WO2022221441A2 - Products and compositions - Google Patents

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WO2022221441A2
WO2022221441A2 PCT/US2022/024672 US2022024672W WO2022221441A2 WO 2022221441 A2 WO2022221441 A2 WO 2022221441A2 US 2022024672 W US2022024672 W US 2022024672W WO 2022221441 A2 WO2022221441 A2 WO 2022221441A2
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oligomeric compound
compound according
region
nucleoside
nos
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WO2022221441A3 (en
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Dmitry Samarsky
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Sirnaomics Inc
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Sirnaomics Inc
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Priority to IL307655A priority Critical patent/IL307655A/en
Priority to CA3215347A priority patent/CA3215347A1/en
Priority to BR112023021231A priority patent/BR112023021231A2/en
Priority to EP22788875.7A priority patent/EP4323523A4/en
Priority to AU2022258464A priority patent/AU2022258464A1/en
Priority to CN202280040778.8A priority patent/CN117500926A/en
Priority to JP2023562925A priority patent/JP2024514887A/en
Publication of WO2022221441A2 publication Critical patent/WO2022221441A2/en
Publication of WO2022221441A3 publication Critical patent/WO2022221441A3/en
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
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    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21027—Coagulation factor XIa (3.4.21.27)

Definitions

  • FXI Factor XI
  • Methods, compounds, and compositions are provided for reducing expression of FXI mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate thromboembolic diseases, such as deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.
  • thromboembolic diseases such as deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.
  • thromboembolic diseases such as deep vein thrombosis, venous or arterial thrombosis,
  • coagulation comprises a cascade of reactions culminating in the conversion of soluble fibrinogen to an insoluble fibrin gel.
  • the steps of the cascade involve the conversion of an inactive zymogen to an activated enzyme.
  • the active enzyme then catalyzes the next step in the cascade.
  • Coagulation Cascade The coagulation cascade may be initiated through two branches, the tissue factor pathway (also “extrinsic pathway”), which is the primary pathway, and the contact activation pathway (also “intrinsic pathway”).
  • TF cell surface receptor tissue factor
  • extravascular cells pericytes, cardiomyocytes, smooth muscle cells, and keratinocytes
  • vascular monocytes and endothelial cells upon induction by inflammatory cytokines or endotoxin.
  • TF is the high affinity cellular receptor for coagulation Factor VIIa, a serine protease.
  • VIIa In the absence of TF, VIIa has very low catalytic activity, and binding to TF is necessary to render VIIa functional through an allosteric mechanism (Drake et al., Am J Pathol 1989, 134: 1087-1097).
  • the TF-VIIa complex activates Factor X to Xa.
  • Xa in turn associates with its co-factor Factor Va into a prothrombinase complex which in turn activates prothrombin, (also known as Factor II or Factor 2) to thrombin (also known as Factor Ila, or Factor 2a).
  • Thrombin activates platelets, converts fibrinogen to fibrin and promotes fibrin cross-linking by activating Factor XIII, thus forming a stable plug at sites where TF is exposed on extravascular cells.
  • thrombin reinforces the coagulation cascade response by activating Factors V and VIII.
  • the contact activation pathway is triggered by activation of Factor XII to Xlla.
  • Factor Xlla converts XI to XIa
  • XIa converts IX to IXa.
  • IXa associates with its cofactor VIIIa to convert X to Xa.
  • Factor Xa associates with Factor Va to activate prothrombin (Factor II) to thrombin (Factor Ila).
  • Factor XI enhances both the formation and stability of clots in vitro, but is not thought to be involved in the initiation of clotting. Rather, Factor XI is important in the propagation phase of clot growth (von de Borne, et al., Blood Coagulation and Fibrinolysis, 2006, 17:251-257).
  • TAFI thrombin activatable fibrinolysis inhibitor
  • Inhibition of coagulation At least three mechanisms keep the coagulation cascade in check, namely the action of activated protein C, antithrombin, and tissue factor pathway inhibitor.
  • Activated protein C is a serine protease that degrades cofactors Va and VIIIa. Protein C is activated by thrombin with thrombomodulin, and requires coenzyme Protein S to function.
