METHODS AND COMPOSITIONS FOR TREATING A PROPROTEIN CONVERTASE SUBTILISIN KEXIN (PCSK9) GENE-ASSOCIATED DISORDER
The invention relates to methods of inhibiting the expression of a PCSK9 gene in a subject, as well as therapeutic and prophylactic methods for treating subjects having a lipid disorder, such as a hyperlipidemia using RNAi agents, e.g., double-stranded RNAi agents, targeting the PCSK9 gene.
1 . A method of inhibiting the expression of a PCSK9 gene in a subject, comprising administering to the subject a fixed dose of about 25 mg to about 800 mg of a double-stranded ribonucleic acid (RNAi) agent,
wherein the double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 3544-3623 of the nucleotide sequence of SEQ ID NO:1, thereby inhibiting the expression of the PCSK9 gene in the subject.
2 . A method of treating a subject having a disorder that would benefit from reduction in PCSK9 expression, comprising administering to the subject a fixed dose of about 25 mg to about 800 mg of a double-stranded ribonucleic acid (RNAi) agent,
wherein the double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 3544-3623 of the nucleotide sequence of SEQ ID NO:1, thereby treating the subject having a disorder that would benefit from reduction in PCSK9 expression.
3 . The method of claim 1 or 2 , wherein the fixed dose is administered to the subject at an interval of once a week.
4 . The method of claim 1 or 2 , wherein the fixed dose is administered to the subject at an interval of once every two weeks.
5 . The method of claim 1 or 2 , wherein the fixed dose is administered to the subject at an interval of once a month.
6 . The method of claim 1 or 2 , wherein the fixed dose is administered to the subject at an interval of once a quarter.
7 . The method of claim 1 or 2 , wherein the fixed dose is administered to the subject at an interval of biannually.
8 . The method of claim 3 , wherein the subject is administered a fixed dose of about 25 mg to about 50 mg once a week.
9 . The method of claim 4 , wherein the subject is administered a fixed dose of about 50 mg to about 100 mg once every two weeks.
10 . The method of claim 5 , wherein the subject is administered a fixed dose of about 100 mg to about 200 mg once a month.
11 . The method of claim 6 , wherein the subject is administered a fixed dose of about 200 mg to about 800 mg once a quarter.
12 . The method of claim 7 , wherein the subject is administered a fixed dose of about 200 mg to about 800 mg biannually.
13 . The method of claim 1 or 2 , wherein the RNAi agent is administered to the subject in a dosing regimen that includes a loading phase followed by a maintenance phase.
14 . The method of claim 13 , wherein the dose administered to the subject during the loading phase is the same as the dose administered to the subject during the maintenance phase.
15 . The method of claim 1 or 2 , further comprising administering an additional therapeutic agent to the subject.
16 . The method of claim 15 , wherein the additional therapeutic agent is a statin.
17 . The method of claim 15 , wherein the additional therapeutic agent is an anti-PCSK9 antibody.
18 . The method of claim 17 , wherein the anti-PCSK9 antibody is selected from the group consisting of alirocumab (Praluent), evolocumab (Repatha), and bococizumab.
19 . The method of claim 1 or 2 , wherein the antisense strand comprises the nucleotide sequence 5′-ACAAAAGCAAAACAGGUCUAGAA-3′(SEQ ID NO: 685).
20 . The method of claim 1 or 2 , wherein the sense strand comprises the nucleotide sequence 5′-CUAGACCUGUTUUGCUUUUGU-3′ (SEQ ID NO: 686).
21 . The method of claim 1 or 2 , wherein the double-stranded ribonucleic acid RNAi agent comprises at least one modified nucleotide.
22 . The method of claim 1 or 2 , wherein substantially of the nucleotides of the sense strand are modified nucleotides; substantially all of the nucleotides of the antisense strand are modified nucleotides; all of the nucleotides of the sense strand are modified nucleotides; or all of the nucleotides of the antisense strand are modified nucleotides.
23 . The method of claim 1 or 2 , wherein the double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the nucleotide sequence 5′-ACAAAAGCAAAACAGGUCUAGAA-3′ (SEQ ID NO: 685) and the sense strand comprises the nucleotide sequence 5′-CUAGACCUGUTUUGCUUUUGU-3′ (SEQ ID NO: 686).
24 . The method of claim 23 , wherein the sense strand comprises the nucleotide sequence of 5′-csusagacCfuGfudTuugcuuuugu-3′ (SEQ ID NO: 687) and the antisense strand comprises the nucleotide sequence of 5′-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3′ (SEQ ID NO: 688) (AD-60212),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage.
25 . The method of claim 1 or 2 , wherein the double-stranded ribonucleic acid RNAi agent further comprises a ligand.
26 . The method of claim 1 or 2 , wherein the subject is a human.
27 . The method of claim 26 , wherein the human subject has a disorder that would benefit from reduction in PCSK9 expression.
28 . The method of claim 2 or 27 , wherein the disorder that would benefit from reduction in PCSK9 expression is hyperlipidemia.
29 . The method of claim 28 , wherein the hyperlipidemia is hypercholesterolemia.
30 . The method of claim 1 or 2 , wherein the double stranded RNAi agent is administered to the subject subcutaneously; or intramuscularly.
31 . The method of claim 1 or 2 , wherein PCSK9 expression is inhibited by at least about 30%.
32 . The method of claim 1 or 2 , wherein the RNAi agent is administered in a pharmaceutical composition.
33 . A kit for performing the method of claim 1 or 2 , comprising
a) the RNAi agent, and
b) instructions for use, and
c) optionally, means for administering the RNAi agent to the subject.