(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-11376238-B2
Publication Date
2022-07-05
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 invention relates to Compound (1), Posiphen® ((3aR)-1,3a,8-trimethyl-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate), and pharmaceutically acceptable salts, for use as a therapeutic for neurodegeneration and dementia. The document identifies neurotoxic aggregating proteins, including APP/Aβ, SNCA/alpha-synuclein, prions, SOD, Tau, and HTT, as being linked by shared misfolding and translation regulation mechanisms involving 5′UTR/IRP1-IRE-like elements.
The therapeutic rationale states that posiphen (Compound (1)) and metabolites inhibit production and aggregation of neurotoxic proteins, and that this is reflected in reduced cerebrospinal fluid (CSF) biomarkers. The document further reports pharmacokinetic performance targets for plasma and brain exposure, including peak plasma circulating level and sustained plasma levels, and a brain-to-plasma ratio.
The document describes clinical and translational intent for using posiphen-based compositions to treat neurodegenerative disorders that include Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease (HD), prion diseases, ALS, and tauopathies, with treatment through administration of a pharmaceutical composition comprising posiphen (and/or salts). It also states an additional mechanistic feature that the pharmaceutical composition inhibits the synthesis of HTT.
Claims Coverage
The provided claim set includes two independent methods for ameliorating Huntington’s disease in a human patient, each grounded in daily administration of posiphen (or a pharmaceutically acceptable salt) within specified dose ranges together with pharmaceutically acceptable excipients. Across the independent claims, the inventive feature coverage centers on a daily dosing regimen for Huntington’s disease and, in the claim family, inhibition of HTT synthesis as a functional biological effect.
Daily administration of posiphen for ameliorating Huntington's disease
A method of ameliorating Huntington's disease in a human patient by 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 Huntington's disease.
Daily administration regimen for ameliorating Huntington's disease with posiphen composition
A method of ameliorating Huntington's disease in a human patient by 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, to a human patient suffering from Huntington's disease.
Inhibition of HTT synthesis
The pharmaceutical composition inhibits the synthesis of HTT.
The independent claims define methods to ameliorate Huntington’s disease using posiphen (or a pharmaceutically acceptable salt) in a specified daily dose range together with pharmaceutically acceptable excipients, with further claim-family coverage describing quantitative pharmacokinetic parameters and, as a functional mechanism, inhibition of HTT synthesis.
Stated Advantages
Reduces CSF biomarkers by percentages described in the document for sAPPα, sAPPβ, Tau, and pTau.
Inhibits production/aggregation of neurotoxic proteins through posiphen (and metabolites).
Achieves pharmacokinetic targets including peak plasma level, sustained plasma levels, and brain-to-plasma ratio described in the document.
Documented Applications
Therapeutic use for neurodegeneration and dementia, including treatment of Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease (HD), prion diseases, ALS, and tauopathies.
Amelioration of Huntington’s disease in a human patient by administering a pharmaceutical composition containing posiphen (or a pharmaceutically acceptable salt).
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