  • Antithrombin is a serine protease inhibitor (serpin) that inhibits serine proteases: thrombin, Xa, Xlla, XIa and IXa. Tissue factor pathway inhibitor inhibits the action of Xa and the TF-VIIa complex.
  • serpin serine protease inhibitor
  • thrombin serine protease inhibitor
  • Xa Xa
  • Xlla XIa
  • IXa Tissue factor pathway inhibitor inhibits the action of Xa and the TF-VIIa complex.
  • Disease Thrombosis is the pathological development of blood clots, and an embolism occurs when a blood clot migrates to another part of the body and interferes with organ function. Thromboembolism may cause conditions such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke.
  • Warfarin is typically used to treat patients suffering from atrial fibrillation.
  • the drug interacts with vitamin K-dependent coagulation factors which include Factors II, VII, IX and X.
  • Anticoagulant proteins C and S are also inhibited by warfarin. Drug therapy using warfarin is further complicated by the fact that warfarin interacts with other medications, including drugs used to treat atrial fibrillation, such as amiodarone. Because therapy with warfarin is difficult to predict, patients must be carefully monitored in order to detect any signs of anomalous bleeding. Heparin functions by activating antithrombin which inhibits both thrombin and Factor X (Bjork I, Lindahl U. Mol Cell Biochem.198248: 161-182). Treatment with heparin may cause an immunological reaction that makes platelets aggregate within blood vessels that can lead to thrombosis.
  • HIT heparin-induced thrombocytopenia
  • LMWH can also inhibit Factor II, but to a lesser degree than unfractioned heparin (UFH).
  • UHF unfractioned heparin
  • LMWH has been implicated in the development of HIT.
  • Several direct oral anticoagulants have been FDA-approved for the treatment of thrombotic disease, including four Factor Xa inhibitors Betrixaban, Apixaban, Rivaroxaban and Edoxaban and one direct thrombin inhibitor Dabigatran. (Smith, M., Surg Clin N Am 201898:219-238).
  • Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression (Fire et a.l, 1998, Nature.1998 Feb 19;391 (6669):806-11 and Elbashir et at., 2001 , Nature.2001 May 24;411 (6836):494-88) by a mechanism that has been termed RNA interference (RNAi).
  • RNAi RNA interference
  • RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger loaded into the RISC complex.
  • RISC RNA-induced silencing complex
  • Interfering RNA (iRNA) such as siRNAs, antisense RNA, and micro-RNA are oligonucleotides that prevent the formation of proteins by gene-silencing i.e. inhibiting gene translation of the protein through degradation of mRNA molecules. Gene-silencing agents are becoming increasingly important for therapeutic applications in medicine.
  • An aim is to, therefore, provide compounds, methods, and pharmaceutical compositions for the treatment of thromboembolic diseases as described herein, which comprise oligomeric compounds that modulate and inhibit, gene expression by RNAi.
  • Summary Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression, and associated therapeutic uses. Specific oligomeric compounds and sequences are described herein. This summary is not intended to identify key features or essential features of the subject matter as described herein, nor is it intended to be used to determine the scope of that subject matter. Detailed Description and Embodiments The embodiments described below are exemplary but the skilled artisan will recognize that additional embodiments may be achieved.
  • Figures 3 to 12 show the screening results for FXI gene expression as a percentage of gene expression in non-treated cells for oligomeric compounds including oligonucleotides of Table 1a / 1b of Example 1.
  • Figure 13 provides dose response curves for the 26 FXI lead compounds as identified in Example 2.
  • Figure 14 provides dose response curves for the 5 FXI lead compounds as identified further to the results of Figure 13.
  • Figures 15 to 17 show the overall sequences for oligomeric compounds F11-91, F11-46, F11-152.
  • Figure 18 shows compounds which have been selected for medicinal chemistry.
  • Figure 19 shows performance of the compounds shown in Figure 18.
  • Figure 20 show compounds which have been designed on the basis of the results shown in Figure 19.
  • Figure 21 shows data for the compounds displayed in Figure 20.
  • Figure 22 shows the structure of compounds tested in humanized mice.
  • Figure 23 shows the data obtained from testing in humanized mice.
