis cases. The combination of FXR agonist/FGF19 analogue with ASBT inhibitor targets multiple pathways simultaneously, providing enhanced therapeutic response while maintaining a relatively simple two-drug regimen that can be administered orally.
Data Source
AI summary
A method of treating a cholestasis liver condition in a subject by administering to the subject a first compound and a second compound, wherein the first compound is a fibroblast growth factor 19 (FGF19) analogue, and/or a bile acid-activated farnesoid x receptor (FXR) agonist, and the second compound is an apical sodium-dependent bile acid transporter (ASBT) inhibitor.