Method for treatment of COVID-19-associated conditions

Inventors

Masuda, Esteban • Markovtsov, Vadim

Assignees

Rigel Pharmaceuticals Inc

Abstract

Provided herein are a variety of methods that involve administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient having or suspected of having a COVID-19 infection. In some embodiments, the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient having, suspected of having or expected to develop acute respiratory distress syndrome, acute kidney injury, and/or thrombosis. In some embodiments, the method may comprise administering fostamatinib, an active component thereof or a pharmaceutically acceptable salt thereof to a patient having, suspected of having or expected to develop symptoms associated with a cytokine response. Aspects of the methods may further include identifying a patient with kidney malfunction, e.g., acute kidney injury, and/or thrombosis.

Core Innovation

The invention provides metabolic design of cyclic and acyclic phosphate/phosphite ester prodrugs in which enzymatic cleavage occurs in vivo. The cleavage is esterase-triggered when the cyclic phosphate substituent Rh is hydrogen or lower alkyl, and liver CYP-mediated oxidative cleavage is used when Rh is aryl or heteroaryl. The prodrug design also includes phosphite and phosphite ester oxidative conversion to phosphate analogs by oxidative enzymes such as oxidase/oxoreductase.

The disclosed invention concerns methods of treatment that administer to a patient having, suspected of having, or expected to develop a disease state associated with COVID-19 infection. The methods include administering a compound of a claimed formula, or a pharmaceutically acceptable salt thereof, and use patient selection based on disease status. The disclosed embodiments link COVID-19-associated pathological responses to cytokine response and cytokine storm, and also cover coronavirus infections including SARS-CoV and MERS-CoV.

The disclosed invention further specifies treatment for acute respiratory distress syndrome, including patients having, suspected of having, or expected to develop acute respiratory distress syndrome. The disclosed description links acute respiratory distress syndrome to FcR/CLEC signaling and to SYK inhibition, including modulation of CLEC-dependent cytokine release, and also links FcγR-mediated ARDS to FcγRIIA/CLEC2/GPVI signaling and to NETosis in thrombosis contexts. The disclosed approach aims to preserve normal hemostasis while addressing these pathways.

A key stated aspect is improved solubility of the prodrug relative to the active compound, described as an increase of approximately 81–2000×, for example from about 1–2 μg/mL to greater than 5 mg/mL, to support oral dissolution and improved bioavailability. The disclosure additionally addresses formulation and composition options and provides extensive coverage of pharmaceutically acceptable salts, hydrates, solvates, and N-oxides. In addition, the disclosed invention relates to treating thrombosis/thrombotic events and acute kidney injury and kidney malfunction in the context of COVID-19-associated disease.

Claims Coverage

The independent claims cover administering compounds of the claimed formula (or pharmaceutically acceptable salts) for three treatment purposes: COVID-19 infection, acute respiratory distress syndrome, and sepsis. Across the dependent claims, the coverage includes additional inventive features relating to patient selection, delivery route, and structural-variant constraints for the administered compound.

Overall, the claim set provides treatment methods that administer compounds of a specified formula for COVID-19 infection, acute respiratory distress syndrome, and sepsis, with dependent coverage that refines patient selection using D-dimer and narrows administration to oral/IV systemic routes and pulmonary routes via inhaler or nebulizer. Additional dependent coverage constrains the administered compound to specific structural features shown in the figures.

Stated Advantages

Documented Applications