  • Figure 24 shows the design of an in vivo study with compound 91-Conv-31.
  • Figure 25 shows performance of a compound in an in vivo study in terms of Factor XI activity knock- down.
  • Figure 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study.
  • Figure 27 shows the read-out of the tests illustrated in Figure 26.
  • Figure 28 presents data demonstrating a lack of side effects. Definitions Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art.
  • Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in "Carbohydrate Modifications in Antisense Research” Edited by Sangvi and Cook, American Chemical Society , Washington D.C., 1994; “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21 st edition, 2005; and “Antisense Drug Technology, Principles, Strategies, and Applications” Edited by Stanley T. Crooke, CRC Press, Boca Raton, Florida; and Sambrook et al., "Molecular Cloning, A laboratory Manual,” 2 nd Edition, Cold Spring Harbor Laboratory Press, 1989, which are hereby incorporated by reference for any purpose.
  • excipient means any compound or mixture of compounds that is added to a composition as provided herein that is suitable for delivery of an oligomeric compound.
  • nucleoside means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides.
  • Nucleosides may be linked to a phosphate moiety, phosphate- linked nucleosides also being referred to as “nucleotides”.
  • “chemical modification” or “chemically modified” means a chemical difference in a compound when compared to a naturally occurring counterpart. Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and internucleoside linkage modifications. In reference to an oligonucleotide, chemical modification does not include differences only in nucleobase sequence.
  • furanosyl means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom.
  • naturally occurring sugar moiety means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA.
  • a “naturally occurring sugar moiety” as referred to herein is also termed as an "unmodified sugar moiety".
  • such a “naturally occurring sugar moiety” or an “unmodified sugar moiety” as referred to herein has a -H (DNA sugar moiety) or –OH (RNA sugar moiety) at the 2'-position of the sugar moiety, especially a -H (DNA sugar moiety) at the 2'-position of the sugar moiety.
  • sugar moiety means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside.
  • modified sugar moiety means a substituted sugar moiety or a sugar surrogate.
  • substituted sugar moiety means a furanosyl that has been substituted.
  • Substituted sugar moieties include, but are not limited to furanosyls comprising substituents at the 2'-position, the 3'-position, the 5'-position and / or the 4'-position. Certain substituted sugar moieties are bicyclic sugar moieties.
  • 2'-substituted sugar moiety means a furanosyl comprising a substituent at the 2'- position other than H or OH. Unless otherwise indicated, a 2'-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2' -substituent of a 2'-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring).
  • MOE means -OCH2CH2OCH3.
  • 2'-F nucleoside refers to a nucleoside comprising a sugar comprising fluorine at the 2' position.
  • the fluorine in a 2'-F nucleoside is in the ribo position (replacing the OH of a natural ribose).
  • Duplexes of uniformly modified 2′-fluorinated (ribo) oligonucleotides hybridized to RNA strands are not RNase H substrates while the ara analogs retain RNase H activity.
  • sucrose surrogate means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside sub-units are capable of linking together and / or linking to other nucleosides to form an oligomeric compound which is capable of hybridizing to a complementary oligomeric compound.
  • Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen.
  • Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents).
  • Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid).
  • Sugar surrogates include without limitation morpholinos, cyclohexenyls and cyclohexitols.
  • "bicyclic sugar moiety” means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure.
  • the 4 to 7 membered ring is a sugar ring.
  • the 4 to 7 membered ring is a furanosyl.
  • the bridge connects the 2 '-carbon and the 4 '-carbon of the furanosyl.
  • nucleotide means a nucleoside further comprising a phosphate linking group.
  • linked nucleosides may or may not be linked by phosphate linkages and thus includes, but is not limited to “linked nucleotides.”
  • linked nucleosides are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked).
  • nucleobase means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified.
  • unmodified nucleobase or “naturally occurring nucleobase” means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U).
  • modified nucleobase means any nucleobase that is not a naturally occurring nucleobase.
  • modified nucleoside means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides.
  • Modified nucleosides can comprise a modified sugar moiety and / or a modified nucleobase.
  • bicyclic nucleoside or “BNA” means a nucleoside comprising a bicyclic sugar moiety.
  • locked nucleic acid nucleoside or “LNA” means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH2-O-2'bridge.
  • 2 '-substituted nucleoside means a nucleoside comprising a substituent at the 2'- position of the sugar moiety other than H or OH.
  • a 2 '-substituted nucleoside is not a bicyclic nucleoside.
  • deoxynucleoside means a nucleoside comprising 2'-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA).
  • a 2'- deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil).
  • oligonucleotide means a compound comprising a plurality of linked nucleosides.
  • an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and / or unmodified deoxyribonucleosides (DNA) and / or one or more modified nucleosides.
  • modified oligonucleotide means an oligonucleotide comprising at least one modified nucleoside and / or at least one modified internucleoside linkage.
  • linkage or “linking group” means a group of atoms that link together two or more other groups of atoms.
  • internucleoside linkage means a covalent linkage between adjacent nucleosides in an oligonucleotide.
  • naturally occurring internucleoside linkage means a 3' to 5' phosphodiester linkage.
  • modified internucleoside linkage means any internucleoside linkage other than a naturally occurring internucleoside linkage.
  • a "modified internucleoside linkage" as referred to herein can include a modified phosphorous linking group such as a phosphorothioate or phosphorodithioate internucleoside linkage.
  • terminal internucleoside linkage means the linkage between the last two nucleosides of an oligonucleotide or defined region thereof.
  • phosphorus linking group means a linking group comprising a phosphorus atom and can include naturally occurring phosphorous linking groups as present in naturally occurring RNA or DNA, such as phosphodiester linking groups, or modified phosphorous linking groups that are not generally present in naturally occurring RNA or DNA, such as phosphorothioate or phosphorodithioate linking groups.
  • Phosphorus linking groups can therefore include without limitation, phosphodiester, phosphorothioate, phosphorodithioate, phosphonate, methylphosphonate, phosphoramidate, phosphorothioamidate, thionoalkylphosphonate, phosphotriesters, thionoalkylphosphotriester and boranophosphate.
  • internucleoside phosphorus linking group means a phosphorus linking group that directly links two nucleosides.
  • "oligomeric compound” means a polymeric structure comprising two or more substructures. In certain embodiments, an oligomeric compound comprises an oligonucleotide, such as a modified oligonucletide.
  • an oligomeric compound further comprises one or more conjugate groups and / or terminal groups and / or ligands.
  • an oligomeric compound consists of an oligonucleotide.
  • an oligomeric compound comprises a backbone of one or more linked monomeric sugar moieties, where each linked monomeric sugar moiety is directly or indirectly attached to a heterocyclic base moiety.
  • oligomeric compounds may also include monomeric sugar moieties that are not linked to a heterocyclic base moiety, thereby providing abasic sites.
  • Oligomeric compounds may be defined in terms of a nucleobase sequence only, i.e., by specifying the sequence of A, G, C, U (or T).
  • the structure of the sugar-phosphate backbone is not partictularly limited and may or may not comprise modified sugars and/or modified phosphates.
  • oligomeric compounds may be more comprehensively defined, i.e, by specifying not only the nucleobase sequence, but also the structure of the backbone, in particular the modification status of the sugars (unmodified, 2'-OMe modified, 2'-F modified etc.) and/or of the phosphates.
  • terminal group means one or more atom attached to either, or both, the 3 ' end or the 5' end of an oligonucleotide. In certain embodiments, a terminal group comprises one or more terminal group nucleosides.
  • conjugate or “conjugate group” means an atom or group of atoms bound to an oligonucleotide or oligomeric compound. In certain embodiments, a conjugate group links a ligand to a modified oligonucleotide or oligomeric compound.
  • conjugate groups can modify one or more properties of the compound to which they are attached, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and / or clearance properties.
  • conjugate linker or “linker” in the context of a conjugate group means a portion of a conjugate group comprising any atom or group of atoms and which covalently link an oligonucleotide to another portion of the conjugate group.
  • the point of attachment on the oligomeric compound is the 3 '-oxygen atom of the 3'-hydroxyl group of the 3' terminal nucleoside of the oligonucleotide.
