Compositions and methods for treating synucleinopathies
Inventors
Chase, Thomas N. • Clarence-Smith, Kathleen E.
Assignees
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Publication Number
US-10799484-B2
Publication Date
2020-10-13
Expiration Date
Abstract
The present invention describes the use of a 5HT3-antagonist, in combination with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, to reduce adverse effects and to facilitate the neuroprotective treatment of a patient suffering from a synucleinopathic disorder to enable a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine daily dose without the dose-limiting adverse effects caused by pramipexole when administered alone.
Core Innovation
The document describes a method for treating a synucleinopathy in a patient by administering, in combination, a 5HT3-antagonist and a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine. The approach combines a 5HT3-antagonist, for example ondansetron, with a pramipexole-related compound, for example dexpramipexole or pramipexole, to address dose-limiting gastrointestinal adverse effects associated with pramipexole treatment.
Mechanistically, the combination is stated to normalize the monomeric-to-oligomeric alpha-synuclein ratio in CNS-derived plasma exosomes. Alpha-synuclein oligomerization and aggregation are referenced as relevant pathological features associated with synucleinopathies, including Parkinson’s disease, Lewy body dementia, multiple system atrophy, and GBA-related parkinsonism.
The document further describes fixed-dose combinations and co-administered pharmaceutical formulations, including oral formulations and transdermal therapeutic systems. An example is provided as a Phase I single-blind study in which adding ondansetron is described as increasing the maximum tolerated dose of pramipexole, preventing gastrointestinal dose-limiting toxicity, and yielding higher first intolerable dose and maximum tolerated dose compared with pramipexole alone.
Claims Coverage
The independent claim covers a daily-dose combination therapy for treating a synucleinopathy using two drug classes: a 5HT3-antagonist and a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine. The inventive features across the claim set are the combination regimen itself and dependent limitations on indication, dosage ranges, and specific drug embodiments.
Daily administration of 5HT3 antagonist with benzothiazole-2-amine for synucleinopathy treatment
Administering to a patient in need thereof an effective daily dose of a 5HT3-antagonist in combination with a therapeutically effective daily dose of a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine.
Synucleinopathy selected from Parkinson’s disease, Lewy body dementia, glucocerebrosidase gene mutations, or multiple system atrophy
Treating the synucleinopathy as selected from Parkinson's disease, Lewy body dementia, mutations in the glucocerebrosidase gene, and multiple system atrophy.
Effective daily dose range for the 5HT3 antagonist
Using an effective daily dose of the 5HT3 antagonist in the range of 1 mcg to 300 mg.
Benzothiazole-2-amine embodiment as pramipexole dihydrochloride monohydrate in a specified amount per unit form
Using 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine as pramipexole dihydrochloride monohydrate in an amount per unit form of 6.5 mg to 42 mg.
Ondansetron hydrochloride dihydrate and pramipexole dihydrochloride monohydrate in specified amounts relative to ondansetron base
Using a composition in which the 5HT3 antagonist is ondansetron hydrochloride dihydrate and pramipexole dihydrochloride monohydrate is present at specified amounts relative to ondansetron base.
Co-formulation in a dosage unit pharmaceutical composition with pharmaceutical carrier or vehicle and per-unit amount ranges
Co-formulating a 5-HT3-antagonist with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine in a dosage unit pharmaceutical composition mixed with a pharmaceutical carrier or vehicle, with antagonist per unit from 1 µbcg to 300 mg and the benzothiazole compound per unit from 0.125 mg to 3000 mg.
Overall, the claim coverage centers on daily administration of a 5HT3-antagonist combined with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine for synucleinopathy treatment, with dependent limitations specifying particular synucleinopathy categories and defining dosage ranges and specific drug embodiments, including ondansetron hydrochloride dihydrate and pramipexole dihydrochloride monohydrate, as well as dosage-unit co-formulation constraints.
Stated Advantages
Widening the pramipexole therapeutic window by reducing dose-limiting gastrointestinal adverse effects.
Enabling substantially higher pramipexole/(S)-enantiomer doses.
Increasing maximum tolerated dose of pramipexole by preventing gastrointestinal dose-limiting toxicity, with higher first intolerable dose and maximum tolerated dose versus pramipexole alone.
Normalizing the monomeric-to-oligomeric alpha-synuclein ratio in CNS-derived plasma exosomes.
Documented Applications
Treating synucleinopathies including Parkinson’s disease, Lewy body dementia, multiple system atrophy, and GBA-related parkinsonism.
A Phase I single-blind study describing use of adding ondansetron to increase maximum tolerated dose of pramipexole.
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