HK1141735A - Novel combinations of neramexane for the treatment of neurodegenerative disorders - Google Patents

Description

New composition of neramexane for the treatment of neurodegenerative diseases

Technical Field

[0001] The present invention relates to compositions comprising neramexane and a Glutamate Release Inhibitor (GRI), and the use of such compositions in the treatment of neurodegenerative diseases.

Background

[0002] Glutamate is the major excitatory neurotransmitter in the CNS, and glutamate dysfunction is implicated in the symptomology of acute neurodegenerative diseases (e.g., stroke and injury), chronic neurodegenerative diseases (e.g., parkinson's disease, alzheimer's disease, huntington's disease, ALS), and many neurological and psychiatric diseases (e.g., epilepsy, parkinson's disease, drug dependence, depression, anxiety and chronic diseases).

[0003] Excitotoxicity promotes neuronal degeneration in a number of CNS disorders, including ischemia, injury and epilepsy, as well as chronic disorders such as Alzheimer's Disease (AD), parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). Glutamate activates postsynaptic receptors, including ionotropic N-methyl-D-aspartate (NMDA) receptors. Over-activation of NMDA receptors has been hypothesized to play a key role in neurodegenerative diseases [ Krieger et al, c.trends Pharmacol Sci, 1996, 17, 114-; danysz et al, NeurotoxRes, 2002, 4, 119-; arundine and Tymianski, Cell Calcium, 2004, 34, 325-.

[0004] Motor neuron diseases are neurodegenerative diseases which involve the progressive loss of motor neurons. Examples of motor neuron diseases include Amyotrophic Lateral Sclerosis (ALS), virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

[0005] The use of Glutamate Release Inhibitors (GRIs), such as riluzole, lamotrigine, phenytoin, gabapentin, pregabalin and lubeluzole, has been suggested as a promising approach to the treatment of neurodegenerative diseases. Because of the mode of action of GRI, i.e., blocking glutamate transmission before it blocks neuronal firing during a period when it becomes neurotoxic or seizures, GRI is considered to be effective in treating neurodegenerative diseases [ Benismon et al, N Engl J Med, 1994, 330, 585-; lacomblez et al, Lancet, 1996, 347, 1425-.

[0006] Amyotrophic Lateral Sclerosis (ALS) involves both upper and lower motor neurons. The disease exists in both sporadic and genetic forms, which are clinically indistinguishable. The mechanisms underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease are still unknown; however, an important hypothesis for selective motor neuron death is glutamate-mediated excitotoxicity [ Rothstein, et al, Clin Neurosci, 1995, 3, 348-.

[0007]Riluzole, also known as 2-amino-6-trifluoromethoxybenzothiazole or 6- (trifluoromethoxy) benzothiazol-2-amine, is the only drug approved for the treatment of Amyotrophic Lateral Sclerosis (ALS) and is currently being treated by Sanofi AventisAnd (5) selling. Riluzole showed improvement in bulbar and limb function, but only a minor improvement in survival time, albeit statistically significant (i.e., up to 90 days as compared to placebo). Thus, there is a need for improved drug therapy for ALS.

[0008] Approximately 20% of cases of ALS are monogenic and autosomal dominant (familial ALS-fALS). The most common cause of fALS is a point mutation in the gene encoding superoxide dismutase 1(SOD1), an enzyme responsible for the scavenging of peroxide ions (SOD1) [ Rosen et al, Nature.1993; 362(6415): 59-62].

[0009] The pathological hallmarks of ALS are degeneration of the lower motor neurons in the brainstem and spinal cord, and the upper motor neurons in the motor cortex, as well as the corticospinal tract, with reactive gliosis. Although many possible mechanisms have been proposed in ALS that emanate in association with SOD1, the exact pathogenesis of selective motor neuron death in ALS has not been elucidated [ Van dam et al, neuroregenerative dis.2005; 2: 147-159].

[0010] Overexpression of the SOD1 gene mutation in mice and rats mimics the clinical and pathological features of ALS in humans, where motor neurons are degenerated and animals die shortly after onset of symptoms. High levels of mutant SOD1 RNA were required for development of ALS-like phenotype during the short life span of mice. Experimental models of ALS play a key role in understanding the pathogenesis of ALS, and testing new therapeutic interventions aimed at preventing neurodegeneration [ Gurney, N Engl J med.1994 Dec 22; 331(25): 1721-2; dal Canto et al, Am J Pathol.1994Dec; 145(6): 1271-9]. Transgenic SOD1(G93A) mice represent one of the most common models for therapeutic intervention [ Julien, Drug Discovery Today: model winter 2006; 3(4): 331-339)].

[0011] The mechanisms and processes responsible for the loss of selectivity of motor neurons remain unknown and may be multifactorial. An important hypothesis for selective motor neuron death is glutamate-mediated excitotoxicity [ Rothstein et al, ann. neurol.1990, 28, 18-25; rothstein, Clinical Neuroscience, 1995, 3, 348-; shaw et al, Neurol, 1997, 244, S3-S14 ]. Excitotoxicity describes neuronal degeneration induced by hyperstimulation of glutamate receptors released by presynaptic terminals. For a detailed description of the mechanism of excitotoxicity and their association with ALS, see VanDamme et al, neuroregenerative Dis, 2005, 2: 147-159.

[0012] In recent years, ALS studies have been aimed at developing anti-excitotoxic compounds such as riluzole, which interfere with excitatory neurotransmission [ Ludolph et al, J Neural fransm, 1999[ Suppl ] 55: 79-95].

[0013] Over-activation of the N-methyl-D-aspartate (NMDA) receptor appears to be an important mechanism for neuronal degeneration in a broad spectrum of neurological disorders [ Lipton, et al, N EnglJ Med, 1994 Mar 3, 330 (9): 613-22].

[0014] Memantine, a noncompetitive NMDA receptor antagonist, has shown positive effects in SOD1(G93A) ALS-mouse model in disease progression and survival [ Wanget, Eur J Neurosci, 2005Nov, 22 (9): 2376-80].