  • the point of attachment on the oligomeric compound is the 5'-oxygen atom of the 5'-hydroxyl group of the 5' terminal nucleoside of the oligonucleotide.
  • the bond for forming attachment to the oligomeric compound is a cleavable bond. In certain such embodiments, such cleavable bond constitutes all or part of a cleavable moiety.
  • conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and ligand portion that can comprise one or more ligands, such as a carbohydrate cluster portion, such as an N-Acetyl-Galactosamine, also referred to as "GalNAc", cluster portion.
  • the carbohydrate cluster portion is identified by the number and identity of the ligand.
  • the carbohydrate cluster portion comprises 2 GalNAc groups.
  • the carbohydrate cluster portion comprises 3 GalNAc groups and this is particularly preferred.
  • the carbohydrate cluster portion comprises 4 GalNAc groups.
  • Such ligand portions are attached to an oligomeric compound via a cleavable moiety, such as a cleavable bond or cleavable nucleoside.
  • a cleavable moiety such as a cleavable bond or cleavable nucleoside.
  • the ligands can be arranged in a linear or branched configuration, such as a biantennary or triantennary configurations.
  • "cleavable moiety” means a bond or group that is capable of being cleaved under physiological conditions.
  • a cleavable moiety is cleaved inside a cell or sub- cellular compartments, such as an endosome or lysosome.
  • a cleavable moiety is cleaved by endogenous enzymes, such as nucleases.
  • a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds.
  • a cleavable moiety is a phosphodiester linkage.
  • cleavable bond means any chemical bond capable of being broken.
  • carbohydrate cluster means a compound having one or more carbohydrate residues attached to a linker group.
  • modified carbohydrate means any carbohydrate having one or more chemical modifications relative to naturally occurring carbohydrates.
  • carbohydrate derivative means any compound which may be synthesized using a carbohydrate as a starting material or intermediate.
  • carbohydrate means a naturally occurring carbohydrate, a modified carbohydrate, or a carbohydrate derivative.
  • a carbohydrate is a biomolecule including carbon (C), hydrogen (H) and oxygen (O) atoms.
  • Carbohydrates can include monosaccharide, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides or polysaccharides, such as one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and / or one or more mannose moieties.
  • a particularly preferred carbohydrate is N-Acetyl-Galactosamine moieties.
  • "strand” means an oligomeric compound comprising linked nucleosides.
  • the linker is not particularly limited, but includes phosphodiesters and variants thereof as disclosed herein.
  • a strand may also be viewed as a plurality of linked nucleotides in which case the linker would be a covalent bond.
  • the term "construct” means a region of linked nucleosides which is defined in terms of nucleobase sequence and sugar modifications. A construct may coincide with a strand or compound, but may also be part thereof.
  • single strand or “single-stranded” means an oligomeric compound comprising linked nucleosides that are connected in a continuous sequence without a break therebetween. Such single strands may include regions of sufficient self-complementarity so as to be capable of forming a stable self-duplex in a hairpin structure.
  • hairpin means a single stranded oligomeric compound that includes a duplex formed by base pairing between sequences in the strand that are self-complementary and opposite in directionality.
  • hairpin loop means an unpaired loop of linked nucleosides in a hairpin that is created as a result of hybridization of the self-complementary sequences. The resulting structure looks like a loop or a U-shape.
  • short hairpin RNA also denoted as shRNA, comprises a duplex region and a loop connecting the regions forming the duplex. The end of the duplex region which does not carry the loop may be blunt-ended or carry (a) 3' and/or (a) 5' overhang(s).
  • the construct is blunt-ended.
  • Such molecules are also referred to as "mxRNAs".
  • mxRNA is in particular understood as defined in WO 2020/044186 A2 which is incorporated by reference herein in its entirety.
  • Particularly preferred hairpin RNAs in accordance with the invention are those shown in Tables 6 and 7 and Figures 15 to 18, 20 and 22.
  • "directionality" means the end-to-end chemical orientation of an oligonucleotide based on the chemical convention of numbering of carbon atoms in the sugar moiety meaning that there will be a 5′-end defined by the 5′ carbon of the sugar moiety, and a 3′-end defined by the 3' carbon of the sugar moiety.
