Relacorilant GR Modulation for Lean Mass Preservation in Cushing's
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Solution Overview
Problem
Current treatments for Cushing's syndrome do not effectively address muscle weakness and loss of tissue lean mass, which are prevalent symptoms affecting up to 60% of patients, despite successful treatment of the underlying condition.
Innovation Solution
Administration of the heteroaryl ketone fused azadecalin compound relacorilant, which modulates cortisol binding to the glucocorticoid receptor, is effective in increasing tissue lean mass, reducing muscle weakness, and improving muscle strength in patients with Cushing's syndrome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for Cushing's syndrome are used to treat cortisol excess, then cortisol levels are reduced, but muscle weakness and loss of tissue lean mass persist and are not addressed
Solution Approach 1:
The patent applies this principle by using a GR modulator that selectively blocks cortisol binding to glucocorticoid receptors in muscle tissue while allowing cortisol to bind to other receptors. This converts the harmful catabolic effect of cortisol on muscle into a beneficial selective blockade, preventing muscle protein breakdown and promoting tissue lean mass preservation without interfering with cortisol's other physiological functions
Solution Approach 2:
The invention implements local quality by creating a tissue-specific effect where the GR modulator preferentially acts on muscle tissue glucocorticoid receptors. This selective localization allows the treatment to address muscle weakness and tissue lean mass loss specifically in muscle tissue while maintaining normal cortisol function in other organs and systems
2Weight of moving object
If weight loss treatment is applied to CS patients, then body weight is reduced, but tissue lean mass may be further depleted
Solution Approach 1:
The patent converts the harmful effect of cortisol-induced muscle catabolism into a benefit by using the GR modulator to selectively block cortisol binding in muscle tissue. This prevents the breakdown of muscle proteins during weight loss, allowing body weight reduction to occur primarily through fat loss while preserving or even increasing tissue lean mass
Solution Approach 2:
The invention changes the physiological parameter of cortisol-receptor interaction in muscle tissue by introducing a GR modulator. This parameter change alters the metabolic state of muscle cells, shifting them from a catabolic state (protein breakdown) to an anabolic or neutral state (protein preservation), thereby enabling weight loss without tissue lean mass depletion
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Relacorilant administration results in a significant increase in tissue lean mass by 1.8%, reduction in body weight by up to 40-50%, and improvement in muscle strength, as indicated by a 1.5% reduction in the time required to stand from a sitting position, over a 22-week period.
Implementation Method 1
Cortisol action requires that cortisol bind to the glucocorticoid receptor (GR)
Data Source
AI summary
Applicant discloses methods and uses of the heteroaryl ketone fused azadecalin compound relacorilant for treating patients suffering from endogenous hypercortisolism (CS) (including Cushing's syndrome and Cushing's Disease) effective reduce or prevent the loss of tissue lean mass; in embodiments, the methods and uses are effective to increase tissue lean mass as compared to the patient's tissue lean mass prior to administration of relacorilant. The methods and uses of relacorilant for treating patients suffering from CS are further effective to reduce body weight and waist circumference of the patient.Therapeutic amounts of relacorilant may be between about 50 milligrams per day (mg/day) and up to about 800 mg/day, e.g., 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, or 500 mg/day. The treatments may be oral treatments, and relacorilant may be administered with food, or without food. Relacorilant is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone, which has the structure: