Methods of Treating Transthyretin (TTR) Mediated Amyloidosis

Abstract

Disclosed herein are methods for reducing or arresting an increase in a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a human subject by administering an effective amount of a transthyretin (TTR)-inhibiting composition.

1 . A method for reducing a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) or arresting an increase in a NIS or a mNIS+7 in a human subject having a TTR related disorder, the method comprising administering to the human subject an effective amount of a transthyretin (TTR)-inhibiting composition, wherein the effective amount reduces a concentration of serum TTR protein to below 50 μg/ml or by at least 80%. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the TTR-inhibiting composition is an siRNA, an antisense molecule, an siRNA or an antisense molecule targeting a TTR gene, patisiran, or a revusiran. 
     
     
         4 . The method of  claim 1 , wherein the TTR related disorder is Familial Amyloidotic Polyneuropathy (FAP), FAP with a documented TTR mutation, Familial amyloidotic cardiomyopathy (FAC), transthyretin-mediated amyloidosis (ATTR), or symptomatic polyneuropathy. 
     
     
         5 . The method of  claim 1 , wherein the method results in a reduction of NIS or mNIS+7 by at least 10%, and/or results in arresting the increase of NIS or mNIS+7. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the serum TTR protein concentration is reduced to below 40 μg/ml, 25 μg/ml, or 10 μg/ml; and/or the serum TTR protein concentration is reduced by at least 85%, 90%, or 95%. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the TTR-inhibiting composition is patisiran. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the TTR-inhibiting composition is administered intravenously. 
     
     
         14 - 38 . (canceled) 
     
     
         39 . The method of  claim 9 , wherein the effective amount of the TTR-inhibiting composition is 0.01 to 0.5 mg/kg, 0.15 to 0.3 mg/kg, or 0.3 mg/kg. 
     
     
         40 . The method of  claim 9 , wherein the effective amount of the TTR-inhibiting composition is 0.3 mg/kg. 
     
     
         41 . The method of  claim 9 , wherein the TTR-inhibiting composition is administered once every 21 days. 
     
     
         42 . The method of  claim 9 , wherein the TTR-inhibiting composition is administered at a dose of 0.3 mg/kg once every 21 days via a 70 minute infusion of 1 mL/min for 15 minutes followed by 3 mL/min for 55 minutes. 
     
     
         43 . The method of  claim 9 , wherein the TTR-inhibiting composition is administered at two doses every 21-28 days via a 60 minute infusion of 3.3 mL/min, or via a 70 minute infusion of 1.1 mL/min for 15 minutes followed by 3.3 mL/min for 55 minutes. 
     
     
         44 . The method of  claim 1 , wherein the subject receives a premedication before administration to reduce the risk of infusion-related reactions. 
     
     
         45 . The method of  claim 1 , wherein the subject receives the premedication on the evening before and the day of administration. 
     
     
         46 . The method of  claim 1 , wherein the premedication comprises (a) dexamethasone, acetaminophen, diphenhydramine, and ranitidine; (b) dexamethasone, acetaminophen, cetirizine, and ranitidine; or (c) dexamethasone, paracetamol (acetaminophen), an H2 blocker and an H1 blocker. 
     
     
         47 . The method of  claim 46 , wherein the H2 blocker is ranitidine or famotidine. 
     
     
         48 . The method of  claim 46 , wherein the H1 blocker is cetirizine, hydroxyzine or fexofenadine. 
     
     
         49 . The method of  claim 1 , wherein the subject has cardiomyopathy. 
     
     
         50 . The method of  claim 1 , wherein the subject has does not have cardiomyopathy.