Arimoclomol for treating glucocerebrosidase associated disorders

Abstract

The present invention relates to an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximioyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), for use in a method of treating glucocerebrosidase associated disorders.

1 . An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of treating a glucocerebrosidase (GBA)-associated disorder. 
     
     
         2 . The active pharmaceutical ingredient for use according to  claim 1 , wherein said GBA-associated disorder is not Gaucher's disease (GD). 
     
     
         3 . The active pharmaceutical ingredient for use according to  claim 1 , wherein said GBA-associated disorder is a GBA-associated alpha-synucleinopathy. 
     
     
         4 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated alpha-synucleinopathy is selected from the group consisting of GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA). 
     
     
         5 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is GBA-associated parkinsonism. 
     
     
         6 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is GBA-associated Parkinson's disease. 
     
     
         7 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with reduced GBA enzyme levels. 
     
     
         8 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with reduced GBA enzyme activity. 
     
     
         9 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with reduced GBA enzyme activity and/or levels and said GBA gene is wild-type, and the reduction in GBA activity is due to suppression of activity of the protein or repression of transcription or translation of the gene/protein or is idiopathic. 
     
     
         10 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with one or more individual GBA gene mutations. 
     
     
         11 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein the individual with a GBA-associated disorder remain clinically unaffected re Gaucher's disease. 
     
     
         12 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with one or more heterozygous GBA gene mutation. 
     
     
         13 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated disorder is associated with a homozygous GBA gene mutation, wherein said GBA-associated disorder is not Gaucher's disease. 
     
     
         14 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said one or more individual GBA gene mutations are mild (associated with GD type I). 
     
     
         15 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said one or more individual GBA gene mutations are severe (associated with GD type II and III). 
     
     
         16 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA gene mutation is selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S and IVS2+1G>A/N188S. 
     
     
         17 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA gene mutation is L444P. 
     
     
         18 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA gene mutation is E326K. 
     
     
         19 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA gene mutation is N370S. 
     
     
         20 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA-associated disorder is a L444P, A456P, V460V heterozygote. 
     
     
         21 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA-associated disorder is a GBA mutation carrier, such as an obligate carrier, such as a carrier which is clinically unaffected re. Gaucher's disease. 
     
     
         22 . The active pharmaceutical ingredient for use according to any of the preceding claims wherein said GBA-associated disorder is a clinically unaffected parent or sibling of a Gaucher's disease patient. 
     
     
         23 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with reduced GBA enzyme levels and/or reduced GBA enzyme activity. 
     
     
         24 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with one or more GBA gene mutations. 
     
     
         25 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with one or more heterozygous GBA gene mutations. 
     
     
         26 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with one or more homozygous or compound heterozygous GBA gene mutations. 
     
     
         27 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with one or more GBA gene mutations selected from the group consisting of L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R and P415R. 
     
     
         28 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with a heterozygous or a homozygous N370S/N370S GBA gene mutation. 
     
     
         29 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with a genetically high-risk Parkinson's disease GBA genotype. 
     
     
         30 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said GBA-associated Parkinson's disease is associated with idiopathic reduced GBA enzyme activity and/or levels with no accompanying GBA gene mutations identified. 
     
     
         31 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is the racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. 
     
     
         32 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. 
     
     
         33 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. 
     
     
         34 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is selected from the group consisting of
 (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and   (−)-(S)—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.   
     
     
         35 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. 
     
     
         36 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is selected from the group consisting of
 N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, and   N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.   
     
     
         37 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said active pharmaceutical ingredient is selected from the group consisting of
 (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate;   (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate;   (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate; and   (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.   
     
     
         38 . The active pharmaceutical ingredient for use according to any of the preceding claims, wherein said treatment is prophylactic, curative or ameliorating. 
     
     
         39 . An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of reducing risk in an individual of developing a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease, wherein said individual has reduced GBA level and/or reduced GBA activity. 
     
     
         40 . The active pharmaceutical ingredient for use according to  claim 39 , wherein said individual with reduced GBA level and/or activity has one or more GBA gene mutation, such as a heterozygous GBA gene mutation or such as a homozygous GBA gene mutation. 
     
     
         41 . The active pharmaceutical ingredient for use according to any of  claims 39 - 40 , wherein said GBA-associated disorder is a GBA-associated alpha-synucleinopathy, such as a GBA-associated alpha-synucleinopathy selected from the group consisting of GBA-associated parkinsonism, GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA). 
     
     
         42 . The active pharmaceutical ingredient for use according to  claim 40 , wherein said GBA-associated disorder is GBA-associated Parkinson's disease. 
     
     
         43 . The active pharmaceutical ingredient for use according to any of  claims 39 - 42 , wherein said individual has GBA activity and/or levels of about 5 to 95% of hypothetical wild type activity and/or levels, such as 5 to 10%, such as 10 to 20%, such as 20 to 30%, such as 30 to 40%, such as 40 to 50%, such as 50 to 60%, such as 60 to 70%, such as 70 to 80%, such as 80 to 90%, such as 90 to 95% of hypothetical wild type activity and/or levels. 
     
     
         44 . An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof, for use in a method of one or more of
 a. increasing GBA activity,   b. increasing GBA levels (or amount),   c. increasing the amount of active mutant GBA,   d. increasing the amount of active wild type GBA,   e. enhancing folding of ER-retained mutant GBA,   f. increasing the amount of processed/maturated GBA,   g. increasing the amount of matured (post-ER) GBA,   h. increasing the amount of matured GBA reaching the lysosomes, and/or   i. reducing alpha-synuclein aggregation.   
     
     
         45 . A composition, such as a pharmaceutical composition, comprising—separately or together—an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol); and one or more further active ingredients; for use in the treatment of a glucocerebrosidase (GBA)-associated disorder other than Gaucher's disease (GD), including GBA-associated alpha-synucleinopathies such as GBA-associated Parkinson's disease (PD), GBA-associated dementia with Lewi bodies (DLB) and GBA-associated multiple system atrophy (MSA).