[0015] Methamphetamine, a well-known uncompetitive NMDA receptor antagonist, has shown a positive effect in the treatment of mood swings and pseudobulbar effects [ U.S. patent No. 5,206,248 ]. Mood swings (EL) are a central nervous system disorder in which patients experience dramatic and considerable mood changes that can easily be evoked and that can quickly disappear. False bulbing effect (PBA) is a more severe form of emotional instability in which there are uncontrollable laughing and/or crying events that are unpredictable and appear to have little or no relationship to actual events or the actual feelings of an individual. EL and PBA are associated with neurodegenerative diseases that may include, but are not limited to, Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), dementia including alzheimer's disease, parkinson's disease, stroke, and traumatic brain injury. Schiffer and Pope provide a detailed description of PBA, [ j.neuropsychiatry clin.neurosci, 2005, 17(4), 447-.

[0016] Neramexane, also known as 1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane, is one of the members of the orally active 1-aminocyclohexanes and is useful in the treatment of various diseases, in particular in the treatment of certain neurological diseases, including alzheimer's disease and neuropathic pain. The therapeutic effect of neramexane is believed to be related to the inhibition of the action of excess glutamate at NMDA receptors located in nerve cells, for which reason the compounds are also classified as NMDA antagonists or NMDA receptor antagonists. More specifically, neramexane appears to be a low to moderate affinity, uncompetitive NMDA receptor antagonist believed to selectively block the excitotoxic effects associated with aberrant glutamate transmission.

Summary of The Invention

[0017] The present invention relates to compositions comprising neramexane and a Glutamate Release Inhibitor (GRI), and the use of such compositions in the treatment of neurodegenerative diseases.

[0018] Another aspect of the invention relates to compositions comprising neramexane and a Glutamate Release Inhibitor (GRI), and the use of such compositions in the treatment of mood swings (EL) and/or pseudobulbar effect (PBA) associated with neurodegenerative diseases.

[0019] Another aspect of the invention relates to the use of neramexane for the treatment of mood swings (EL) and/or pseudobulbar effect (PBA) associated with neurodegenerative diseases.

[0020] Another aspect of the invention relates to the use of Glutamate Release Inhibitors (GRI) for the treatment of mood swings (EL) and/or pseudobulbar effect (PBA) associated with neurodegenerative diseases.

[0021] Another aspect of the invention relates to compositions comprising neramexane and a Glutamate Release Inhibitor (GRI), and the use of such compositions in the treatment of motor neuron diseases including Amyotrophic Lateral Sclerosis (ALS), virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

[0021] Another aspect of the invention relates to a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) selected from riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, phenytoin, sipatriptan, MS-153 and FP-0011, and the use of such a composition in the treatment of motor neuron diseases including Amyotrophic Lateral Sclerosis (ALS), virally induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

[0023] Another aspect of the invention relates to a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) selected from the group consisting of riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, phenytoin, citalopram, MS-153 and FP-0011, and the use of such a composition in the treatment of Amyotrophic Lateral Sclerosis (ALS).

[0024] Another aspect of the invention relates to a composition comprising neramexane and riluzole, and a method of treating an individual diagnosed with Amyotrophic Lateral Sclerosis (ALS), comprising administering an effective amount of a composition of neramexane and riluzole to the individual.

[0025] Another aspect of the invention relates to the use of a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) for the manufacture of a medicament for the treatment of a neurodegenerative disease.

[0026] Another aspect of the invention relates to the use of a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) for the manufacture of a medicament for the treatment of a motor neuron disorder, comprising Amyotrophic Lateral Sclerosis (ALS), virally induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

[0027] Another aspect of the invention relates to the use of a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) selected from riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, phenytoin, sipatrizole, MS-153 and FP-0011 for the manufacture of a medicament for the treatment of a motor neuron disease comprising Amyotrophic Lateral Sclerosis (ALS), virally induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

[0028] Another aspect of the invention relates to the use of a composition comprising neramexane and a Glutamate Release Inhibitor (GRI) selected from the group consisting of riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, fosphenytoin, citalopram, MS-153 and FP-0011, for the preparation of a medicament for the treatment of Amyotrophic Lateral Sclerosis (ALS).

[0029] Another aspect of the invention relates to the use of a composition comprising neramexane and riluzole for the preparation of a medicament for the treatment of an individual diagnosed with Amyotrophic Lateral Sclerosis (ALS).

[0030] Another aspect of the invention relates to a method of treating a neurodegenerative disease in an individual in need of treatment comprising administering a first dose of neramexane and a second dose of a glutamate Release inhibitor, wherein the first dose and the second dose in the composition are effective in treating the neurodegenerative disease.

[0031] Another aspect of the invention relates to such a method wherein the glutamate Release inhibitor is selected from the group consisting of riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, fosphenytoin, sipatrizole, MS-153 and FP-0011.

[0032] Another aspect of the invention relates to such a method wherein the neurodegenerative disease is a motor neuron disease.

[0033] Another aspect of the invention relates to such a method, wherein the motor neuron disease is amyotrophic lateral sclerosis.

[0034] Another aspect of the invention relates to a method of treating amyotrophic lateral sclerosis in an individual in need of treatment, comprising administering a first dose of neramexane and a second dose of riluzole, wherein the first dose and the second dose in the composition are effective in treating amyotrophic lateral sclerosis.

[0035] Another aspect of the invention relates to a method of treating a mood swing (EL) and/or a pseudobulbar effect (PBA) associated with a neurodegenerative disorder in a subject in need of treatment comprising administering a first dose of neramexane and a second dose of a Glutamate Release Inhibitor (GRI), wherein the first dose and the second dose in the composition are effective in treating the mood swing (EL) and/or the pseudobulbar effect (PBA) associated with a neurodegenerative disorder.

[0036] Another aspect of the invention relates to a method of treating a mood swing (EL) and/or a pseudobulbar effect (PBA) associated with a neurodegenerative disease in an individual in need of treatment comprising administering a therapeutically effective amount of neramexane.

[0037] Another aspect of the invention relates to a method of treating a mood swings (EL) and/or pseudobulbar effect (PBA) associated with a neurodegenerative disease in a subject in need of treatment comprising administering a therapeutically effective amount of a Glutamate Release Inhibitor (GRI).

[0038] Another aspect of the invention relates to a pharmaceutical composition for treating a neurodegenerative disease comprising a therapeutically effective amount of a combination of neramexane and a Glutamate Release Inhibitor (GRI), and at least one pharmaceutically acceptable excipient.

