Methods of treating liver disorders or lipid disorders with a THR-beta agonist
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Publication Number
US-11806353-B2
Publication Date
2023-11-07
Expiration Date
Abstract
The present invention provides a method for treating a liver disorder or lipid disorder in a subject in need thereof with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a stereoisomer, a salt thereof, or a morphic form thereof.
Core Innovation
The document discloses methods for treating lipid disorders in a subject in need thereof using a THR-beta agonist, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (“Compound A”). The approach includes administering Compound A daily for a first period of time, then using biomarker measurements to determine a subject’s sensitivity to Compound A. The sensitivity result is used to determine a second dose of Compound A for a second period of time.
The disclosed biomarker strategy uses sex hormone-binding globulin (SHBG). A first biomarker test is performed on a first biological sample obtained from the subject to measure a first expression level of SHBG prior to the daily Compound A administration, and a second biomarker test is performed on a second biological sample to measure a second expression level of SHBG after Compound A treatment. A change or degree of change in SHBG expression based on the results is determined, and the change or degree of change is indicative of sensitivity to Compound A for selecting the second dose.
The document further describes Compound A as a specific morphic form defined by an X-ray powder diffraction pattern, including peaks at approximately 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ (Form I). It also documents strong liver tissue uptake and predominant fecal and biliary elimination, together with limited penetration into many non-liver tissues, supported by rat and dog ADME/PK and radiolabel studies and transporter/hepatobiliary disposition findings.
Claims Coverage
The partial content provided includes one independent claim directed to a biomarker-guided dosing method for treating lipid disorders using SHBG to determine sensitivity, followed by administration of a second Compound A dose. Additional dependent refinements specify a Compound A morphic form, a first administration time window, and pharmacokinetic testing based on Compound A metabolite levels.
SHBG-based sensitivity determination for second dosing
Performing a first biomarker test that measures an initial expression level of SHBG, administering Compound A daily for a first period of time, performing a second biomarker test that measures a second expression level of SHBG, determining a change or degree of change in SHBG expression indicative of the subject’s sensitivity to Compound A, and administering a second dose of Compound A for a second period of time based on the sensitivity result.
SHBG measurement in first and second biological samples
Measuring SHBG expression level in a first biological sample obtained from the subject and measuring SHBG expression level in a second biological sample obtained from the subject after Compound A administration.
Morphic form of Compound A defined by X-ray powder diffraction peaks
Providing Compound A in a morphic form defined by an X-ray powder diffraction pattern with peaks at approximately 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ (Form I).
Two-period Compound A administration with time constraint for first period
Administering a first dose of Compound A daily for a first period of time and specifying that the first period of time is in the range of about 2–21 days.
Pharmacokinetic test using Compound A metabolite level at a predetermined time
Including a pharmacokinetic test in which the level of a Compound A metabolite is measured in a biological sample at a predetermined time after administering the first dose.
Across the provided claim set, the core claim centers on using SHBG measured before and after a first daily administration of Compound A to determine sensitivity and to select a subsequent second dose. Additional provided dependent refinements specify a Compound A morphic form by X-ray diffraction peaks, constrain the first administration and testing time window, and include pharmacokinetic testing based on Compound A metabolite levels at a predetermined post-dose time.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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