Miricorilant Glucocorticoid Modulator Reducing Liver Fat
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Solution Overview
Problem
Current treatments for fatty liver diseases, particularly non-alcoholic fatty liver disease (NAFLD) and related conditions, lack effective methods for reducing liver fat and preventing progression to liver fibrosis and cirrhosis.
Innovation Solution
Administration of the non-steroidal glucocorticoid receptor modulator miricorilant, a cyclohexyl pyrimidine compound, which reduces liver fat levels and associated inflammation, thereby addressing the underlying causes of fatty liver diseases such as NAFLD and NASH.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If no pharmacologic treatment is administered, then liver fat levels remain high and disease progression continues, but there are no approved treatments available
Solution Approach 1:
The patent applies parameter changes by modifying the glucocorticoid receptor's ligand-binding properties through the use of non-steroidal modulators (miricorilant). This changes the pharmacological parameters of receptor activation, enabling selective modulation that reduces liver fat without the side effects of traditional glucocorticoids. The compound alters the binding affinity and activation profile to achieve therapeutic effects where no prior treatment existed.
2Quantity of substance
If long-term experimental treatment is administered, then liver fat reduction of 30% or more is achieved, but treatment duration requires 24 weeks or longer
Solution Approach 1:
The patent employs preliminary action by using miricorilant to rapidly initiate liver fat reduction within weeks rather than requiring 24+ weeks of traditional treatment. The non-steroidal GRM acts quickly to block lipogenic gene expression and promote fat oxidation, achieving significant fat reduction in a compressed timeframe. This preliminary and accelerated action reduces the treatment duration while maintaining or exceeding the 30% fat reduction threshold.
3Object-generated harmful factors
If traditional glucocorticoids are used, then anti-inflammatory effects are achieved, but harmful side effects occur
Solution Approach 1:
The patent applies local quality by designing miricorilant to selectively modulate the glucocorticoid receptor in specific tissues (particularly liver) while avoiding the systemic side effects of traditional glucocorticoids. The non-steroidal structure enables tissue-selective binding and activation, providing localized anti-inflammatory and fat-reducing effects without the harmful systemic effects like immunosuppression, bone loss, and metabolic disturbances associated with conventional glucocorticoid therapy.
Data Source
AI summary
Applicant discloses methods and compositions for reducing liver fat and for treating fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis; alcohol related fatty liver diseases including, alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH), and alcoholic cirrhosis; and liver fibrosis). Significant liver fat reductions were obtained in human patients after only between 30 to 44 days of administration of 600 mg/day or 900 mg/day of the cyclohexyl pyrimidine glucocorticoid receptor modulator miricorilant. Liver fat reductions ranged from 38.5% to 73.8% (magnetic resonance imaging measurements in 4 of 5 patients receiving miricorilant, measured between 16-64 days after cessation of miricorilant administration). A further effect of miricorilant was an increase in liver alanine amino transferase (ALT) and aspartate amino transferase (AST). Mouse studies showed that miricorilant reduced measures of NAFLD, body weight, liver weight, and liver collagen and galectin-3 levels.