[0039] Another aspect of the invention relates to a pharmaceutical composition for the treatment of motor neuron diseases including Amyotrophic Lateral Sclerosis (ALS), virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy, comprising a therapeutically effective amount of a composition of neramexane and a Glutamate Release Inhibitor (GRI), and at least one pharmaceutically acceptable excipient, the Glutamate Release Inhibitor (GRI) comprising riluzole, RP66055, gabapentin, pregabalin, lamotrigine, berrozole, phenytoin, sipatriplex, MS-153 and FP-0011.

[0040] Another aspect of the invention relates to a pharmaceutical composition for the treatment of Amyotrophic Lateral Sclerosis (ALS), comprising a therapeutically effective amount of a composition comprising neramexane and riluzole, and at least one pharmaceutically acceptable carrier or excipient.

[0041] Another aspect of the invention relates to a pharmaceutical composition for treating Amyotrophic Lateral Sclerosis (ALS) comprising a therapeutically effective amount of a composition comprising neramexane and riluzole in an immediate release or sustained release formulation.

Detailed Description

[0042] The term "combination" for active ingredients is used herein to define either a single pharmaceutical composition (formulation) comprising two active agents (e.g., a pharmaceutical composition comprising neramexane and riluzole), or two separate pharmaceutical compositions administered in combination, wherein each pharmaceutical composition comprises one active agent (e.g., a pharmaceutical composition comprising neramexane or riluzole).

[0043] Within the meaning of the present invention, the term "co-administration" is used to refer to the simultaneous, or sequential administration of neramexane and a GRI (e.g., riluzole) in one composition. However, for continuous administration to be considered "combined", neramexane and the second active agent must be administered separately at a time interval which still allows the overall beneficial effect of treating neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) to be achieved in a mammal.

[0044] The term "treating" as used herein refers to alleviating or alleviating at least one symptom of a disease in an individual. Within the meaning of the present invention, the term "treatment" also means preventing, delaying onset (i.e. the time before clinical manifestation of the disease) and/or reducing the risk of developing or worsening the disease.

[0045] As used herein, the term "motor neuron disease" includes Amyotrophic Lateral Sclerosis (ALS), virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease, and spinal muscular atrophy.

[0046] Neramexane (1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane) is disclosed in U.S. patent nos. 6,034,134 and 6,071,966, the subject matter of which is incorporated herein by reference. Neramexane, which may be used according to the invention in any form of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, any statement in this description concerning neramexane should be understood as also referring to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0047] As used herein, the term "Glutamate Release Inhibitor (GRI)" includes riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, fosphenytoin, sipatrizine, MS-153 and FP-0011.

[0048] Riluzole (2-amino-6-trifluoromethoxybenzathiazole or 6 (trifluoromethoxy) benzothiazol-2-amine) is disclosed in U.S. patent No. 4,370,338, the subject matter of which is incorporated herein by reference. Riluzole, in accordance with the present invention, may be used in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description regarding riluzole should be understood as referring also to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0049] RP66055(3- {2- [1- (4-fluorophenyl-piperazine) ] ethyl } -2-imino-6-trifluoromethoxybenzothiazole) is disclosed in Jimonet al, Bioorg Med Chem, 19942: 793-8. RP66055 can be used in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives according to the invention, and any reference in this description to RP66055 should be understood to also refer to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0050] Gabapentin (2- [1- (aminomethyl) cyclohexyl ] acetic acid)) may be used according to the invention in any form of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description concerning gabapentin should be understood as referring also to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0051] Pregabalin ((S) -3- (aminomethyl) -5-methylhexanoic acid) may be used according to the invention in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description relating to pregabalin should be understood to also refer to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0052] Lamotrigine (6- (2, 3-p-toluenesulphonic acid) -1, 2, 4-triazine-3, 5-diamine) may be used according to the invention in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description concerning lamotrigine should be understood as also referring to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0053] Lubeluzole ((S) -4- [ (2-benzothiazolyl) methylamino ] - α - [ (3, 4-difluoro-phenoxy) methyl ] -1-piperidineethanol) is disclosed in U.S. patent No. 5,434,168. Lubeluzole can be used according to the invention in any form of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description concerning lubeluzole should be understood as also referring to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0054] Phosphaphenytoin (2, 5-dioxo-4, 4-diphenyl-imidazolin-1-yl) methoxyphosphonic acid) may be used according to the invention in any of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description concerning fosphenytoin should be understood to also refer to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0055] Xipamidrine (2- (4-methylpiperazin-1-yl) -5- (2, 3, 5-trichlorophenyl) pyrimidin-4-amine) can be used according to the invention in any form of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description about xipamidrine should be understood as referring to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0056] MS-153((R) - (-) -5-methyl-1-nicotinoyl-2-dihydropyrazole) may be used according to the invention in any form of its pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives, and any statement in this description concerning MS-153 should be understood to also refer to such salts, solvates, isomers, conjugates, prodrugs, metabolites and derivatives.

[0057] Pharmaceutically acceptable salts include, but are not limited to, acid addition salts such as those prepared with hydrochloric, methanesulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acids. All of these salts (or other similar salts) can be prepared by conventional methods. The nature of the salt is not critical, so long as it is non-toxic and does not substantially interfere with the desired pharmacological activity.

[0058] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense to refer to a molecule that is structurally similar to a control molecule (e.g., neramexane or riluzole), but has been modified in a targeted and regulatory manner to replace one or more particular substituents of the control molecule with alternative substituents to produce a molecule that is structurally similar to the control molecule. The synthesis and screening of analogs (e.g., using structural and/or biochemical analysis) to identify slightly improved forms of known compounds with improved or biased properties (e.g., higher potency and/or selectivity for specific target receptor types, greater penetration of the mammalian blood brain barrier, fewer side effects, etc.) is a well-known drug design approach in pharmaceutical chemistry.

[0059] The term "therapeutically effective" as applied to a dose or amount refers to the amount of a compound or pharmaceutical composition that is sufficient to produce the desired activity upon administration to a mammal in need thereof.

[0060] The term "subthreshold" refers to the amount of active ingredient that is insufficient to produce a response when the active ingredient is used as a monotherapy, i.e., an amount below the minimum effective amount.

[0061] The term "suboptimal" in the same context refers to the amount of active ingredient that produces a response but not the maximum extent of the response, which is obtained with higher amounts.

