Compositions and methods for treating transthyretin (ttr) mediated amyloidosis

A method of treating hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with polyneuropathy in a human patient in need thereof, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, 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.

A method of treating hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with cardiomyopathy in a human patient in need thereof, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, wherein the patisiran drug product is administered intravenously once every 3 weeks 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.

A method of treating hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with cardiomyopathy and polyneuropathy in a human patient in need thereof, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, 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, 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.

A method for reducing a modified Neuropathy Impairment Score (mNIS+7) composite neurological impairment score in a human patient having hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with polyneuropathy, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, 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.

A method for stabilizing or improving a quality of life, a motor strength, a disability, a gait speed, a nutritional status, and/or an autonomic symptom in a human patient having hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with or without polyneuropathy and/or cardiomyopathy, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, wherein the patisiran drug product is administered intravenously once every 3 weeks, wherein the method results in stabilization or improvement of the quality of life, the motor strength, the disability, the gait speed, the nutritional status, and/or the autonomic symptom, respectively, compared to baseline as determined before administration of the patisiran drug product.

A method for stabilizing or improving at least one neuropathy related clinical endpoint selected from the group consisting of a Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QOL-DN), a NIS-W, a Rasch-built Overall Disability Scale (R-ODS), a 10-meter walk test (10-MWT), a modified body mass index (mBMI), and a COMPASS-31 score, in a human patient having hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with or without polyneuropathy and/or cardiomyopathy, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, wherein the patisiran drug product is administered intravenously once every 3 weeks, wherein the method results in stabilization or improvement of the at least one clinical endpoint compared to baseline as determined before administration of the patisiran drug product

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 hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with or without polyneuropathy and/or cardiomyopathy, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, wherein the patisiran drug product is administered intravenously once every 3 weeks, 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.

A method for stabilizing or improving a FAP stage and/or a PND score and/or a serum percent TTR concentration in a human patient having hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with or without polyneuropathy and/or cardiomyopathy, the method comprising administering to the patient a patisiran drug product as described in Table 1A, 1B, or 1C at a dose of 0.3 mg siRNA per kg body weight, wherein the patisiran drug product is administered intravenously once every 3 weeks, wherein the method results in stabilization or improvement of the FAP stage and/or the PND score and/or the serum percent TTR concentration, respectively, compared to baseline as determined before administration of the patisiran drug product.

The method of any of the above claims, 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.

The method of any of the above claims, 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.

The method of any of the above claims, wherein the method results in stabilization or regression of a PND score compared to baseline as determined before administration of the patisiran drug product.

The method of any of the above claims, 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.

The method of any of the above claims, wherein the patient is administered the patisiran drug product for at least 12 months, 18 months, 24 months, 30 months, or 36 months.

The method of any of the above claims, wherein the patient is in need of treatment for hereditary transthyretin-mediated amyloidosis (hATTR 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.

The method of any of the above claims, further comprising administering to the patient the following premedications:

• dexamethasone, oral paracetamol/acetaminophen, diphenhydramine, and ranitidine.

The method of any of the above claims, further comprising administering to the patient an oral daily dose of the USDA recommended daily allowance of vitamin A.

The method of any of the above claims, further comprising administering a tetramer stabilizer.

The method of any of the above claims, wherein administration of at least one drug is performed by the patient.

The method of any of the above claims, wherein administration of at least one drug is performed by a medical professional.

The method of any of the above claims, wherein administration is performed over 80 minutes.

The method of any of the above claims, wherein baseline is an average.