(3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate and methods of treating or preventing neurodegeneration
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Publication Number
US-11382893-B2
Publication Date
2022-07-12
Expiration Date
Abstract
The invention includes an amount of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate for administering to a subject and also a method of preventing or treating neurotoxicity or neurodegenerative processes in a subject in need thereof using the amount thereof.
Core Innovation
The described invention provides methods for preventing or treating neurodegeneration and neurotoxicity by administering posiphen, also referred to as (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate (Compound (1)), or a pharmaceutically acceptable salt thereof. The approach is framed around achieving defined plasma pharmacokinetic/pharmacodynamic targets through administration of a pharmaceutical composition with pharmaceutically acceptable excipients.
The document connects Compound (1) to disease-modifying effects by lowering APP/Aβ and by translating other neurotoxic aggregating proteins, including α-synuclein and prion-associated proteins, via IRP1/IRE 5′UTR-mediated regulation. Background and biomarker rationale are provided using cerebrospinal fluid markers such as sAPPα, sAPPβ, Tau, and p-Tau, linking target engagement and therapeutic effect to measurable markers.
For practical implementation, the document specifies human treatment with a once-a-day basis and constrains exposure relationships, including peak plasma circulating levels and plasma maintenance durations, as well as brain-to-plasma level relationships and metabolite references (Compounds (2)–(4)). A proof-of-mechanism human study context is described, including treatment of MCI patients, alongside additional examples relating to amyloid reduction and pharmacokinetic differences across species.
Claims Coverage
The independent claim coverage centers on ameliorating Prion’s disease in a human patient by once-daily administration of posiphen or a pharmaceutically acceptable salt thereof within a specified daily dose range, with pharmaceutically acceptable excipients. The claim set further adds route-of-administration options, pharmacokinetic exposure constraints, and a functional requirement tied to inhibiting prion production.
Once-daily posiphen dosing with defined daily amount range
Administering a pharmaceutical composition consisting of posiphen or a pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/day to about 30 mg/day together with one or more pharmaceutically acceptable excipients, on a once a day basis to a human patient suffering from Prion's disease.
Route-specific once-daily administration of posiphen
Administering posiphen or a pharmaceutically acceptable salt once daily with a specified route of administration, including orally and intravenously, each with respective daily dose ranges as stated in the dependent claim text.
Exposure control by peak plasma level range
Using a method such that the peak plasma circulating level of posiphen in a human patient ranges from about 10 ng/mL to about 160 ng/mL.
Exposure control by maintaining plasma level threshold over time
Maintaining the plasma circulating level of posiphen at a value equal to or greater than about 20 ng/mL for at least 9 hours after administering the pharmaceutical composition.
Functional requirement to inhibit prion production
Including using a pharmaceutical composition that inhibits the production of prions in humans.
Overall, the claims focus on once-a-day administration of posiphen or a salt with pharmaceutically acceptable excipients to ameliorate Prion’s disease, and further narrow the regimen through route-of-administration specification, quantitative plasma exposure constraints, and a requirement that the composition inhibits prion production.
Stated Advantages
Documented Applications
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