[0062] The term "additive" refers to the combined effect of administering two compounds, wherein the total response is equal to, or nearly equal to, the sum of the responses of the compounds when administered as monotherapy.

[0063] The term "synergistic" refers to the combined effect of administering two therapeutic compounds, wherein the total response is greater than the sum of the two individual effects. The term synergistic also refers to the combined effect of administering an amount of one compound that produces an unmeasurable response when administered as monotherapy, but produces an overall response that is greater than the response of the second compound alone when administered in combination with the other therapeutic compound.

[0064] The phrase "pharmaceutically acceptable" when used with a composition of the invention refers to the molecular entities and other components of such composition that are physiologically tolerable and do not generally produce adverse effects when administered to a mammal (e.g., a human). The term "pharmaceutically acceptable" also refers to those approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0065] The term "carrier" for the pharmaceutical compositions of the present invention refers to a diluent, excipient, or carrier with which the active compound (e.g., neramexane) is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" twentieth edition, a.r. gennaro.

[0066] The term "about" or "approximately" generally refers to values within 20%, alternatively within 10%, including values within 5% of a given value or range. Alternatively, particularly in biological systems, the term "about" refers to within about a logarithm (i.e., an order of magnitude), including within two factors of a given value.

[0067] In conjunction with the methods of the present invention, also provided are pharmaceutical compositions comprising a therapeutically effective amount of neramexane and/or a therapeutically acceptable amount of a GRI (e.g., riluzole). The compositions of the present invention may further comprise a carrier or excipient (all pharmaceutically acceptable). The composition may be formulated for once-a-day administration, twice-a-day administration, or three times a day administration.

[0068] The compositions or individual active ingredients of the present invention may be used in the manufacture of a medicament for the treatment of one of the diseases in question, wherein the medicament is suitable or appropriate for the particular administration disclosed herein (e.g., once a day, twice a day, or three times a day). For this purpose, the package leaflet and/or the patient information contain corresponding information.

[0069] According to the present invention, the dosage form of the composition may be the following solid, semi-solid or liquid formulation.

[0070] The compositions may be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. The compositions may be administered orally in the form of capsules, tablets, etc., or as semi-solid or liquid formulations (see Remington' pharmaceutical Sciences, 20th Edition, a.r. geno).

[0071] For oral administration in tablet or capsule form, the compositions may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gels, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like.

[0072] Tablets may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, and the like. Alternatively, the tablets may be coated with a polymer which is soluble in a readily volatile organic solvent or mixture of organic solvents. In particular embodiments, neramexane is formulated as an Immediate Release (IR) or sustained release (MR) tablet. Immediate release solid dosage forms allow for release of most or all of the active ingredient in a short period of time, such as 60 minutes or less, thereby enabling rapid absorption of the drug (e.g., the immediate release formulations of neramexane are disclosed in U.S. published applications 2006/0002999 and 2006/0198884, the subject matter of which is incorporated herein by reference). Sustained release solid oral dosage forms allow for sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over a similar extended time interval, and/or to modify other pharmacokinetic properties of the active ingredient (e.g., sustained release formulations of neramexane are disclosed in U.S. published application 2007/0141148, the subject matter of which is incorporated herein by reference).

[0073] For the preparation of soft capsules, the active substances can be mixed with, for example, vegetable oils or polyethylene glycols. With the above-mentioned excipients for tablets, such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin, the hard capsules can comprise granules of the active substance. Liquid or semisolid drugs may also be filled into hard capsules.

[0074] The compositions of the present invention may also be incorporated into microspheres or microcapsules, such as those prepared from polyglycolic/lactic acid (PGLA) (see U.S. Pat. Nos. 5,814,344; 5,100,669 and 4,849,222; PCT publication Nos. WO 95/11010 and WO 93/07861). Biocompatible polymers may also be used to achieve controlled release of the drug, including, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0075] Formulations of the compositions of the present invention in semi-solid or liquid form may also be used. The active ingredient (i.e., neramexane and/or, for example, riluzole) may constitute 0.1 to 99% by weight of the formulation, more specifically 0.5 to 20% by weight of the formulation for injection, and 0.2 to 50% by weight of the formulation suitable for oral administration.

[0076] In one embodiment of the invention, the composition is administered in a sustained release formulation. By reducing the incidence of adverse drug reactions, sustained release dosage forms provide a means for improving patient compliance and for ensuring effective and safe treatment. Sustained release dosage forms can be used to prolong the pharmacological effect after administration and reduce the variability of the drug in plasma concentrates throughout the dose interval, thereby eliminating or reducing the peaks, compared to immediate release dosage forms.

[0077] The sustained release dosage form may comprise a core coated with or containing a drug. The core is then coated with a release modifying polymer having the drug dispersed therein. The release modifying polymer gradually disintegrates, releasing the drug over time. Thus, when the composition is exposed to a liquid phase environment, i.e., the gastrointestinal tract, the outermost layer of the composition effectively slows down to regulate the dispersion of the drug through the coating. The net rate of drug diffusion depends primarily on the ability of the gastric fluid to penetrate the coating or matrix and the solubility of the drug itself.

[0078] In another embodiment of the invention, the composition is formulated in an oral liquid formulation. Liquid preparations for oral use may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may suitably be formulated to provide controlled or prolonged release of the active compound. For example, oral liquid formulations of neramexane are described in PCT International application No. PCT/US2004/037026, the subject matter of which is incorporated herein by reference.

[0079] For oral liquid forms, the compositions may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), anhydrous carriers (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxy-benzoate or sorbic acid), and the like. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form. For example, the solution may comprise about 0.2% to about 20% by weight neramexane, the balance being a mixture of sugar with ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other excipients as thickening agents.

[0080] In another embodiment, a therapeutically effective amount of the active is administered in an oral solution comprising a preservative, a sweetener, a solubilizing agent, and a solvent. Oral solutions may contain one or more buffers, flavoring agents or additional excipients. In a further embodiment, peppermint or other flavoring is added to the oral liquid formulation.

[0081] For administration by inhalation, the compositions may conveniently be delivered in the form of an aerosol spray presentation from a pressurised pack or spray device, with the aid of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0082] Solutions for parenteral application by injection may be prepared in aqueous solutions of water-soluble pharmaceutically acceptable salts of the active substance, preferably in concentrates of about 0.5% to about 10% by weight. These solutions may also contain stabilizers and/or buffers and may conveniently be presented in different dosage unit ampoules.

