Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
Inventors
Rosen, Kenneth M. • Riesinger, Steven Wayne • McKerracher, Lisa • Bond Moritz, Lisa
Assignees
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Publication Number
US-11701366-B2
Publication Date
2023-07-18
Expiration Date
Abstract
Provided are methods of treating a cerebral cavernous malformation (CCM) and methods of treating cerebral aneurysm in a mammal with certain rho kinase inhibitors.
Core Innovation
The disclosure describes prophylactic and therapeutic use of rho kinase inhibitors for treating neurological conditions, including cerebral cavernous malformations (CCM/cavernous angioma/cavernoma) and cerebral aneurysms, including cerebral saccular aneurysms, in mammals. It links rho kinase (ROCK)/Rho overactivation to endothelial barrier disruption, impaired angiogenesis, increased permeability and leakage, and aneurysm formation and rupture, and states that ROCK inhibition can rescue endothelial phenotypes and improve vascular-related defects associated with these conditions.
The disclosure emphasizes ROCK2-selective rho kinase inhibitor formulations, including BA-1049 and its (R)-enantiomer and racemate, as well as other candidate ROCK inhibitors listed in the disclosure. It describes oral pharmaceutical formulations comprising a therapeutically effective amount of a rho kinase inhibitor for treatment in a patient to reduce one or more symptoms of the neurological condition, and includes pharmaceutically acceptable salts and formulations in the therapeutic context.
Mechanistic and biological characterization in the disclosure includes assessment of ROCK I versus ROCK II expression and localization, endothelial cell barrier integrity-related readouts, and biomarkers consistent with target engagement and reduced ROCK activity. The disclosure reports endpoints that include reductions in lesion and aneurysm number and size, changes in lesion or aneurysm maturation stages, and related measures such as iron deposition/leakage and inflammation, alongside endothelial proliferation-related outcomes, and it also describes comparison against Fasudil within the overall experimental support described.
Claims Coverage
The partial content identifies one independent method claim and multiple dependent refinements, including additional specification of neurological condition(s) and formulation/salt details. Across the independent claim and its dependent refinements, the coverage focuses on oral administration of a therapeutically effective amount of a specific rho kinase inhibitor compound (Compound 1) or a pharmaceutically acceptable salt to reduce one or more symptoms of specified neurological conditions.
Oral administration of Compound 1 for symptom reduction
A method for treating a patient having a neurological condition by orally administering a pharmaceutical formulation comprising a therapeutically effective amount of a rho kinase inhibitor, where the rho kinase inhibitor is Compound 1 or a pharmaceutically acceptable salt, wherein administering the pharmaceutical formulation results in reduction of one or more symptoms of the neurological condition.
Neurological condition scope including CCM, aneurysm, and CCM mutations
The neurological condition is any of cerebral cavernous malformation, cavernous angioma, stroke, cerebral aneurysm, vasospasm, subarachnoid hemorrhage, cavernoma, a mutation in CCM1, a mutation in CCM2, a mutation in CCM3, or combinations thereof.
Cavernous angioma as a specific treated neurological condition
A refinement where the neurological condition is cavernous angioma.
Symptom and feature defined neurological condition coverage
A refinement where the neurological condition is characterized by one or more specified symptoms, including symptomatic hemorrhage and other listed neurological and vascular/endothelial/Rho signaling-related features.
Compound 1 provided as pharmaceutically acceptable salt with counterion
A refinement defining that Compound 1 is provided as a pharmaceutically acceptable salt with a pharmaceutically acceptable counterion.
Pharmaceutical formulation including pharmaceutically acceptable carrier
A refinement defining that the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.
Lesion and aneurysm reduction and maturation changes in CCM and cerebral aneurysms
A refinement in which treatment results in specific reductions and maturation changes for cerebral cavernous malformation lesions, cerebral aneurysms including saccular aneurysms, and cavernomas, including reductions in number and or size and reductions in maturation into clinically significant lesions or aneurysms.
Overall, the claim set in the partial content covers oral treatment using a rho kinase inhibitor specified as Compound 1 or pharmaceutically acceptable salts to reduce one or more symptoms across a defined set of neurological conditions, with dependent coverage narrowing to cavernous angioma and to symptom or feature defined manifestations, and additional formulation refinements plus specified lesion and aneurysm number, size, and maturation reduction outcomes.
Stated Advantages
Reduction of one or more symptoms of the neurological condition.
Documented Applications
Therapeutic use in a patient for neurological conditions including cerebral cavernous malformation, cavernous angioma, cavernoma, and cerebral aneurysm including cerebral saccular aneurysm, in mammals, using prophylactic and therapeutic ROCK inhibitor formulations.
Use of ROCK2-selective rho kinase inhibitor formulations, including BA-1049, its (R)-enantiomer and racemate, and other candidate ROCK inhibitors, as supported by mechanistic and efficacy endpoints described in the disclosure.
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