Use of sGC stimulators for the treatment of nonalcoholic steatohepatitis (NASH)
Inventors
Im, G-yoon Jamie • Currie, Mark G. • SHEPPECK, James Edward • Renhowe, Paul Allan • Ge, Pei • Masferrer, Jaime L.
Assignees
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Publication Number
US-11357777-B2
Publication Date
2022-06-14
Expiration Date
Abstract
The present disclosure relates to methods, uses, pharmaceutical compositions and kits comprising an sGC stimulator or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for the treatment of Nonalcoholic Steatohepatitis (NASH).
Core Innovation
The invention relates to compounds of Formula I′ and pharmaceutically acceptable salts thereof, and to defined sGC stimulator chemical classes including compounds of Formula IA, Formula IB, Formula IC, Formula XZ, and Formula XY, with extensive Markush-style substituent and ring variables and depicted example compounds. The structural scope includes heteroaryl and heterocyclic ring systems, fluorine substituents, heteroatoms N/O/S, and specified linkage and ring relationship types, with table-listed and labeled embodiments supporting selection of particular compounds.
The invention further relates to using an sGC stimulator, including compounds within the defined formula scope and pharmaceutically acceptable salts, for treating NASH in a patient in need thereof by administering a therapeutically effective amount. The disclosure states that this approach is associated with measurable improvements in NASH-related pathology, biomarkers, symptoms, and weight loss outcomes, and with goals of slowing or halting progression to cirrhosis and increasing survival time in patients diagnosed with NASH.
The disclosure also describes translational and animal-model evidence supporting anti-inflammatory, anti-steatotic, and anti-fibrotic effects of sGC stimulator treatment in NASH-related settings. It further states that combination therapy is contemplated with additional therapeutic agents, including anti-diabetic agents and antiobesity drugs, and also lists other co-administered agent categories such as NO donors, cGMP/eNOS modulators, PDE inhibitors, calcium channel blockers, endothelin receptor antagonists, prostacyclin analogues, lipid-lowering agents, anticoagulants, and GLP-1 agonists.
Claims Coverage
The claim coverage centers on treating NASH by administering a therapeutically effective amount of an sGC stimulator or a pharmaceutically acceptable salt, with multiple dependent refinements. The merged inventive features cover measurable NASH-related outcomes, slowing or halting progression to cirrhosis and/or increasing survival time, chemical scope defined by Formula IA and other stated formulas/table-listed options, and optional combination therapy with additional therapeutic agents.
Treating NASH with sGC stimulator administration
A method of treating NASH in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulator or a pharmaceutically acceptable salt thereof.
Measurable NASH-related improvements
Administration of the sGC stimulator, alone or with another therapeutic agent, results in one or more observable/measurable improvements including decreased liver steatosis or abnormal fat accumulation in the liver, decreased inflammation and fibrosis-related severity, reduced elevations of liver enzyme levels and inflammatory cytokine levels, reduction in fatigue and weakness and/or inhibition of weight loss.
Slowing or halting progression to cirrhosis and increasing survival time
Administration of the sGC stimulator is aimed at or results in slowing or halting NASH progression to cirrhosis, and/or increasing survival time in patients diagnosed with NASH.
Defined chemical scope by Formula IA, Formula IB, Formula IC, Formula XZ, and Formula XY
The method uses an sGC stimulator that is a compound of Formula IA, Formula IB, Formula IC, Formula XZ, or Formula XY, or a pharmaceutically acceptable salt of that compound.
Selecting from table-depicted options
The method includes selecting the sGC stimulator from options depicted in Tables X, XX, XXX, IV or XIV, or from other stated table-listed compounds.
Combination therapy with additional therapeutic agents
The method further includes administering the sGC stimulator or a pharmaceutically acceptable salt in combination with one or more additional therapeutic agents, including anti-diabetic agents, antiobesity drugs, and other stated agent categories.
Overall, the claims focus on NASH treatment by administration of an sGC stimulator or pharmaceutically acceptable salt, with refinements for measurable treatment outcomes, disease progression and survival goals, defined chemical embodiments, table-listed selections, and combination therapy with additional agents.
Stated Advantages
Decreased liver steatosis or abnormal fat accumulation in the liver.
Decreased inflammation and fibrosis-related severity.
Reduced elevations of liver enzyme levels and inflammatory cytokine levels.
Reduction in fatigue and weakness.
Inhibition of weight loss.
Slowing or halting progression of NASH to cirrhosis.
Increasing survival time in patients diagnosed with NASH.
Anti-inflammatory effects, including decreased TNFα/IL-6 and increased IL-10.
Anti-steatotic effects, including reduction of hepatic triglycerides/steatosis.
Anti-fibrotic effects, including reduction of fibrosis markers, fibrosis histology, and Sirius Red collagen deposition.
Higher liver concentration versus plasma concentration ratios.
Minimal oral hypotension.
Documented Applications
Treating NASH in a patient in need thereof by administering an sGC stimulator or a pharmaceutically acceptable salt.
Use in NASH treatment with measurable improvements in liver pathology, biomarkers, symptoms, and/or weight loss.
Use to slow or halt NASH progression to cirrhosis and/or increase survival time in patients diagnosed with NASH.
Combination therapy for NASH with anti-diabetic agents, antiobesity drugs, and other additional therapeutic agents.
Use in NASH-related animal models and fibrosis models, including prophylactic treatment and reduction of inflammatory gene expression, inflammatory infiltrate, NAS score, fibrosis markers, and Sirius Red collagen deposition.
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