[0083] Dosage units for rectal application may be solutions or suspensions, or may be prepared in the form of suppositories or retention enemas, containing neramexane mixed with a neutral fatty base, or in the form of gel rectal capsules containing the active substance mixed with vegetable or paraffin oils.

[0084] The formulations of the present invention may be delivered parenterally, that is, by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.), by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0085]The present invention also provides a pharmaceutical package or kit comprising one or more containers containing the active substance (i.e., neramexane and/or, for example, riluzole) and, optionally, the components of the formulation. In a particular embodiment, the composition is provided as an oral solution (2mg/ml) for use with a 2 spoon capacity syringe (dosage)) And (4) administration. Each oral syringe has a blue hatch mark for measurement, with the line to the right of the syringe (tip down) representing tsp units, and the line to the left representing ml units.

[0086] The optimal therapeutically effective amount of the components of the compositions of the present invention can be determined experimentally, taking into account the exact mode of administration in which the drug is administered, instructions directing administration, the individual involved (e.g., weight, health, age, sex, etc.), and the preferences and experience of the attending physician or veterinarian.

[0087]The compounds may be administered by standard pharmaceutical procedures,for example, by measuring LD₅₀(lethal dose for 50% of the population) and ED₅₀(a therapeutically effective dose in 50% of the population), toxicity and therapeutic efficacy of the compositions of the invention are determined in experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as LD₅₀/ED₅₀. Compositions that exhibit large therapeutic indices are preferred.

[0088] Suitable daily dosages of the active compounds according to the invention in human therapy are approximately 0.01 to 10mg/kg body weight for oral administration and 0.001 to 10mg/kg body weight for parenteral administration. Suitable daily dosages of neramexane (e.g., neramexane mesylate) are in the range of from about 5mg to about 150mg per day, such as from about 5mg to about 120mg per day, from about 5mg to about 100mg, or from about 5mg to about 50mg per day. A suitable daily dose of neramexane (e.g., neramexane mesylate) is 6.25mg, 12.5mg, 25mg, 50mg, or 75mg per day. Suitable daily doses of riluzole are in the range of about 5mg to about 150mg per day, such as from about 5mg to about 100mg per day, such as from about 50mg to about 100mg per day, such as 50mg twice a day.

[0089] The daily doses indicated herein will be administered in one or two dosage units, e.g. once, twice or three times daily. A suitable dose per dosage unit is thus the daily dose divided (e.g. equally) by the number of dosage units administered per day, and is thus generally about equal to the daily dose or one half, one third, one fourth or one sixth thereof. The dose per dosage unit can therefore be calculated from each daily dose as described herein. A daily dose of 5mg, depending on the dosage regimen chosen, may be regarded as providing a dosage per dosage unit of, for example, about 5mg, 2.5mg, 1.67mg, 1.25mg and 0.83 mg. Accordingly, a dose of 150mg per day corresponds to a dose per dosage unit of approximately 150mg, 75mg, 50mg, 37.5mg and 25mg for the corresponding dosage regime.

Detailed description of the preferred embodiments

[0090] The following examples illustrate the invention without limiting its scope.

Example 1: effect of neramexane in combination with riluzole in ALS mouse model

[0091] Overexpression of the SOD1 gene mutation in mice and rats mimics the clinical and pathological features of ALS in humans, where motor neurons are degenerated and animals die shortly after onset of symptoms. Transgenic SOD1(G93A) mice represent one of the most common models for evaluating therapeutic interventions.

[0092] The mice used in this study were characterized by overexpression of the human mutated enzyme Cu/ZnSOD1 with a missense mutation from glycine to alanine at position 93 (G93A). The mRNA level of mutant SOD1 was 40 times higher than the normal mRNA level of endogenous mouse SOD 1. [ Gurney M.E., J.neurol.Sci., 1997, 152 Suppl 1, S67-73]

[0093] Transgenic mice bearing high copy number human mutant SOD1(G93A) had a lifespan of about 130 days [ Gurney m.e., j.neurol.sci., 1997, 152 Suppl 1, S67-73], disease onset at about 90 days of age, and paresis in one or both hind limbs of the mice at 110 days of age [ Wang et al, Eur J neurosci.2005nov; 22(9): 2376-80].

[0094] For the purpose of correcting the pathogenesis of ALS, neramexane was tested in a SOD1(G93A) transgenic mouse model of ALS. Comparing the efficacy of neramexane with that of riluzole and memantine, which have shown positive effects in an ALS mouse model [ Wang et al, Eur J neurosci.2005 Nov; 22(9): 2376-80]. Combination therapy of riluzole and neramexane was also tested.

Materials and methods

Animal(s) production

[0095] The mouse model of SOD1-G93A was used in this study. This model is well established for studies on Motor Neuron Disease (MND). This mouse is characterized by overexpressing the human mutated enzyme Cu/Zn SOD1, which shows a missense mutation from glycine to alanine at position 93 (G93A), and was used as a mouse model of the familial form of Amyotrophic Lateral Sclerosis (ALS). The specific name of the variety is B6SJL-TgN (SOD1-G93A)1 Gur/J.

[0096]Mice were housed individually, allowed to enter and exit the cages at 38 days of age, and allowed to acclimatize for 7 days before the study began. Drug treatment was started on day 45. Light circulation, automatic temperature and humidity control. The illumination time was 5:00am-6:30 pm. Daily monitoring indicated that temperature and humidity were maintained within the target ranges of 20 ℃. + -. 3 ℃ and 80. + -. 10%, respectively. Animals were housed in polypropylene cages (ca 26x20x14cm, covered with a grid upon arrival (1/cage). The cage, bed, and water bottle were changed at regular intervals, i.e., every 7 days. The animal can optionally consume a standard diet (MZEreich). Animals can freely obtain household high-quality tap water. To monitor the activity level, the animals were allowed to access a rotating cage.

Medicine

[0097] Neramexane was supplied as neramexane mesylate by MERZ pharmaceutical. Memantine is supplied by MERZ pharmaceutical company. Riluzole is supplied by Sequoia Research Products. Riluzole and neramexane are administered orally. The medicine is dissolved in drinking water. The calculation was based on the average consumption of 6mL/24 h. Memantine was administered subcutaneously twice daily. For all pharmaceutical preparations, an average adult body weight of 19g (female mice) and 24g (male mice) was assumed.