  • duplex In a duplex or double stranded oligonucleotide, the respective strands run in opposite 5' to 3' directions to permit base pairing between them.
  • duplex also abbreviated as “dup”, means two or more complementary strand regions, or strands, of an oligonucleotide or oligonucleotides, hybridized together by way of non- covalent, sequence-specific interaction therebetween. Most commonly, the hybridization in the duplex will be between nucleobases adenine (A) and thymine (T), and / or (A) adenine and uracil (U), and / or guanine (G) and cytosine (C).
  • A adenine
  • T thymine
  • U adenine and uracil
  • G guanine
  • C cytosine
  • the duplex may be part of a single stranded structure, wherein self-complementarity leads to hybridization, or as a result of hybridization between respective strands in a double stranded molecule.
  • double strand or double stranded means a pair of oligomeric compounds that are hybridized to one another.
  • a double-stranded oligomeric compound comprises a first and a second oligomeric compound.
  • expression means the process by which a gene ultimately results in a protein. Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenlyation, addition of 5 '-cap), and translation.
  • transcription refers to the first of several steps of DNA based gene expression in which a target sequence of DNA is copied into RNA (especially mRNA) by the enzyme RNA polymerase. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA sequence called a primary transcript.
  • target sequence means a sequence to which an oligomeric compound is intended to hybridize to result in a desired activity with respect to Factor XI expression. Oligonucleotides have sufficient complementarity to their target sequences to allow hybridization under physiological conditions.
  • nucleobase complementarity or “complementarity” when in reference to nucleobases means a nucleobase that is capable of base pairing with another nucleobase.
  • adenine (A) is complementary to thymine (T).
  • adenine (A) is complementary to uracil (U).
  • guanine (G) is complementary to cytosine (C).
  • complementary nucleobase means a nucleobase of an oligomeric compound that is capable of base pairing with a nucleobase of its target sequence.
  • nucleobases at a certain position of an oligomeric compound are capable of hydrogen bonding with a nucleobase at a certain position of a target sequence
  • the position of hydrogen bonding between the oligomeric compound and the target sequence is considered to be complementary at that nucleobase pair.
  • Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity.
  • non-complementary in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another.
  • complementary in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides) means the capacity of such oligomeric compounds or regions thereof to hybridize to a target sequence, or to a region of the oligomeric compound itself, through nucleobase complementarity.
  • Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated.
  • complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary).
  • complementary oligomeric compounds or regions are 80%> complementary.
  • complementary oligomeric compounds or regions are 90%> complementary.
  • complementary oligomeric compounds or regions are 95% complementary. In certain embodiments, complementary oligomeric compounds or regions are 100% complementary.
  • self-complementarity in reference to oligomeric compounds means a compound that may fold back on itself, creating a duplex as a result of nucleobase hybridization of internal complementary strand regions. Depending on how close together and / or how long the strand regions are, then the compound may form hairpin loops, junctions, bulges or internal loops.
  • mismatch means a nucleobase of an oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a target sequence, or at a corresponding position of the oligomeric compound itself when the oligomeric compound hybridizes as a result of self-complementarity, when the oligomeric compound and the target sequence and / or self- complementary regions of the oligomeric compound, are aligned.
  • hybridization means the pairing of complementary oligomeric compounds (e.g., an oligomeric compound and its target sequence).
  • the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.
  • hydrogen bonding which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.
  • specifically hybridizes means the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site.
  • "fully complementary” in reference to an oligomeric compound or region thereof means that each nucleobase of the oligomeric compound or region thereof is capable of pairing with a nucleobase of a complementary nucleic acid target sequence or a self-complementary region of the oligomeric compound.
  • a fully complementary oligomeric compound or region thereof comprises no mismatches or unhybridized nucleobases with respect to its target sequence or a self- complementary region of the oligomeric compound.
  • percent complementarity means the percentage of nucleobases of an oligomeric compound that are complementary to an equal-length portion of a target nucleic acid. Percent complementarity is calculated by dividing the number of nucleobases of the oligomeric compound that are complementary to nucleobases at corresponding positions in the target nucleic acid by the total length of the oligomeric compound.
