Compositions and methods for treating transthyretin (TTR) mediated amyloidosis
Disclosed herein are methods for treating hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in a human patient in need thereof by administering an effective amount of a transthyretin (TTR)-inhibiting composition.
1. A method of treating cardiomyopathy in a human patient with transthyretin-mediated amyloidosis (TTR amyloidosis), the method comprising administering to the patient a patisiran drug product,
wherein the patisiran drug product comprises an siRNA which consists of a sense strand comprising the nucleotide sequence 5′-GuAAccAAGAGuAuuccAudTdT-3′ and an antisense strand comprising the nucleotide sequence 5′-AUGGAAuACUCUUGGUuACdTdT-3′, wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, a is 2′-O-methyladenosine, c is 2′-O-methylcytidine, g is 2′-O-methylguanosine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine,
wherein the siRNA is formulated in a composition comprising (6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and α-(3′-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000-C-DMG),
wherein the patisiran drug product is administered intravenously once every 3 weeks at a dose of 0.3 mg siRNA per kg body weight, and the method results in stabilization or improvement of a serum NT-proBNP concentration and/or a left ventricle (LV) strain and/or a LV wall thickness compared to baseline as determined before administration of the patisiran drug product.
2. The method of claim 1 , wherein the TTR amyloidosis is with cardiomyopathy and polyneuropathy, and wherein the patisiran drug product is administered intravenously once every 3 weeks, wherein the method results in a decrease in the modified Neuropathy Impairment Score (mNIS+7) composite neurological impairment score from baseline as determined at 18 months, wherein baseline is the mNIS+7 score of the patient before administration of the patisiran drug product.
3. A method for stabilizing or improving a serum NT-proBNP concentration and/or a left ventricle (LV) strain and/or a LV wall thickness in a human patient having transthyretin-mediated amyloidosis (TTR amyloidosis) with cardiomyopathy, the method comprising administering to the patient a patisiran drug product,
wherein the patisiran drug product comprises an siRNA which consists of a sense strand comprising the nucleotide sequence 5′-GuAAccAAGAGuAuuccAudTdT-3′ and an antisense strand comprising the nucleotide sequence 5′-AUGGAAuACUCUUGGUuACdTdT-3′, wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, a is 2′-O-methyladenosine, c is 2′-O-methylcytidine, g is 2′-O-methylguanosine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine,
wherein the siRNA is formulated in a composition comprising (6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and α-(3′-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000-C-DMG),
wherein the patisiran drug product is administered intravenously once every 3 weeks at a dose of 0.3 mg siRNA per kg body weight, and
wherein the method results in stabilization or improvement of the serum NT-proBNP concentration and/or the left ventricle (LV) strain and/or the LV wall thickness, respectively, compared to baseline as determined before administration of the patisiran drug product.
4. The method of claim 2 , wherein the change from baseline of the mNIS+7 score is −6.0 points.
5. The method of claim 2 , wherein the decrease from baseline of mNIS+7 score is also determined at 9 months.
6. The method of claim 2 , wherein the method results in an improvement over baseline in one or more neuropathy related clinical endpoints selected from the group consisting of
a. a Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QOL-DN); and
b. a NIS-W; and
c. a Rasch-built Overall Disability Scale (R-ODS); and
d. a 10-meter walk test (10-MWT); and
e. a modified body mass index (mBMI); and
f. a COMPASS-31 score.
7. The method of claim 6 , wherein the method results in an improvement in all of the neuropathy related clinical endpoints.
8. The method of claim 6 , wherein the method results in an improvement in a Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QOL-DN) and a COMPASS-31 score and a 10-meter walk test.
9. The method of claim 6 , wherein the method results in a serum percent TTR concentration reduction in the patient compared to baseline as determined before administration of the patisiran drug product.
10. The method of claim 2 , wherein the method results in stabilization or regression of a FAP stage in the patient compared to baseline as determined before administration of the patisiran drug product.
11. The method of claim 2 , wherein the method results in stabilization or regression of a PND score compared to baseline as determined before administration of the patisiran drug product.
12. The method of claim 2 , wherein the method results in a decrease in an intra epidermal nerve fiber density in a skin biopsy compared to baseline as determined before administration of the patisiran drug product.
13. The method of claim 2 , wherein the patient is administered the patisiran drug product for at least 12 months, 18 months, 24 months, 30 months, or 36 months.
14. The method of claim 3 , wherein the patient is in need of treatment for transthyretin-mediated amyloidosis (TTR amyloidosis) with cardiomyopathy and the method results in an improvement or a stabilization of a cardiac marker and/or an echocardiogram parameter compared to baseline as determined before administration of the patisiran drug product.
15. The method of claim 14 , wherein the cardiac marker is a serum NT-proBNP concentration and the echocardiogram parameter is a left ventricle (LV) strain or a LV wall thickness.
16. The method of claim 1 , further comprising administering to the patient the following premedications: dexamethasone, oral paracetamol/acetaminophen, diphenhydramine, and ranitidine.
17. The method of claim 1 , further comprising administering to the patient the following premedications:
a. IV dexamethasone 10 mg, or equivalent; and
b. oral paracetamol/acetaminophen 500 mg, or equivalent; and
c. IV histamine H1 receptor antagonist (H1 blocker): diphenhydramine 50 mg, or equivalent other IV H1 blocker or hydroxyzine 25 mg or fexofenadine 30 or 60 mg PO or cetirizine 10 mg PO; and
d. IV histamine H2 receptor antagonist (H2 blocker): ranitidine 50 mg or famotidine 20 mg, or equivalent other H2 blocker dose.
18. The method of claim 16 , wherein the premedications are administered approximately one hour prior to each patisiran drug product administration.
19. The method of claim 1 , further comprising administering to the patient an oral daily dose of the USDA recommended daily allowance of vitamin A.
20. The method of claim 1 , further comprising administering a tetramer stabilizer, wherein the tetramer stabilizer is tafamidis or diflunisal.
21. The method of claim 1 , wherein the patient
a. is Caucasian; and/or
b. lives in North America; and/or
c. is 65 years old or older; and/or
d. is male; and/or
e. has FAP Stage I; and/or
f. has FAP Stage II; and/or
g. has a baseline mNIS+7 score between 8 and 165; and/or
h. has a Val30 Met TTR mutation; and/or
i. has one or more TTR mutations found in Table X; and/or
j. has echocardiographic evidence of cardiac amyloid involvement; and/or
k. has a history of prior long term TTR tetramer stabilizer use.
22. The method of claim 1 , wherein administration is performed over 80 minutes.
23. The method of claim 1 , wherein baseline is an average.
24. The method of claim 1 , wherein the siRNA is formulated in a composition comprising 13.0 mg/mL of (6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 3.3 mg/mL of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 6.2 mg/mL of cholesterol, and 1.6 mg/mL of α-(3′-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000-C-DMG).
25. The method of claim 3 , wherein the siRNA is formulated in a composition comprising 13.0 mg/mL of (6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 3.3 mg/mL of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 6.2 mg/mL of cholesterol, and 1.6 mg/mL of α-(3′-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000-C-DMG).
26. The method of claim 1 , wherein the TTR amyloidosis is a hereditary TTR amyloidosis.
27. The method of claim 3 , wherein the TTR amyloidosis is a hereditary TTR amyloidosis.