Treatment of

[0098] Once the genotyping results were obtained (approximately 30 days old), transgenic mice were randomly assigned to treatment groups so that the treatment groups were evenly distributed throughout the caging system.

[0099] Treatment groups and animal numbers were arranged as follows:

group of	Treatment group	Dosage level (mg.kg)-1.day-1)*	Number of animals
				1	Vehicle control	0	Male mice n-12 female mice n-12
2	Riluzole	35	Male mice n-12 female mice n-12
				3	Memantine	20	Male mice n-12 female mice n-12

4	Neramexane	50150	Male mice n-16 female mice n-16
				5	Neramexane, riluzole, neramexane and riluzole	50+35150+35	Male mice n-16 female mice n-16

With dosages of the respective salts

[0100] Treatment was started at 45 days of age and stopped at the end of the disease. Animals in treatment group 3 were dosed subcutaneously twice daily using a steel dosing cannula at a constant dose volume of 100 μ l each time. The concentration of the solution was determined by the average adult body weight of male (24g) and female (19g) animals. Animals of treatment groups 2, 4 and 5 were dosed with drug (riluzole, neramexane, a combination of neramexane plus riluzole) dissolved in drinking water. The concentration of the solution was determined by the average adult body weight of male (24g) and female (19g) animals, and by the average consumption of 6ml of drinking water. The consumption of drinking water was randomly checked.

[0101]

Data evaluation

[0102] To determine the therapeutic efficacy of the drug, 4 parameters were analyzed per treatment group.

1. Age of onset of disease

2. Age of first paresis

3. Age at end stage of disease (survivor)

4. Motion characteristics in a rotating cage

TABLE 1 age of onset of disease

n: number of mice analyzed, LC: below a 95% confidence interval, UC: confidence interval above 95%

TABLE 2 age of first paresis

n: number of mice analyzed, LC: below a 95% confidence interval, UC: confidence interval above 95%

TABLE 3 survivors

n: number of mice analyzed, LC: below a 95% confidence interval, UC: confidence interval above 95%

TABLE 4 analysis of locomotor Activity in rotating cages

n: number of mice analyzed, Rev's: rotation, rp: rpm/per, LC: lower signaling interval, UC: upper confidence interval

Results

[0102] The most effective treatment occurred in the combination group (i.e. oral administration of neramexane and riluzole) relative to 3 parameters showing delayed disease progression (age of onset, age of first paresis and survivors), which was delayed by 5 to 7 days, with statistically significant differences in age of onset and age of first paresis. Motor capacity analysis showed no evidence of delayed disease progression in any of the test groups.

Example 2:evaluation of neramexane in combination with riluzole for the treatment of amyotrophic lateral sclerosis (ALS)

[0103] The goal of this experimental plan was to conduct a clinical trial to evaluate the efficacy of a composition comprising neramexane and riluzole in the treatment of Amyotrophic Lateral Sclerosis (ALS). Patients with ALS who are to be treated with a composition comprising neramexane and riluzole demonstrate reduced disease progression which is significantly greater than the reduction in disease progression provided by riluzole monotherapy.

Design of research

[0104] The main objective of this study was to study the effect of neramexane on disease progression and the effect of neramexane in combination with riluzole on disease progression in patients suffering from ALS (as determined by ALS-FRS-r).

[0105] Adaptive design methods were used for this study. After treatment of a total of 150 patients was completed, a formal sample size assessment was performed based on non-blind intermittent analysis. Non-blind intermittent analyses were performed by an independent data monitoring committee.

[0106] To ensure that the sites of disease onset are evenly distributed within both treatment groups, it is known that the site of disease onset is an important covariate, randomized by this factorial stratification.

Statistical methods and populations for analysis

[0107] In order to assess eligibility for participation in the study, patients must meet the following criteria:

sign informed consent

Male or female patients aged 18 or older and 75 years or younger, diagnosed as possible experimentally supported, or as exact ALS, based on modified El Escorial criteria, familial or sporadic forms of ALS

ALS-FRS-r > 33 and < 43 at screening

Monthly reduction in ALS-FRS-r score > 0.4 and < 1.2 in disease progression as determined by the subject (calculated from the duration of disease from the first occurrence of pareses and bulbar symptoms and screening score)

First diagnosis of pareses and bulbar symptoms > 9 months before baseline

Vital Capacity (VC) > 70% of normal values based on age

Expecting the patient to understand the nature of the study, the potential risks or discomfort, and to follow the observations and dosing schedules according to a predetermined schedule

For patients undergoing riluzole treatment: administering a fixed dose of 100mg per day for at least 6 weeks prior to baseline

For women with childbirth potential (last menstruation less than 1 year before screening): negative pregnancy test at baseline, adequate method of birth control must be used

[0108] Patients meeting any of the following criteria were excluded from the study:

ventilation or tracheotomy requiring invasion

Non-invasive ventilation

Percutaneous Endoscopic Gastrostomy (PEG) at screening

Diagnosis of other neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and the like

Monoclonal globulins and associated hematologic malignancies

·BMI＜18

Patients with clinically relevant abnormal ECG findings

Patients with clinically relevant neurological or psychiatric disorders other than ALS or other serious or uncontrolled systemic diseases (e.g., cardiovascular (including heart rhythm disorders), renal, pulmonary, hepatic, endocrine, hematological, or gastrointestinal), which may interfere with the trial

ALS and frontotemporal dementia

Patients with systolic blood pressure greater than 160mm Hg or less than 90mm Hg, or diastolic blood pressure greater than 100mm Hg or less than 50mm Hg, with or without immobilized antihypertensive drug, at screening or at baseline observation

Deep vein thrombosis and pulmonary embolism

Patients with dysregulation of orthotropia

AST or ALT > 2.5 times the upper limit of normality

Known renal insufficiency

Creatinine > 1.5 times the upper limit of Normal

Clinically significant disturbances of absorption in the upper gastrointestinal tract

Use of NMDA antagonists (memantine, dextromethorphan, ketamine) or cannabinoids

Abuse of ethanol, analgesic, or narcotic substances during the last 6 months prior to baseline

Patients in need of concomitant treatment with any prohibited drug

Study of drugs participating in any survey or use of drugs from any study within 3 months prior to baseline

Patients previously participating in the study or any other neramexane test

Patients with known allergies, hypersensitivity, or intolerance to neramexane, amantadine, ketamine, memantine, or riluzole add an additional component of the study drug

Lactating women, or pregnant women positively confirmed by pregnancy test

The patient may not comply with the study indication and/or his/her evidence or suspicion of unreliability or trustworthiness

The patient is unwilling or unable to understand the information provided to him/her as part of advising consent, particularly evidence or suspicion about the risk and discomfort that he/she will agree to be exposed to

CRO, employees of the research center or Merz drug company or direct relatives of employees,

[0109] the observations on the predetermined schedule used to evaluate each patient are as follows:

[0110] observation 1 (initial screening): after signing the consent form, subjects were evaluated, in term of primary and secondary parameters. Eligibility of subjects for study participation was assessed by examination of inclusion/exclusion criteria.

