Methods of treating central nervous system disorders via administration of nanoparticles of an mTOR inhibitor and an albumin
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Publication Number
US-12324860-B2
Publication Date
2025-06-10
Expiration Date
Abstract
The present application provides methods of treating a CNS disorder (such as glioblastoma and epilepsy) in an individual, comprising systemically (e.g., intravenously or subcutaneously) administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, such as sirolimus or a derivative thereof) and an albumin, optionally further comprising administering a second agent (such as an anti-VEGF antibody, a proteasome inhibitor, or an alkylating agent).
Core Innovation
The invention relates to treating epilepsy in an individual by systemically administering a composition comprising nanoparticles comprising albumin-bound sirolimus, where the ratio of albumin to sirolimus in the nanoparticles is from about 1:1 to about 9:1. The invention further addresses medically intractable epilepsy contexts, including cortical dysplasia/type 2A/2B and seizure-related criteria used to define eligible individuals.
The partial content also describes patient selection using mTOR-activation aberrations and aberrant expression, activity, and phosphorylation markers associated with mTOR signaling outputs. Examples include phosphorylated 4EBP1, phosphorylated S6K, and phosphorylated AKT, together with genes associated with mTOR signaling and related pathways.
In addition, the partial content describes mTOR inhibitor albumin-bound nanoparticle composition embodiments, including albumin/HSA as a stabilizer and surfactant-free and/or Cremophor-free embodiments. Further composition detail includes nanoparticle diameter specifications, albumin-to-sirolimus weight ratios within the claimed range, and crosslinking/disulfide aspects as described.
Claims Coverage
The independent claim covers a method of treating epilepsy via systemic administration of albumin-bound sirolimus nanoparticles with an albumin:sirolimus ratio of about 1:1 to about 9:1. The related claim set further includes patient-selection features based on mTOR-activation aberrations and additional nanoparticle-parameter constraints.
Systemic administration of albumin-bound sirolimus nanoparticles with an albumin:sirolimus ratio of 1:1 to 9:1
Treating epilepsy in an individual by systemically administering an effective amount of a composition comprising nanoparticles comprising albumin-bound sirolimus, wherein the ratio of albumin to sirolimus in the nanoparticles is from about 1:1 to about 9:1.
Nanoparticle average diameter no greater than about 200 nm
The nanoparticle composition has an average nanoparticle diameter of no greater than about 200 nm.
Parenteral administration
The nanoparticle composition is administered to an individual parenterally.
mTOR-activation aberration-based individual selection
Selecting an individual for treatment based on whether they have an mTOR-activation aberration.
mTOR-activating aberration occurring in specified mTOR-associated genes
The mTOR-activating aberration is an aberration occurring in one or more genes selected from PTEN, TSC1, TSC2, AKT1, MTOR, PI3K, PIK3CA, PIK3CG, RHEB, TP53, NF1, NF2, FGFR4, and BAP1.
Overall, the claims coverage centers on treating epilepsy using systemically administered albumin-bound sirolimus nanoparticles with a specified albumin:sirolimus ratio, optionally narrowed by nanoparticle size, administration route, and selection of individuals having mTOR-activation aberrations tied to specified gene sets.
Stated Advantages
Surprising BBB penetration and sustained CNS presence after systemic administration.
Improved treatment outcomes framed through response measures and PFS/OS and symptom amelioration.
Documented Applications
Treatment of epilepsy in an individual using a nanoparticle composition comprising albumin-bound sirolimus (ABI-009).
Clinical study use in recurrent high-grade glioma, including ABI-009 alone and in combination with bevacizumab, MRZ/marizomib, and CCNU.
Clinical study use in newly diagnosed glioblastoma, including example regimens of ABI-009 alone and in combination with TMZ/RT with RANO 2010 ORR as a primary endpoint and MRI/PFS/OS assessment timing.
Phase I single-center safety study concept for surgically refractory epilepsy using weekly IV ABI-009 with seizure-frequency outcomes and mild AEs reporting.
Preclinical PK/biodistribution and toxicology application involving brain rapamycin exposure and comparisons of brain distribution persistence versus rapid blood clearance, and subcutaneous bioavailability versus intravenous [procedural detail omitted for safety].
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