  • percent identity means the number of nucleobases in a first nucleic acid that are the same type (independent of chemical modification) as nucleobases at corresponding positions in a second nucleic acid, divided by the total number of nucleobases in the first nucleic acid.
  • modulation means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression.
  • nucleoside having a modification of a first type may be an unmodified nucleoside.
  • differentiately modified mean chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified naturally occurring RNA nucleoside are “differently modified,” even though the naturally occurring nucleoside is unmodified.
  • DNA and RNA oligonucleotides are "differently modified," even though both are naturally-occurring unmodified nucleosides.
  • Nucleosides that are the same but for comprising different nucleobases are not differently modified.
  • a nucleoside comprising a 2'-OMe modified sugar moiety and an unmodified adenine nucleobase and a nucleoside comprising a 2'-OMe modified sugar moiety and an unmodified thymine nucleobase are not differently modified.
  • “the same type of modifications” refers to modifications that are the same as one another, including absence of modifications.
  • RNA nucleosides having the same type modification may comprise different nucleobases.
  • region or regions or “portion” or “portions”, mean a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the subject-matter and definitions described herein. Typically such regions or portions comprise at least 10, at least 11, at least 12 or at least 13 linked nucleosides. For example, such regions can comprise 13 to 20 linked nucleosides, such as 13 to 16 or 18 to 20 linked nucleosides.
  • first region as defined herein consists essentially of 18 to 20 nucleosides and a second region as defined herein consists essentially of 13 to 16 linked nucleosides.
  • pharmaceutically acceptable carrier or diluent means any substance suitable for use in administering to an animal.
  • a pharmaceutically acceptable carrier or diluent is sterile saline.
  • such sterile saline is pharmaceutical grade saline.
  • substituteduent and “substituent group” means an atom or group that replaces the atom or group of a named parent compound.
  • a substituent of a modified nucleoside is any atom or group that differs from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2'- substituent is any atom or group at the 2 '-position of a nucleoside other than H or OH).
  • Substituent groups can be protected or unprotected.
  • compounds of the present disclosure have substituents at one or at more than one position of the parent compound. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as oxygen or an alkyl or hydrocarbyl group to a parent compound.
  • substituents can be present as the modification on the sugar moiety, in particular a substituent present at the 2'-position of the sugar moiety.
  • groups amenable for use as substituents include without limitation, one or more of halo, hydroxyl, alkyl, alkenyl, alkynyl, acyl, carboxyl, alkoxy, alkoxyalkylene and amino substituents.
  • substituents as described herein can represent modifications directly attached to a ring of a sugar moiety (such as a halo, such as fluoro, directly attached to a sugar ring), or a modification indirectly linked to a ring of a sugar moiety by way of an oxygen linking atom that itself is directly linked to the sugar moiety (such as an alkoxyalkylene, such as methoxyethylene, linked to an oxygen atom, overall providing an MOE substituent as described herein attached to the 2'-position of the sugar moiety).
  • alkyl as used herein, means a saturated straight or branched monovalent C 1-6 hydrocarbon radical, with methyl being a most preferred alkyl as a substituent at the 2'-position of the sugar moiety.
  • the alkyl group typically attaches to an oxygen linking atom at the 2' position of the sugar, therefore, overall providing an –O-alkyl substituent, such as an -OCH 3 substituent, on a sugar moiety of an oligomeric compound as described herein.
  • alkylene means a saturated straight or branched divalent hydrocarbon radical of the general formula -CnH2n- where n is 1-6.
  • alkenyl means a straight or branched unsaturated monovalent C 2-6 hydrocarbon radical, with ethenyl or propenyl being most preferred alkenyls as a substituent at the 2'-position of the sugar moiety.
  • degree of unsaturation that is present in an alkenyl radical is the presence of at least one carbon to carbon double bond.
  • alkynyl means a straight or branched unsaturated C2-6 hydrocarbon radical, with ethynyl being a most preferred alkynyl as a substituent at the 2'-position of the sugar moiety.
  • the degree of unsaturation that is present in an alkynyl radical is the presence of at least one carbon to carbon triple bond.