[0111] Observation 2 (baseline): inspection based on inclusion/exclusion criteria. The subjects were evaluated for eligibility for the study. Subjects were familiarized with the study procedure and concomitant medication. Subjects were enrolled in the study and dispensed as described below.

[0112] Observation 3 to 9: these observations occurred 1, 2, 3, 6, 9, 12 and 15 months after baseline. Subjects were assessed for the occurrence of concomitant medications as well as adverse events since the last observation. The primary and secondary parameters are evaluated. The medication is dispensed as follows.

[0113] Observation 10: this observation occurred on day 31 after the last dose. ALS-FRS-r scores and changes from baseline in secondary parameters were evaluated.

Administration of neramexane/riluzole compositions

Neramexane

[0114] Neramexane mesylate 25mg extended release tablet and an equivalent placebo tablet were administered as film coated tablets.

[0115] Neramexane (or blank) was gradually increased to a maximum daily dose of 75mg, administered for one week at the initial daily dose of 25mg, and increased in steps of increasing the dose of 25mg every other week.

[0116] Study medication was provided in 3 tablets per day (morning, noon and evening). During week 1 of the escalating dose phase, patients received 1 neramexane tablet and two placebo tablets per day. During week 2, patients received 2 neramexane tablets and 1 placebo tablet per day. During week 3 (and continuing until month 15 of the study), patients received either 3 neramexane tablets or 2 neramexane tablets per day and 1 placebo tablet (depending on the tolerability of the subject).

Riluzole

[0117] Riluzole is administered in a commercially available tablet containing 50mg of riluzole at a dose of 100mg per day.

Efficacy of

[0118] The patient is evaluated using a functional rating scale as well as a quality of life scale.

[0119] Preliminary results

ALS-FRS-r score changes from baseline 15 months after double-blind treatment in the ITT subtype.

[0120] Secondary outcome

ALS-FRS-r score changes from baseline 3 months and 9 months after double-blind treatment.

Change in the slope of disease progression in the subject (ALS-FRS-r decrease per month from baseline to the end of month 15 of double-blind treatment compared to screening values)

Time to event (event defined as death, tracheotomy, invasive ventilation, or non-invasive ventilation, and occurrence of each individual event)

Number of patients with percutaneous endoscopic gastrostomy tubes (PEG) 15 months after double-blind treatment

Change from baseline during non-invasive ventilation daily after 3, 9 and 15 months of double-blind treatment

Area under the Vital Capacity (VC) curve, expressed as percentage of age normality between screening observations and the end of the 15 th month of double-blind treatment

Area under the maximum Vital Capacity (VC) curve, expressed as percentage of age normality between screening observations and the end of the 15 th month of double-blind treatment

Change in muscle Strength from baseline measured by Manual muscle Strength test (MMT) after double-Blind treatment for 3, 9 and 15 months

Change in the neural center study-unstable scale (CNS-LS) from baseline after 3, 9 and 15 months of double-blind treatment

Change from baseline in the pathological laugh and cry scale (PLACS) after 3, 9 and 15 months of double-blind treatment

Change from baseline in a simple form health survey (SF-36) after 9 and 15 months of double-blind treatment

Time to onset of non-invasive ventilation

Time to onset of percutaneous endoscopic gastrostomy tube (PEG)

Data analysis

[0121] Using the ANCOVA method, the change in ALS-FRS-r scores from baseline after 15 months of double-blind treatment (primary efficacy analysis) and during the course of the study (secondary efficacy parameter) was analyzed for ITT subtypes using the centers, treatment groups, and site of disease onset (medulla oblongata or spinal cord) as factors and baseline values as covariates. The primary efficacy analysis was based only on patients with a fixed riluzole dose at baseline.

[0122] Changes from baseline during non-invasive ventilation were analyzed using the same ANCOVA method as described above, but without factor expansion.

[0123] Changes in the subject's slope and final MMT score for disease progression were analyzed non-parametrically using the ANCOVA method, with graded data factoring in the center, treatment group, and site of disease onset (medulla oblongata or spinal cord), and a randomized graded slope or graded MMT score at baseline as covariates, respectively.

[0124] The time versus event curves were compared by treatment with the chi-square test and after adjusting the site of disease onset (medulla oblongata or spinal cord) with the Cox proportional hazards model.

[0125] The number of patients with percutaneous endoscopic gastrostomy tubes, the AUC of the Vital Capacity (VC) and the maximum vital capacity (FVC) were analyzed using the ANCOVA method, with the center, treatment group, and site of disease onset (medulla oblongata or spinal cord) as factors.

[0126] The SF-36 score was analyzed using the ANCOVA method with the center, treatment group, and site of disease onset (medulla oblongata or spinal cord) as factors, and the corresponding baseline values as covariates.

[0127] Changes in the neurological study-intolerance scale (CNS-LS) in the center from baseline after 3, 9 and 15 months of double-blind treatment were analyzed using the ANCOVA method with the center, treatment group, and site of disease onset (medulla oblongata or spinal cord) as factors and baseline values as covariates.

[0128] Changes in the pathological laugh and cry vectors (PLACS) after 3, 9 and 15 months of double-blind treatment were analyzed using the ANCOVA method with the center, treatment group, and site of onset of the disease (medulla oblongata or spinal cord) as factors and baseline values as covariates, starting from baseline.

[0129] For all efficacy analyses, the intended treatment principles were used, considering that all randomized patients had an intake of at least one study drug (neramexane or placebo), and a post-baseline determination of ALS-FRS-r score.

