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 treating polyneuropathy in a human subject having a TTR related disorder, the method comprising administering to the human subject an effective amount of a salt form of patisiran,
wherein patisiran is an siRNA consisting of a sense strand consisting of the nucleotide sequence 5′-GuAAccAAGAGuAuuccAudTdT-3′ and an antisense strand consisting of the nucleotide sequence 5′-AUGGAAuACUCUUGGUuACdTdT-3′,
wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, c is 2′-O-methylcytidine, u is 2′-O-methyluridine, and dT is 2′-deoxythymidine;
wherein the salt form of patisiran is formulated in DLin-MC3-DMA, DSPC, cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline,
wherein the salt form of patisiran is administered via intravenous infusion; and
wherein the subject receives a premedication before infusion to reduce the risk of infusion-related reactions.
2 . (canceled)
3 . (canceled)
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 a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) by at least 10%.
6 . The method of claim 1 , wherein the method results in arresting the increase of NIS or mNIS+7.
7 . The method of claim 1 , wherein the method reduces the serum TTR protein concentration to below 40 μg/ml, 25 μg/ml, or 10 μg/ml.
8 . The method of claim 1 , wherein the method reduces the serum TTR protein concentration by at least 85%, 90%, or 95%.
9 . The method of claim 1 , wherein the salt form of patisiran is administered at a dose of 0.3 mg/kg.
10 . The method of claim 1 , wherein the salt form of patisiran is administered once every 21 days.
11 . The method of claim 1 , wherein the salt form of patisiran is administered once every 21 days at a dose of 0.3 mg/kg via an infusion of 1 mL/min for 15 minutes followed by an infusion of 3 mL/min.
12 - 14 . (canceled)
15 . The method of claim 7 , wherein the concentration of serum TTR protein is determined by an immunochemistry based assay, an enzyme-linked immunosorbent assay (ELISA), an assay to determine Vitamin A concentration, an assay to determine RBP concentration, or an assay to determine TTR mRNA concentration.
16 - 38 . (canceled)
39 . The method of claim 1 , wherein the premedication comprises dexamethasone, paracetamol (acetaminophen), an H2 blocker and an H1 blocker.
40 . The method of claim 39 , wherein
(i) the H2 blocker is ranitidine or famotidine; and/or
(ii) the H1 blocker is diphenhydramine, cetirizine, hydroxyzine or fexofenadine.
41 . The method of claim 1 , wherein the premedication comprises dexamethasone, acetaminophen, diphenhydramine, and ranitidine.
42 . The method of claim 1 , wherein the premedication comprises dexamethasone, acetaminophen, cetirizine, and ranitidine.
43 . The method of claim 1 , wherein the subject receives the premedication on the evening before or the day of infusion.
44 . A pharmaceutical composition comprising
a salt form of patisiran, wherein patisiran is an siRNA consisting of a sense strand consisting of the nucleotide sequence 5′-GuAAccAAGAGuAuuccAudTdT-3′ and an antisense strand consisting of the nucleotide sequence 5′-AUGGAAuACUCUUGGUuACdTdT-3′, wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, c is 2′-O-methylcytidine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine;
DLin-MC3-DMA, DSPC, cholesterol, and PEG2000-C-DMG in isotonic phosphate buffered saline.