Granted Patent
B2
US 12,421,516 · App. 18/346,099 · Granted Sep 23, 2025
Antisense oligomers targeting PCSK9
Inventors:
Nanna Albæk (Hørsholm, DK); Maj Hedtjärn (Hørsholm, DK); Marie Wickstrom Lindholm (Hørsholm, DK); Niels Fisker Nielsen (Hørsholm, DK); Andreas Petri (Hørsholm, DK); Jacob Ravn (Hørsholm, DK)
Assignee:
ROCHE INNOVATION CENTER COPENHAGEN A/S
C12N15/1137A61K47/545A61K47/549A61K47/554C12N15/113A61K31/712C12N2310/11C12N2310/3231C12N2310/341C12N2310/351C12N2310/3515C12N2320/32C12N2330/30
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Abstract
The present invention relates to oligomeric compounds and conjugates thereof that target Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for a range of medical disorders, such as hypercholesterolemia and related disorders.
Claims (30)
1. An antisense oligonucleotide (ASO) comprising 10 to 16 nucleotides from the sequence aatgctacaaaaccca (SEQ ID NO:26) wherein:
(i) the ASO is 10 to 25 contiguous nucleotides in length;
(ii) the ASO comprises at least one nucleotide analogue;
(iii) the ASO targets a target region of a pre-mRNA or mature mRNA encoding PCSK9; and,
(iv) the ASO shows less kidney toxicity than an ASO of SEQ ID NO:1.
2. The ASO of claim 1 , wherein the at least one nucleotide analogue comprises an LNA unit.
3. The ASO of claim 2 , wherein the LNA unit is oxy-LNA, thio-LNA, amino-5 LNA, 5′-methyl-LNA, ENA, cET, cMOE or a combination thereof.
4. The ASO of claim 1 , wherein all the internucleoside linkages are phosphorothioate, and at least one of the phosphorothioate internucleoside linkages comprises a chiral center in the R conformation or in the S conformation.
5. The ASO of claim 1 wherein kidney toxicity is determined using a KIM-1 expression assay.
6. The ASO of claim 1 , wherein the ASO is a gapmer.
7. The ASO of claim 1 , wherein the ASO targets a target region comprising an exon sequence.
8. The ASO of claim 1 , wherein the ASO targets a target region comprising an intron sequence.
9. The ASO of claim 1 , wherein the ASO targets a target region comprising an intron-exon junction sequence.
10. An ASO conjugate comprising and ASO of claim 1 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to the ASO directly or via a linker positioned between the contiguous ASO sequence and the non-nucleotide or non-polynucleotide moiety.
11. The ASO conjugate of claim 10 , wherein the non-nucleotide or non-polynucleotide moiety is a liver targeting moiety that is attached to the 5′-end or to the 3′-end of the ASO.
12. The ASO conjugate of claim 11 , wherein the liver targeting moiety comprises at least one asialoglycoprotein receptor targeting conjugate moiety.
13. The ASO conjugate of claim 12 , wherein the asialoglycoprotein receptor targeting conjugate moiety comprises a monovalent, divalent, trivalent, or tetravalent GalNAc cluster.
14. A pharmaceutical composition comprising a compound comprising an ASO of claim 1 and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant.
15. A method of treating a disorder selected from the group consisting of atherosclerosis, hyperlipidemia, hypercholesterolemia, HDL/LDL cholesterol imbalance, coronary artery disease (CAD), or coronary heart disease (CHD) in a subject in need thereof, the method comprising administering comprising administering an effective amount of a compound comprising an ASO of claim 1 to the subject.
16. The method of claim 15 , wherein the dyslipidemia is familial hyperlipidemia (FCHL) or acquired hyperlipidemia.
17. The method of claim 15 , wherein the hypercholesterolemia is familiar hypercholesterolemia or statin resistant hypercholesterolemia.
18. The method of claim 15 , further comprising the administration of a therapeutic agent selected from the group consisting of a statin, a bile sequestering resin, nicotinic acid, a fibric acid derivative, probucol, neomycin, dextrothyroxine, a plant stanol ester, a cholesterol absorption inhibitor, implitapide, an inhibitor of bile acid transporters, a regulator of hepatic CYP7a, an estrogen replacement therapeutic, and an anti-inflammatory.
19. The method of claim 18 , wherein the statin is selected from the group consisting of lovastatin, cerivastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin, and fluvastatin.
20. The method of claim 15 , wherein the antisense oligonucleotide conjugate is administered intravenously or subcutaneously.
21. The method of claim 15 , wherein the antisense oligonucleotide conjugate is administered as a single dose or as multiple doses.
22. An in vitro method of reducing expression levels and/or activity of PCSK9 in a cell comprising administering an effective amount of a compound comprising an ASO of claim 1 to the cell.
23. A method of reducing expression levels and/or activity of PCSK9 in a subject in need thereof comprising administering an effective amount of a compound comprising an ASO of claim 1 to the subject.
24. A method of reducing cholesterol levels in a subject in need thereof comprising administering to said subject an effective amount of a compound comprising an ASO of claim 1 .
25. A method of manufacturing a compound comprising an ASO of claim 1 , the method comprising chemically synthesizing the compound using sequential synthesis.
26. The method of claim 25 , wherein the sequential synthesis is solid phase oligonucleotide synthesis.
Assignments (2)
CHANGE OF NAME
Recorded Dec 15, 2025
From: ROCHE INNOVATION CENTER COPENHAGEN A/S
To: RICC A/S
Reel/Frame 073951/0141 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 28, 2025
From: ALBÆK, NANNA; RAVN, JACOB; HEDTJARN, MAJ; LINDHOLM, MARIE WICKSTROM; NIELSEN, NIELS FISKER; PETRI, ANDREAS
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 071243/0605 →
Priority Claims (5)
EP 13174092
· Jun 27, 2013
· regional
EP 13192930
· Nov 14, 2013
· regional
EP 13192938
· Nov 14, 2013
· regional
EP 14153253
· Jan 30, 2014
· regional
EP 14168331
· May 14, 2014
· regional
Continuity (5)
Continuation
14897223
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