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-10149856-B2
Publication Date
2018-12-11
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 invention relates to preventing and treating cerebral cavernous malformations (CCMs) and cerebral aneurysms in a mammal using rho kinase (ROCK) inhibitors, with an emphasis on ROCK2-selective inhibitors. The document links rho/ROCK overactivation to endothelial barrier dysfunction and leakage, which are associated with lesion and aneurysm pathology in CCMs.
The document describes methods that administer a pharmaceutical formulation comprising an (R)-enantiomer of a rho kinase inhibitor, or a pharmaceutically acceptable salt thereof. It also identifies candidate rho kinase inhibitors and distinguishes ROCK I versus ROCK II selectivity, including the use of ROCK2-selective inhibition to address CCM and cerebral aneurysm pathology.
The disclosed treatment includes assessing endpoints related to lesion or aneurysm reduction and maturation, including number, size, and maturation for CCM lesions and corresponding aneurysm outcomes. The document also describes mechanistic and comparative evaluations of ROCK inhibition effects on endothelial junctional and actin cytoskeleton-associated markers, and compares the performance of ROCK inhibitors in relevant CCM and aneurysm models.
The document describes in vivo and in vitro assessment of rho-kinase inhibitors, including BA-1049 ((R) and racemate) and Fasudil, for intracranial vascular disorders, including cerebral cavernous malformation (CCM). It further describes analogous in vivo rat aneurysm studies using an intracranial saccular aneurysm context, and in vitro ADME-supporting data for oral absorption potential, including Caco-2 permeability and equilibrium dialysis.
Claims Coverage
The independent claim family covers treatment of CCM in a mammal by administering a therapeutically effective amount of a pharmaceutical formulation comprising an (R)-enantiomer or a pharmaceutically acceptable salt. Dependent claims add oral administration, tablet or capsule dosage forms, combination therapy with at least a second rho kinase inhibitor, and selection of the second inhibitor from specified candidates.
(R)-enantiomer rho kinase inhibitor formulation for CCM treatment
Administering to the mammal a therapeutically effective amount of a pharmaceutical formulation comprising an (R)-enantiomer thereof, or a pharmaceutically acceptable salt thereof, for treating a cerebral cavernous malformation (CCM).
Oral administration of the CCM formulation
Administering the pharmaceutical formulation orally for treating the CCM.
Tablet or capsule dosage form for CCM treatment
Providing the pharmaceutical formulation as a tablet or a capsule for use in the CCM treatment method.
Combination therapy with at least a second rho kinase inhibitor
Administering to the mammal a therapeutically effective amount of at least a second rho kinase inhibitor, and thereby performing the CCM treatment method with combination therapy.
Selected second rho kinase inhibitor from specified candidates
Performing the method using an additional rho kinase inhibitor selected from BA-1042, BA-1043, BA-1044, BA-1050, BA-1051, C3, KD025, Rhopressa, Roclatan, AR-13533, Fasudil, HA-1077, Radicut, azaindole 1, BF66851, BF66852, BF66853, or Y27632.
The claim set centers on CCM treatment in a mammal using a therapeutically effective amount of a pharmaceutical formulation comprising an (R)-enantiomer or a pharmaceutically acceptable salt, with dependent coverage for oral administration and tablet or capsule dosage forms. Additional dependent coverage extends to combination therapy that includes at least a second rho kinase inhibitor, including embodiments where the second inhibitor is selected from a specified list of named candidates.
Stated Advantages
Reduces or treats cerebral cavernous malformations (CCMs) by using rho kinase inhibitor formulations, including (R)-enantiomer and ROCK2-selective approaches as described in the partial content.
Provides a treatment framework that can include combination therapy with at least a second rho kinase inhibitor for CCM treatment as described in the claims and partial content.
Reduces lesion burden and lesion severity markers in CCM models.
Supports prophylactic treatment.
Reduces aneurysm burden in intracranial saccular aneurysm studies.
Provides in vitro support for oral absorption potential (Caco-2 permeability and equilibrium dialysis showing low plasma protein binding and essentially complete recovery).
Documented Applications
Preventing and treating cerebral cavernous malformations (CCMs) in a mammal using rho kinase (ROCK) inhibitor pharmaceutical formulations comprising an (R)-enantiomer or pharmaceutically acceptable salt.
Preventing and/or treating cerebral aneurysms using rho kinase (ROCK) inhibitors, as described in the partial content.
Implementations that use oral administration and tablet or capsule dosage forms for CCM treatment, as refined by dependent claims.
Combination approaches that include at least a second rho kinase inhibitor as part of the CCM treatment method, including embodiments using listed second-inhibitor candidates by name.
Treatment of cerebral cavernous malformation (CCM) in a mammal, including evaluation in mice with existing CCM lesions using MRI and histology endpoints.
Prophylactic treatment in the context of CCM lesions, as supported by the document’s reported outcomes.
Intracranial saccular aneurysm evaluation in rats, including quantification of aneurysm number/size and severity endpoints using MRI, vascular corrosion casts/SEM, and histology.
In vitro assessment supporting oral bioavailability potential, including Caco-2 permeability and equilibrium dialysis for plasma protein binding.
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