Compositions for treating amyotrophic lateral sclerosis
Inventors
Cohen, Daniel • Nabirochkin, Serguei • Chumakov, Ilya • HAJJ, RODOLPHE
Assignees
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Publication Number
US-10342784-B2
Publication Date
2019-07-09
Expiration Date
Abstract
The present invention relates to compositions and methods for the treatment of amyotrophic lateral sclerosis. More specifically, the present invention relates to novel combinatorial therapies for treating amyotrophic lateral sclerosis or a related disorder.
Core Innovation
The invention relates to combinatorial therapies for amyotrophic lateral sclerosis (ALS) and related motor neuron disorders, using a composition comprising mexiletine and cinacalcet, or salts, prodrugs, or sustained-release formulations thereof, administered in an effective amount to a subject suffering from ALS. The described approach is optionally combined with riluzole as an additional component.
The problem addressed is motor neuron degeneration in amyotrophic lateral sclerosis and related motor neuron disorders, including the need for treatments that provide therapeutic benefit, including in contexts where glutamate toxicity is implicated. The disclosed compositions and administration include co-administration, separate administration, and sequential administration, including oral and controlled-/sustained-release formulations.
The disclosed rationale includes protection against glutamate toxicity, supported by in vitro neuronal and nerve-muscle co-culture model results indicating protection and synergy at low drug doses. The invention further includes in vivo efficacy in an SOD1-G93A mouse model, showing improved clinical scoring and behavioral performance, including when the combinatorial therapy is used as adjuncts to riluzole.
Example combinations disclosed in the document include mexiletine-cinacalcet, baclofen-acamprosate, and sulfisoxazole-torasemide, together with dosage ranges for key agents in certain embodiments. The claimed scope includes the use of related motor neuron disorder subtypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), pseudobulbar palsy (PBP), progressive bulbar palsy (PBP), and frontotemporal dementia (FTD).
Claims Coverage
The partial content provides three independent claims. Across these independent claims, the main inventive features revolve around specific named multi-agent drug combinations and their included forms, plus specified adjunct use with riluzole for glutamate toxicity protection.
Mexiletine plus cinacalcet composition for treating ALS or related motor neuron disorder
Administering to a subject suffering from amyotrophic lateral sclerosis (ALS) or a related motor neuron disorder an effective amount of a composition comprising mexiletine and cinacalcet, or salts, or prodrugs, or sustained-release formulations thereof.
Mexiletine plus cinacalcet plus riluzole composition for protecting neuromuscular junctions against glutamate toxicity
Administering to a subject in need thereof a composition comprising mexiletine, cinacalcet and riluzole to protect neuromuscular junctions against glutamate toxicity.
Pharmaceutical composition comprising mexiletine, cinacalcet and riluzole
Providing a pharmaceutical composition comprising mexiletine, cinacalcet and riluzole, or salts, or prodrugs, or sustained-release formulations thereof.
The independent claim coverage centers on administering a therapeutically effective multi-agent composition containing mexiletine and cinacalcet for treating ALS or related motor neuron disorders, and on formulations that further include riluzole for protecting neuromuscular junctions against glutamate toxicity, as well as a corresponding pharmaceutical composition claim covering mexiletine, cinacalcet, and riluzole together.
Stated Advantages
Improved clinical scoring and behavioral performance in an SOD1-G93A mouse model.
Protection against glutamate toxicity in vitro, including neuronal and nerve-muscle co-culture model results showing synergy and strong effects at low drug doses.
Adjunct use with riluzole is described in connection with in vivo efficacy.
Documented Applications
Treating amyotrophic lateral sclerosis (ALS) or a related motor neuron disorder in a subject suffering thereof.
Protecting neuromuscular junctions against glutamate toxicity in a subject in need thereof.
Application to related motor neuron disorder subtypes including primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), pseudobulbar palsy, progressive bulbar palsy, and frontotemporal dementia (FTD).
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