Methods for treating neurodegenerative disorders
Inventors
Hey, John • Kocis, Petr • TOLAR, Martin • FLANZRAICH, NEIL WILLIAM
Assignees
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Publication Number
US-12083082-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Tramiprosate and derivatives thereof are provided herein for treating neurodegenerative disorders such as Alzheimer's disease (AD).
Core Innovation
The invention discloses discovery and characterization of endogenous 3-sulfopropanoic acid (3-SPA) in human cerebrospinal fluid (CSF) and plasma, including in drug-naive subjects. The disclosed endogenous 3-SPA is associated with anti-Aβ42 oligomer effects that are described as comparable to tramiprosate. The document further reports an inverse correlation between CSF 3-SPA concentration and cognitive impairment severity, including Mini Mental State Examination (MMSE) measures such as MMSE=30 being a best-fit level.
The disclosed relationship between CSF 3-SPA concentration and cognitive impairment severity motivates selecting subjects based on a baseline threshold. The selection concept is described as using a threshold level of 3-SPA, including a baseline threshold that is described as approximately <10% of MMSE=30 best-fit level. The invention then includes administering Formula I compounds, including compounds where R is —COOH and related amino-acid substituents, and/or related prodrugs/precursors that increase brain 3-SPA.
The document also provides subject stratification options, including stratification by MMSE range and by APOE4 genotype categories. The stratification is described alongside treatment and prevention of Alzheimer’s disease outcomes, including preventing dementia and cognitive decline, including post–head trauma dementia. The invention further includes extensive embodiments and chemical structures for Formula I variants, including pharmaceutically acceptable salts.
Claims Coverage
The supplied independent claims cover two inventive features: (i) treating a subject suffering from Alzheimer’s disease by administering a Formula I compound, and (ii) preventing cognitive decline and preventing dementia by administering pharmaceutical compositions comprising a compound of a stated formula and pharmaceutically acceptable salts together with pharmaceutically acceptable carriers.
Alzheimer’s disease treatment with Formula I compound (R = —COOH)
A method of treating a subject suffering from Alzheimer's disease comprising administering to the subject an effective amount of a compound having the Formula I (or a pharmaceutically acceptable salt thereof), wherein R is —COOH.
Preventing cognitive decline via Formula-based composition with pharmaceutically acceptable carrier
A method of preventing cognitive decline in a subject comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of the formula (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.
Preventing dementia via Formula-based composition with pharmaceutically acceptable carrier
A method of preventing dementia in a subject comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of the formula (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.
Overall, the claim set indicates that Formula I/Formula-based compounds, including pharmaceutically acceptable salts, are used to treat Alzheimer’s disease when R is —COOH and to prevent cognitive decline and dementia by administering pharmaceutical compositions that include the formula compound(s) and pharmaceutically acceptable carriers. Dependent claim refinements further narrow eligibility using MMSE score ranges and APOE4 genotype categories.
Stated Advantages
Anti-Aβ42 oligomer effects comparable to tramiprosate.
Inverse correlation between CSF 3-SPA concentration and cognitive impairment severity.
Subject selection based on 3-SPA baseline threshold for treatment/prevention.
Prevention of dementia and cognitive decline, including post–head trauma dementia.
Documented Applications
Treating a subject suffering from Alzheimer's disease.
Preventing cognitive decline in a subject.
Preventing dementia in a subject, including post–head trauma dementia.
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