Discussion of the related Art

[0130] The neramexane/riluzole composition treatment group demonstrated a reduction in disease progression that was significantly greater than the reduction in disease progression with riluzole and placebo treatment.

*****

[0131] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0132] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims (41)

1. Use of neramexane or a pharmaceutically acceptable salt thereof in combination with a glutamate Release inhibitor for the preparation of a medicament for the treatment of a neurodegenerative disease.

2. The use according to claim 1, wherein the neurodegenerative disease is a motor neuron disease.

3. Use according to claim 2, wherein the motor neuron disease is selected from the group consisting of amyotrophic lateral sclerosis, virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, kennedy's disease and spinal muscular atrophy.

4. Use as claimed in claim 3, wherein the motor neuron disease is amyotrophic lateral sclerosis.

5. Use as claimed in any one of the preceding claims, wherein the pharmaceutically acceptable salt of neramexane is the mesylate salt.

6. Use according to any preceding claim, wherein the glutamate Release inhibitor is selected from riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, fosphenytoin, sipatriplex, MS-153 and FP-0011 and pharmaceutically acceptable salts thereof.

7. Use as claimed in claim 6, wherein the glutamate Release inhibitor is selected from riluzole and pharmaceutically acceptable salts thereof.

8. Use as claimed in any preceding claim, wherein the medicament is prepared for co-administration with a glutamate Release inhibitor at the same time.

9. Use as claimed in claim 8, wherein the medicament is prepared as a unit dosage form comprising neramexane or a pharmaceutically acceptable salt thereof and a glutamate Release inhibitor.

10. Use as claimed in claim 9, wherein the medicament is prepared for administration of neramexane or a pharmaceutically acceptable salt thereof at a dose of 5 to 150 mg/day, and riluzole or a pharmaceutically acceptable salt thereof at a dose of 5 to 150 mg/day.

11. The use as claimed in claim 10, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is from 5mg to 100mg per day and the dose of riluzole or a pharmaceutically acceptable salt thereof is from 5mg to 100mg per day.

12. The use as claimed in claim 11, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is from 5mg to 75mg per day and the dose of riluzole or a pharmaceutically acceptable salt thereof is from 5mg to 100mg per day.

13. The use as claimed in claim 12, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 25 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

14. The use as claimed in claim 12, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 50 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

15. The use as claimed in claim 12, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 75 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

16. Use according to any of the preceding claims, wherein the medicament is prepared for once a day, twice a day (b.i.d.) or three times a day administration of neramexane or a pharmaceutically acceptable salt thereof in combination with a glutamate Release inhibitor.

17. Use according to any one of claims 9 to 16, wherein the medicament is prepared to provide neramexane or a pharmaceutically acceptable salt thereof in combination with a glutamate Release inhibitor in an immediate release formulation.

18. Use according to any one of claims 9 to 16, wherein the medicament is prepared to provide neramexane or a pharmaceutically acceptable salt thereof in association with a glutamate Release inhibitor in a sustained release formulation.

19. Use of neramexane or a pharmaceutically acceptable salt thereof in combination with a glutamate Release inhibitor for the manufacture of a medicament for the treatment of mood swings and/or pseudobulbar effects.

20. A composition comprising neramexane or a pharmaceutically acceptable salt thereof and a glutamate Release inhibitor for the treatment of mood swings and/or pseudobulbar effects.

21. Use of a glutamate Release inhibitor for the manufacture of a medicament for the treatment of mood swings and/or pseudobulbar effects.

22. Compositions comprising glutamate Release inhibitors for the treatment of mood swings and/or pseudobulbar effects.

23. A pharmaceutical composition comprising neramexane or a pharmaceutically acceptable salt thereof and a glutamate Release inhibitor.

24. The pharmaceutical composition of claim 23, further comprising a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, which is in a solid oral dosage form.

26. A pharmaceutical composition as claimed in any one of claims 23 to 25, wherein neramexane is used as its mesylate salt.

27. The pharmaceutical composition as claimed in any one of claims 23 to 26, wherein the glutamate Release inhibitor is selected from the group consisting of riluzole, RP66055, gabapentin, pregabalin, lamotrigine, lubeluzole, phenytoin, sipatrizole, MS-153 and FP-0011 and pharmaceutically acceptable salts thereof.

28. The pharmaceutical composition of claim 27, wherein glutamate Release inhibitor is selected from riluzole and pharmaceutically acceptable salts thereof.

29. The pharmaceutical composition of claim 28, which is suitably packaged for administration of neramexane or a pharmaceutically acceptable salt thereof at a dose of 5 to 150 mg/day, and riluzole or a pharmaceutically acceptable salt thereof at a dose of 5 to 150 mg/day.

30. The pharmaceutical composition of claim 29, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 5mg to 100 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 5mg to 100 mg/day.

31. The pharmaceutical composition of claim 30, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 5mg to 75 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 5mg to 100 mg/day.

32. The pharmaceutical composition of claim 31, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 25 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

33. The pharmaceutical composition of claim 31, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 50 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

34. The pharmaceutical composition of claim 31, wherein the dose of neramexane or a pharmaceutically acceptable salt thereof is 75 mg/day and the dose of riluzole or a pharmaceutically acceptable salt thereof is 100 mg/day.

35. The pharmaceutical composition as claimed in any one of claims 23 to 34, which is suitably packaged for administration once a day, twice a day (b.i.d.) or three times a day.

36. A pharmaceutical composition as claimed in any one of claims 23 to 35 which is provided as an immediate release formulation.

37. A pharmaceutical composition as claimed in any one of claims 23 to 35 which is provided as a sustained release formulation.

38. A pharmaceutical composition as claimed in any one of claims 23 to 37 for use in the treatment of a neurodegenerative disease.

39. The pharmaceutical composition of claim 38, wherein the neurodegenerative disease is a motor neuron disease.

40. The pharmaceutical composition of claim 39, wherein the motor neuron disease is selected from the group consisting of amyotrophic lateral sclerosis, virus-induced poliomyelitis, lathyrism, primary lateral sclerosis, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, progressive supranuclear palsy, Kennedy's disease, and spinal muscular atrophy.

41. The pharmaceutical composition of claim 40, wherein the motor neuron disease is amyotrophic lateral sclerosis.