Methods of Administering Monomethyl Fumarate and Prodrugs Thereof Having Reduced Side Effects

Abstract

Methods of reducing undesirable side effects during therapeutic treatment using monomethyl fumarate and prodrugs of monomethyl fumarate are disclosed.

1 . A method of systemically administering a therapeutically effective amount of a compound selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a combination thereof, to treat a disease in each patient of a population of patients in need of such treatment, comprising administering the compound(s) to each patient to achieve across the population a maximum average concentration of monomethyl fumarate in the blood plasma of the patients of less than 500 ng/ml. 
     
     
         2 . The method of  claim 1 , wherein the maximum average concentration of monomethyl fumarate in the blood plasma of the patients is less than 400 ng/ml. 
     
     
         3 . A method of systemically administering a therapeutically effective amount of a compound selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a combination thereof, to treat a disease in each patient of a population of patients in need of such treatment, comprising administering the compound(s) to each patient to achieve across the population an average Cmax of monomethyl fumarate in the blood plasma of the patients of less than 1100 ng/ml. 
     
     
         4 . The method of  claim 3 , wherein the average Cmax of monomethyl fumarate in the blood plasma of the patients is less than 600 ng/ml. 
     
     
         5 . A method of systemically administering a therapeutically effective amount of a compound selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a combination thereof, to treat a disease in each patient of a population of patients in need of such treatment, comprising administering the compound(s) to each patient to achieve across the population an average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of the patients of less than 0.25 wt % ng-eq of MMF dosed/ml/hr. 
     
     
         6 . The method of  claim 5 , wherein the average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of the patients is less than 0.20 wt % ng-eq of MMF dosed/ml/hr or is less than 0.15 wt % ng-eq of MMF dosed/ml/hr. 
     
     
         7 . The method of  claim 5 , wherein the average maximum rate of rise in monomethyl fumarate concentration in the blood plasma of the patients is less than 0.10 wt % ng-eq of MMF dosed/ml/hr 
     
     
         8 . The method of  claim 5 , wherein the average maximum rate of rise in monomethyl fumarate concentration is less than 500 ng/mL/hr. 
     
     
         9 . The method of  claim 5 , wherein the average maximum rate of rise in monomethyl fumarate concentration is less than 400 ng/mL/hr. 
     
     
         10 . The method of  claim 1 , wherein incidence of flushing in the population of patients is reduced. 
     
     
         11 . The method of  claim 1 , wherein the disease is selected from multiple sclerosis and psoriasis. 
     
     
         12 . The method of  claim 1 , wherein the disease is selected from adrenal leukodystrophy, AGE-induced genome damage, Alexanders Disease, Alper's Disease, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease, cardiac insufficiency including left ventricular insufficiency, central nervous system vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia with central nervous system hypomyelination, chronic idiopathic peripheral neuropathy, chronic obstructive pulmonary disease, Crohn's disease, diabetic retinopathy, graft versus host disease, hepatitis C viral infection, herpes simplex viral infection, human immunodeficiency viral infection, Huntington's disease, irritable bowel disorder, ischemia, Krabbe Disease, lichen planus, macular degeneration, mitochondrial encephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardial infarction, neurodegeneration with brain iron accumulation, neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, optic neuritis, pareneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressive supranuclear palsy, psoriasis, reperfusion injury, retinopathia pigmentosa, Schilders Disease, subacute necrotizing myelopathy, susac syndrome, transplantation rejection, transverse myelitis, a tumor, ulcerative colitis, Zellweger's syndrome, granulomas including annulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis, acute dermatitis, chronic dermatitis, alopecia areata (totalis and universalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus, Crohn's disease and cutaneous Crohn's disease. 
     
     
         13 . The method of  claim 1 , wherein the compound comprises monomethyl fumarate. 
     
     
         14 . The method of  claim 1 , wherein the compound comprises a prodrug of monomethyl fumarate. 
     
     
         15 . The method of  claim 14 , wherein the compound comprises a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 1  is C 1-6  alkyl. 
     
     
         16 . The method of  claim 15 , wherein the compound comprises dimethyl fumarate. 
     
     
         17 . The method of  claim 1 , wherein the compound is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 2  and R 3  are independently chosen from hydrogen, C 1-6  alkyl, and substituted C 1-6  alkyl; 
 R 4  and R 5  are independently chosen from hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 1-6  alkoxy, substituted C 1-6  alkoxy, C 1-6  alkoxycarbonyl, substituted C 1-6  alkoxycarbonyl, C 1-6  heteroalkyl, substituted C 1-6  heteroalkyl, C 4-12  cycloalkylalkyl, substituted C 4-12  cycloalkylalkyl, C 7-12  arylalkyl, and substituted C 7-12  arylalkyl; or R 4  and R 5  together with the nitrogen to which they are bonded form a ring chosen from a C 5-10  heteroaryl, substituted C 5-10  heteroaryl, C 5-10  heterocycloalkyl, and substituted C 5-10  heterocycloalkyl; 
 wherein each substituent group is independently chosen from halogen, —OH, —CN, —CF 3 , ═O, —NO 2 , benzyl, —C(O)NR 11   2 , —R 11 , —OR 11 , —C(O)R 11 , —COOR 11 , and —NR 11   2  wherein each R 11  is independently chosen from hydrogen and C 1-4  alkyl. 
 
