Use of epothilone d in treating tau-associated diseases including alzheimer's disease

Abstract

Methods of treating Tau-associated diseases, preferably tauopathies, are described using epothilone D that exhibit good brain penetration, long half-life, and high selective retention in brain, and provides effective therapies in treating tauopathies including Alzheimer's disease.

1 . A method of treating a Tau-associated disease comprising administering a therapeutically-effective amount of epothilone D to a patient in need of treatment thereof. 
   
   
       2 . The method of  claim 1 , wherein the Tau-associated disease is Alzheimer's disease. 
   
   
       3 . The method of  claim 1 , wherein the Tau-associated disease is selected from frontotemporal dementia, including the subtype of frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and agyrophilic grain disease, Parkinson's disease, Down syndrome, post-encephalic Parkinsonism, myotonic dystrophy, Niemann-Pick C disease, dementia pugilistica, Blint disease, a prion disease, amyotrophic lateral sclerosis, Parkinsonism-dementia complex of Guam, multiple sclerosis, glaucoma, diabetic retinopathy, and traumatic brain injury. 
   
   
       4 . The method of  claim 2 , wherein the epothilone D is administered orally. 
   
   
       5 . The method of  claim 2 , wherein the epothilone D is administered intravenously. 
   
   
       6 . The method of  claim 2 , wherein the epothilone D has good brain penetrance, long brain half-life, and a high selective brain-to-liver retention rate. 
   
   
       7 . The method of  claim 1  wherein the epothilone D has brain penetrance of 0.5 or more measured at a period between 20 min. and 1 h post-dosing, and either or both of 1) a brain half-life of 24 h or more, and 2) brain to liver selective retention rate of 2 or more at 24 or more hours post-dosing. 
   
   
       8 . The method of  claim 6 , wherein the epothilone D has brain penetrance of 0.5 or more measured at a period between 20 min. and 1 h post-dosing, and either or both of 1) a brain half-life of 24 h or more, and 2) brain to liver selective retention rate of 2 or more at 24 or more hours post-dosing. 
   
   
       9 . The method of  claim 2 , wherein the method is therapeutically effecting in treating AD in the patient without causing drug-induced side effects that would require that use of the epothilone D treatment be discontinued. 
   
   
       10 . The method of  claim 9 , wherein the epothilone D is administered to the patient at a dose of between 0.0001-10 mg/m 2 , administered daily, weekly, or on an intermittent basis. 
   
   
       11 . The method of  claim 10 , wherein the dose of epothilone D is between 0.0001-0.05 mg/m 2 , and the epothilone D is administered as a daily oral dose to a human patient. 
   
   
       12 . The method of  claim 10 , wherein the dose of epothilone D is between 0.01-30 mg/m 2 , and the epothilone D is administered intravenously to a human patient on a weekly, biweekly, monthly, or intermittent dosage cycle. 
   
   
       13 . The method of  claim 12 , wherein the cumulative monthly dose is between 0.1-3 mg/m 2 . 
   
   
       14 . A method of treating Alzheimer's Disease in a human patient, comprising the step of administering a therapeutically effective amount of epothilone D to the patient, wherein the epothilone D is administered orally and wherein the dose of epothilone D calculated on a daily basis (regardless of dosing schedule) is between 0.001-2 mg/m 2 , and wherein the epothilone D is therapeutically effective in having an impact on underlying disease and/or providing cognitive benefits to the patient without causing drug-induced side effects that would require that use of the epothilone D treatment be discontinued. 
   
   
       15 . The method of  claim 14 , wherein the epothilones D is administered orally on a dosing schedule selected from once daily and once a week, and wherein the daily dose of epothilone D is between 0.2 to 2 mg/m 2  and the weekly dose is between 1.4 to 14 mg/m 2 . 
   
   
       16 . A pharmaceutical formulation comprising epothilone D suitable for administration to a human patient in need of treatment for a Tau-associated disease, wherein the formulation is therapeutically effective in treating the Tau-associated disease in the patient without causing drug-induced side effects and/or drug-plasma concentration levels that would require use of said epothilone D formulation to be discontinued. 
   
   
       17 . The pharmaceutical formulation according to  claim 16 , wherein the Tau-associated disease is Alzheimer's Disease, and administration of the formulation provides statistically-significant cognitive benefits and/or impact on underlying disease, without causing drug-induced side effects and/or drug-plasma concentration levels that would require use of said epothilone D formulation to be discontinued. 
   
   
       18 . The formulation according to  claim 16 , wherein said formulation comprises epothilone D in a pharmaceutically acceptable solvent system comprising from about 0 to 50% propylene glycol, about 1 to 10% TPGS, about 0.5 to 10% ethanol, about 0-90% water, and/or about 5 to 85% PEG such as PEG-400.