Use of ppar-delta agonists in the treatment of disease

Abstract

Described herein is the use sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate in the preparation of pharmaceutical compositions for the treatment of diseases or conditions that would benefit by administration with a PPARδ agonist compound.

What is claimed is: 
     
         1 . A method for treating a primary mitochondrial myopathy (PMM) in a human comprising orally administering to the human with PMM about 100 mg of sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II), wherein the human with PMM has at least one mutation or deletion in at least one mitochondrial DNA (mtDNA) gene; at least one mitochondrial DNA (mtDNA) defect; at least one mutation or deletion in at least one nuclear DNA (nDNA) gene involved in mitochondrial function; or a combination thereof. 
     
     
         2 . The method of  claim 1 , wherein Compound II is crystalline Compound II and is characterized as having an XRPD pattern with peaks at 2.8±0.2 °2-Theta, 7.2±0.2 °2-Theta, 13.4±0.2 °2-Theta, 17.8±0.2 °2-Theta, 19.7±0.2 °2-Theta, 19.9±0.2 °2-Theta, and 20.6±0.2 °2-Theta as measured using Cu Kα radiation (crystalline Form 1). 
     
     
         3 . The method of  claim 1 , wherein crystalline Compound II is characterized as having an XRPD pattern substantially the same as shown in  FIG.  1    as measured using Cu Kα radiation (crystalline Form 1). 
     
     
         4 . The method of  claim 1 , wherein treating PMM in the human comprises improving the human's exercise tolerance, improving muscle histology, decreasing pain, decreasing fatigue, improving cognition, improving overall well-being, a reduction in myoglobinuria, reducing tachycardia, a reduction in rhabdomyolysis, a reduction in muscle contracture, reducing the severity of PMM muscle symptoms, reducing impairments in work and activities, increasing survival, or a combination thereof. 
     
     
         5 . The method of  claim 4 , wherein improving the human's exercise tolerance comprises increasing the distance walked during a 6-minute walk test, increasing the distance walked during a 12 minute walk test, increasing stair climbing capacity, increasing the number of stands in a 30 second sit to stand test, decreasing the feeling of exhaustion during exercise, or a combination thereof. 
     
     
         6 . The method of  claim 4 , wherein increasing the distance walked during a 12 minute walk test comprises an increase of at least about 10 meters, at least about 20 meters, at least about 30 meters, at least about 40 meters, at least about 50 meters, at least about 60 meters, at least about 70 meters, at least about 80 meters, at least about 90 meters, at least about 100 meters, at least about 125 meters, or more than about 125 meters as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         7 . The method of  claim 4 , wherein decreasing fatigue in the human comprises decreases in the Modified Fatigue Impact Scale (MFIS) as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         8 . The method of  claim 7 , wherein decreases in the Modified Fatigue Impact Scale (MFIS) comprises decreases in physical functioning subscores of the MFIS. 
     
     
         9 . The method of  claim 7 , wherein decreases in the Modified Fatigue Impact Scale (MFIS) comprises decreases psychosocial functioning subscores of the MFIS. 
     
     
         10 . The method of  claim 7 , wherein decreases in the Modified Fatigue Impact Scale (MFIS) comprises decreases in cognitive functioning subscores of the MFIS. 
     
     
         11 . The method of  claim 4 , wherein decreasing pain comprises decreases in the brief pain inventory (BPI) scores by 1, 2, 3, 4, 5, or more than 5 as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         12 . The method of  claim 4 , wherein improving overall well-being comprises improving physical functioning, improving limitations due to physical health problems, improving limitations due to personal or emotional problems, improving emotional well-being, improving social functioning, or improving perceived change in health, or combinations thereof, as measured 
     
     
         13 . The method of  claim 4 , wherein improving overall well-being comprises reductions in the 36-Item Health Survey scoring as measured as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         14 . The method of  claim 4 , wherein reducing the severity of PMM muscle symptoms comprises Patient Global Impression of Change (PGIC) scores by 1, 2, 3, 4, or more than 4 as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         15 . The method of  claim 4 , wherein reducing impairments in work and activities measure comprises reductions in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) scores by at least 10% points, by at least 15% points, by at least 20% points, by at least 30% points, by at least 35% points, by at least 40% points, by at least 45% points, by at least 50% points, or more than 50% points as measured after about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 52 weeks, or more than about 52 weeks of daily administration of Compound II. 
     