     
     
         18 . The method of  claim 17 , wherein the compound is chosen from:
 (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;   methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate;   and pharmaceutically acceptable salts thereof.   
     
     
         19 . The method of  claim 1 , wherein the compound is a compound of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 6  is chosen from C 1-6  alkyl, substituted C 1-6  alkyl, C 1-6  heteroalkyl, substituted C 1-6  heteroalkyl, C 3-8  cycloalkyl, substituted C 3-8  cycloalkyl, C 6-8  aryl, substituted C 6-8  aryl, and —OR 10  wherein R 10  is chosen from C 1-6  alkyl, substituted C 1-6  alkyl, C 3-10  cycloalkyl, substituted C 3-10  cycloalkyl, C 6-10  aryl, and substituted C 6-10  aryl; R 7  and R 8  are independently chosen from hydrogen, C 1-6  alkyl, and substituted C 1-6  alkyl; and 
 wherein each substituent group is independently chosen from halogen, —OH, —CN, —CF 3 , ═O, —NO 2 , benzyl, —C(O)NR 11   2 , —R 11 , —OR 11 , —C(O)R 11 , —COOR 11 , N(R 11 )C(O)C(R 11 ) 2 NR 11   2 , and —NR 11   2  wherein each R 11  is independently chosen from hydrogen and C 1-4  alkyl. 
 
     
     
         20 . The method of  claim 19 , wherein the compound is chosen from:
 1-(ethoxycarbonyloxy) ethyl methyl (2E)but-2-ene-1,4-dioate;   methyl 1-(methylethoxycarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate;   methyl 1-(2-methylpropanoyloxy)ethyl (2E)but-2-ene-1,4-dioate;   methyl 1-(phenylcarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate;   cyclohexylcarbonyloxybutyl methyl (2E)but-2-ene-1,4-dioate;   [(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl (2E)but-2-ene-1,4-dioate;   1-(cyclohexyloxycarbonyloxy)ethyl methyl (2E)but-2-ene-1,4-dioate;   methyl 2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate;   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoic acid;   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoic acid;   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoic acid;   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-(aminoacetylamino)propanoic acid;   3-1-{{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethoxycarbonyl}}(2S)-2-aminopropanoic acid; and   a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         21 . The method of  claim 1 , wherein the compound is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is an integer from 2 to 6. 
     
     
         22 . The method of  claim 21 , wherein the compound is chosen from:
 methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate;   methyl 3-morpholin-4-ylpropyl (2E)but-2-ene-1,4-dioate;   methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and   a pharmaceutically acceptable salt of any of the foregoing.   
     
     
         23 . A method of systemically administering a therapeutically effective amount of a compound selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a combination thereof, to treat a disease in a patient in need of such treatment, comprising one of a) or b):
 a) orally administering to the patient, at a dosing frequency of not more than twice per day, an enteric-coated oral sustained release dosage form containing a therapeutically effective dose of the compound(s), wherein the dosage form, when subjected to an in vitro dissolution test employing as a dissolution medium 750 mL of 0.1 N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200 mM tribasic sodium phosphate buffer resulting in an adjustment of the pH of the dissolution medium to 6.8, the dissolution medium being maintained at 37° C. and stirred at 100 rpm,   releases: (i) less than 10 wt % of the dose over an initial 2 hours of the in vitro dissolution test; (ii) at least 90 wt % of the dose over not less than an initial 8 hours of the in vitro dissolution test; (iii) no more than 30 wt % of the dose in any one hour during the in vitro dissolution test; and (iv) no more than 40 wt % of the dose in any consecutive two hours during the in vitro dissolution test; or   b) orally administering to the patient, at a frequency of not more than twice per day, a non-enteric-coated oral sustained release dosage form containing a therapeutically effective dose of the compound(s), wherein the dosage form, when subjected to an in vitro dissolution test employing as a dissolution medium 750 mL of 0.1 N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200 mM tribasic sodium phosphate buffer resulting in an adjustment of the pH of the dissolution medium to 6.8,   releases (i) at least 90 wt % of the dose over not less than an initial 8 hours of the in vitro dissolution test; (ii) no more than 30 wt % of the dose in any one hour during the in vitro dissolution test; and (iii) no more than 40 wt % of the dose in any consecutive two hours during the in vitro dissolution test.   
     
     
         24 . The method of  claim 23 , wherein the dosing frequency is twice per day. 
     
     
         25 . The method of  claim 23 , wherein the dosing frequency is once per day. 
     
     
         26 . The method of  claim 25 , wherein the dosage form releases at least 90 wt % of the dose over not less than an initial 10 hours of the in vitro dissolution test.