Methods of Treating Transthyretin (TTR) Mediated Amyloidosis
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.