Methods for treating neurological disorders
Inventors
TOLAR, Martin • Hey, John A. • Kocis, Petr • Yu, Jeremy
Assignees
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Publication Number
US-10471029-B2
Publication Date
2019-11-12
Expiration Date
Abstract
Disclosed herein are methods and compositions for treating, ameliorating, and/or preventing Alzheimer's disease in ApoE4-postitive patients using particular compounds and compositions thereof.
Core Innovation
The invention relates to treating and/or preventing Alzheimer’s disease in ApoE4-positive patients, including homozygous and heterozygous patients, by using tramiprosate and/or a tramiprosate prodrug, Val-APS (L-valyl-3-aminopropanesulfonate). The disclosed approach includes selecting a patient as having a tramiprosate-sensitive form of Alzheimer’s disease based on the presence of two ApoE4 alleles, and then administering a compound effective to treat the disease.
A central aspect is the use of Val-APS, a tramiprosate prodrug, where Val-APS is described as having advantages over tramiprosate in gastrointestinal tolerability and pharmacokinetic behavior. The document associates Val-APS with reduced nausea/vomiting, decreased inter-subject PK variability, and an extended tramiprosate half-life that enables once-daily dosing, while increasing plasma and brain exposure.
The disclosure further describes compound embodiments for the prodrug and related chemical scaffolds, including Formula I and Formula II, with side chains including amino acid substituents (AA1/AA2 or AA1). The patent summary also references preferred prodrug-related embodiments, including OBnSer/OBnGlu variants, and characterizes performance using measures of cognition and function such as ADAS-cog and CDR-SB in ApoE4 subgroups.
Claims Coverage
The document includes two independent methods. Across them, there are three main inventive components: patient selection by ApoE4 allele status to define tramiprosate sensitivity, administration of tramiprosate (independent method 1), and administration of a formula-defined compound (independent method 3).
Selecting a patient based on two ApoE4 alleles
Selecting the patient as having a tramiprosate-sensitive form of Alzheimer's disease based on the presence of two ApoE4 alleles.
Administering tramiprosate effective to treat
Administering to the selected patient tramiprosate in an amount effective to treat the disease.
Administering a compound of a formula effective to treat
Administering to the selected patient a compound having the formula in an amount effective to treat the disease.
Both independent claims require identifying a tramiprosate-sensitive form of Alzheimer’s disease using the presence of two ApoE4 alleles and then administering an amount effective to treat the disease, either by giving tramiprosate or by giving a compound of the disclosed formula.
Stated Advantages
Improved GI tolerability compared to tramiprosate.
Reduced nausea/vomiting.
Decreased inter-subject PK variability.
Extended tramiprosate half-life enabling once-daily dosing.
Increased plasma/brain exposure.
Documented Applications
Treating and/or preventing Alzheimer’s disease in ApoE4-positive patients by selecting tramiprosate-sensitive patients based on two ApoE4 alleles and administering tramiprosate or a tramiprosate prodrug (Val-APS).
Using Val-APS to improve pharmacokinetic/brain exposure behavior, as evaluated with brain accumulation/half-life comparisons and cognition/function measures including ADAS-cog and CDR-SB in ApoE4+ subgroups.
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