Methods of treating liver disorders or lipid disorders with a THR-beta agonist
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Publication Number
US-11090308-B2
Publication Date
2021-08-17
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 invention relates to treating nonalcoholic steatohepatitis in a subject in need thereof by using 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, also identified as MGL-3196 or a stereoisomer, pharmaceutically acceptable salt, or morphic form. The method includes performing a first biomarker test measuring a first expression level of sex hormone-binding globulin (SHBG) followed by administering a first daily dose of Compound A for a first period of time, and then performing a second biomarker test measuring a second SHBG expression level.
The invention determines a change or degree of change in SHBG expression level based on the results from the first and second SHBG biomarker tests. The change or degree of change is used as an indicator of the subject’s sensitivity to Compound A. Based on this sensitivity result, the method administers a second dose of Compound A for a second period of time.
In the described treatment framework, dependent refinements specify aspects of the method including the biological sample type used for SHBG testing, time ranges for the first period of time, and quantitative dosing constraints for the first dose. Additional dependent features further ground the second dose selection using demographic features, medication history, physical information, results from a genetic test and/or a pharmacokinetic test, and results from a physical examination, optionally in combination with the SHBG-based sensitivity result.
Claims Coverage
The provided partial claim set includes one independent claim directed to treating nonalcoholic steatohepatitis using SHBG biomarker testing to guide dose selection of Compound A, with multiple dependent claims refining sample type, time period, dosing ranges, morphic form identification, and factors used to determine the second dose.
SHBG expression change as sensitivity indicator
Performing a first SHBG biomarker test on a first biological sample, administering a first daily dose of Compound A for a first period of time, performing a second SHBG biomarker test on a second biological sample, and determining a change or degree of change in SHBG expression level indicative of the subject’s sensitivity to Compound A.
Dose selection with two dosing periods
Administering a first dose of Compound A daily for a first period of time, and administering a second dose of Compound A for a second period of time based on the sensitivity result from the determined SHBG change or degree of change.
Dose refinement by first dose amount range
Administering the first dose in a range of about 5 to 300 mg.
Dose refinement by first period of time range
Specifying that the first period of time is about 2 to 21 days.
SHBG biomarker sample selection
Using a biological sample that is either a blood sample or a serum sample for measuring SHBG expression levels.
Second dose determination using subject information and test results
Determining the second dose of Compound A based on one or more demographic features, medication history, physical information, results from a genetic test or a pharmacokinetic test on a biological sample, results from a physical examination, or combinations thereof.
Compound A morphic form identified by X-ray powder diffraction peaks
Providing Compound A in a specific morphic form identified by an X-ray powder diffraction pattern having peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ.
Overall, the claim coverage centers on using two SHBG biomarker tests (before and after a first daily dosing period of Compound A) to determine a SHBG expression change indicative of subject sensitivity, and then selecting a second Compound A dose based on that sensitivity. Dependent claims refine the method using sample type, first dosing period range, first dose amount range, optional use of additional subject factors and test results for second-dose determination, and identification of Compound A by a specified morphic form via characteristic X-ray powder diffraction peaks.
Stated Advantages
Provides an approach to determine sensitivity to Compound A using a change or degree of change in SHBG expression level and to administer a second dose based on that sensitivity result.
Documented Applications
Treating nonalcoholic steatohepatitis in a subject in need thereof using Compound A and SHBG biomarker testing to guide dosing.
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