(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
Inventors
Assignees
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Publication Number
US-10383851-B2
Publication Date
2019-08-20
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 neuroprotection through administering posiphen, including (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate (Compound 1/Posiphen), to prevent or treat neurodegeneration. The described approach emphasizes human treatment regimens aimed at providing disease modification, symptomatic improvement, or both, in neurodegenerative disease contexts.
A central aspect is achieving specific PK targets for posiphen exposure, including peak plasma circulating level and duration above a threshold, together with brain exposure characterized by a brain:plasma ratio and steady-state plasma concentration. The invention links these exposure targets to a pharmacodynamic effect described as inhibition of neurotoxic aggregating proteins’ production, including APP/Aβ, alpha-synuclein (SNCA), SOD, Tau, prions, NAC, and HTT.
The background and mechanistic description connect neurodegeneration to protein misfolding/aggregation and translational control involving iron-regulated 5′UTR/IRP1/IRE, in which posiphen is positioned to inhibit production of disease-relevant neurotoxic proteins. The document further includes biomarker reductions in cerebrospinal fluid (CSF), including sAPPα, sAPPβ, and Tau/pTau, and frames the therapeutic use for dementia and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion disease, ALS, and tauopathies.
Claims Coverage
The document includes three independent claims directed to treating Parkinson’s disease and Lewy bodies disease in humans, and to providing disease modification in Parkinson’s and Lewy bodies disease. Across these independent claims, the main inventive features include once-a-day posiphen dosing within defined dosage ranges, pharmaceutical composition with pharmaceutically acceptable excipients, and linking the regimen to disease modification and/or symptomatic improvement, with certain dependent claims further specifying mechanistic SNCA production inhibition and route refinements.
Once-a-day posiphen composition for Parkinson’s and Lewy bodies disease
Administering to a population of human patients suffering from Parkinson’s disease or Lewy bodies disease a pharmaceutical composition consisting of from about 1 mg to about 30 mg of posiphen or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, on a once-a-day basis, such that the treatment provides disease modification, symptomatic improvement, or both.
Once-a-day posiphen composition within a 7.5 mg to 30 mg range
Administering to a population of human patients suffering from Parkinson’s disease or Lewy bodies disease a pharmaceutical composition consisting of from about 7.5 mg to about 30 mg of posiphen or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients on a once-a-day basis, such that the treatment provides disease modification, symptomatic improvement, or both.
Once-a-day posiphen composition for disease modification in Parkinson’s and Lewy bodies disease
Providing disease modification in Parkinson’s and Lewy bodies disease by administering to a population of human patients suffering from Parkinson’s disease or Lewy bodies disease a pharmaceutical composition consisting of from about 4 mg to about 20 mg of posiphen or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, on a once-a-day basis, such that the treatment provides disease modification, symptomatic improvement, or both.
Across the independent claims, the inventive coverage centers on once-a-day administration of posiphen-containing pharmaceutical compositions to humans with Parkinson’s disease and Lewy bodies disease, with specified posiphen dosage ranges and an asserted outcome of disease modification and/or symptomatic improvement. Dependent claims further narrow coverage by adding SNCA production inhibition and by specifying oral or parenteral routes.
Stated Advantages
Disease modification.
Symptomatic improvement.
Both disease modification and symptomatic improvement.
Documented Applications
Treating Parkinson’s disease and Lewy bodies disease in humans by administering posiphen-containing pharmaceutical compositions.
Providing disease modification in Parkinson’s and Lewy bodies disease in humans using once-a-day posiphen-containing pharmaceutical compositions.
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