     
         16 . The method of  claim 2 , wherein crystalline Compound II is further characterized as having a DSC thermogram substantially the same as shown in  FIG.  2    or a DSC thermogram with an endotherm having onset at about 179.5° C. and peak at about 181.6° C. 
     
     
         17 . The method of  claim 2 , wherein crystalline Compound II is further characterized as having a TGA pattern substantially the same as shown in  FIG.  3    or a TGA pattern with a 0.1% w/w loss from 25 to 60° C. and degradation onset at about 250° C. 
     
     
         18 . The method of  claim 2 , wherein crystalline Compound II is further characterized as having an FTIR spectroscopy pattern substantially the same as shown in  FIG.  4    or an FTIR spectroscopy pattern with peaks at about 103 cm −1 , about 838 cm −1 , about 1220 cm −1 , about 1504 cm −1 , and about 1612 cm −1 . 
     
     
         19 . The method of  claim 2 , wherein crystalline Compound II is further characterized as having a Raman spectroscopy pattern substantially the same as shown in  FIG.  5    or a Raman spectroscopy pattern with peaks at about 103 cm −1 , about 126 cm −1 , about 810 cm −1 , about 1158 cm −1 , about 1238 cm −1 , about 1604 cm −1 , and about 1629 cm −1 . 
     
     
         20 . The method of  claim 1 , wherein crystalline Compound II is characterized as having an XRPD pattern substantially the same as shown in  FIG.  6    as measured using Cu Kα radiation (crystalline Form 2). 
     
     
         21 . The method of  claim 2 , wherein crystalline Compound II is characterized as having an XRPD pattern with peaks at about 4.5 2-Theta, about 13.8° 2-Theta, about 17.6°2-Theta, about 19.0° 2-Theta, about 19.6° 2-Theta, about 19.9° 2-Theta, about 20.5°2-Theta, and about 23.0° 2-Theta as measured using Cu Kα radiation (crystalline Form 2). 
     
     
         22 . The method of  claim 2 , wherein crystalline Compound II is characterized as having an XRPD pattern substantially the same as shown in  FIG.  9    as measured using Cu Kα radiation (crystalline Form 3). 
     
     
         23 . The method of  claim 2 , wherein crystalline Compound II is characterized as having an XRPD pattern substantially the same as shown in  FIG.  12    as measured using Cu Kα radiation (crystalline Form 4). 
     
     
         24 . The method of  claim 2 , wherein crystalline Compound II is characterized as having an XRPD pattern substantially the same as shown in  FIG.  15    as measured using Cu Kα radiation (crystalline Form 5). 
     
     
         25 . The method of  claim 2 , wherein crystalline Compound II is characterized as having an XRPD pattern with peaks at about 2.8 2-Theta, about 8.3° 2-Theta, about 8.7° 2-Theta, about 13.1° 2-Theta, about 19.4° 2-Theta, about 20.2° 2-Theta, about 21.3° 2-Theta, and about 24.6° 2-Theta as measured using Cu Kα radiation (crystalline Form 5). 
     
     
         26 . The method of  claim 1 , wherein Compound II is systemically administered to the human in the form of a powder, pill, tablet or capsule. 
     
     
         27 . The method of  claim 1 , further comprising administering at least one additional therapeutic to the human, wherein: the at least one additional therapeutic is ubiquinol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, n-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, folinic acid/leucovorin calcium, resveratrol, acipimox, elamipretide, cysteamine, succinate, NAD agonists, vatiquinone (EPI-743), omaveloxolone (RTA-408), nicotinic acid, nicotinamide, elamipretide, KL133, KH176, or a combination thereof; or wherein the at least one additional therapeutic is an odd-chain fatty acid, odd-chain fatty ketone, L-carnitine, or combinations thereof; or wherein the at least one additional therapeutic is triheptanoin, n-heptanoic acid, a triglyceride, or a salt or thereof, or combinations thereof; or wherein the at least one additional therapeutic is a creatine supplement, a vitamin B-6 supplement, glucagon, sucrose, ribose, an odd-chain fatty acid, odd-chain fatty ketone, L-carnitine, an ACE inhibitor or a combination thereof.