  • the alkynyl group typically attaches to an oxygen linking atom at the 2'-position of the sugar, therefore, overall providing a –Oalkynyl substituent on a sugar moiety of an oligomeric compound as described herein.
  • carboxyl is a radical having a general formula –CO 2 H.
  • acyl means a radical formed by removal of a hydroxyl group from a carboxyl radical as defined herein and has the general Formula -C(O)-X where X is typically C 1-6 alkyl.
  • alkoxy means a radical formed between an alkyl group, such as a C 1-6 alkyl group, and an oxygen atom wherein the oxygen atom is used to attach the alkoxy group either to a parent molecule (such as at the 2'-position of a sugar moiety), or to another group such as an alkylene group as defined herein.
  • alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.
  • Alkoxy groups as used herein may optionally include further substituent groups.
  • alkoxyalkylene means an alkoxy group as defined herein that is attached to an alkylene group also as defined herein, and wherein the oxygen atom of the alkoxy group attaches to the alkylene group and the alkylene attaches to a parent molecule.
  • the alkylene group typically attaches to an oxygen linking atom at the 2'-position of the sugar, therefore, overall providing a – Oalkylenealkoxy substituent, such as an –OCH 2 CH 2 OCH 3 substituent, on a sugar moiety of an oligomeric compound as described herein.
  • a – Oalkylenealkoxy substituent such as an –OCH 2 CH 2 OCH 3 substituent
  • MOE substituent as defined herein and as known in the art.
  • amino includes primary, secondary and tertiary amino groups.
  • halo and halogen mean an atom selected from fluorine, chlorine, bromine and iodine.
  • oligomeric compounds as described herein may have one or more non- hybridizing nucleosides at one or both ends of one or both strands (overhangs) and / or one or more internal non-hybridizing nucleosides (mismatches) provided there is sufficient complementarity to maintain hybridization under physiologically relevant conditions.
  • oligomeric compounds as described herein may be blunt ended at at least one end.
  • the term "comprising" is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and as such there may be present additional steps or elements.
  • each of the constructs of the invention may or may not have a phosphate modification at the 5' end group.
  • each of the above constructs may or may not have a "3x GalNAc” coupled to the 3' end group.
  • a construct bears a 3x GalNAc ligand, such as a "toothbrush" moiety as disclosed herein.
  • Aspect 1 An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250, or SEQ ID NOs 1251 to 1500.
  • An oligomeric compound according to aspect 1 which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence and is selected from the following sequences, or a portion thereof: SEQ ID NOs 251 to 500, or SEQ ID NOs 1501 to 1750.
  • An oligomeric compound according to aspect 1 or 2 wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 13, 27, 39, 46, 91, 98, 103, 105, 109, 120, 140, 146, 151, 152, 163, 182, 183, 199, 207, 210, 218, 220, 223, 224, 238, or SEQ ID NOs 1258, 1263, 1277, 1289, 1296, 1341, 1348, 1353, 1355, 1359, 1370, 1390, 1396, 1401, 1402, 1413, 1432, 1433, 1449, 1457, 1460, 1468, 1470, 1473, 1474, 1488.
  • Aspect 4 Aspect 4.
  • Aspect 5 An oligomeric compound according to any of aspects 1 to 4, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 46, 91, 146, 152, 207, or SEQ ID NOs 1258, 1296, 1341, 1396, 1402, 1457.
  • Aspect 6 An oligomeric compound according to aspect 5, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 296, 341, 396, 402, 457, or SEQ ID NOs 1508, 1546, 1591, 1646, 1652, 1707.
  • Aspect 7 An oligomeric compound according to any of aspects 1 to 4, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 46, 91, 146, 152, 207, or SEQ ID NOs 1258, 1296, 1341, 1396, 1402, 1457.
  • Aspect 6 An
  • Aspect 8 An oligomeric compound according to aspect 7, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 296, 341, 402, or SEQ ID NOs 1546, 1591, 1652.
  • Aspect 9 An oligomeric compound according to any of aspects 1 to 8, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.
  • An oligomeric compound according to aspect 3 and / or 4 wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.
  • Aspect 11 An oligomeric compound according to aspect 5 and / or 6, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207.
  • Aspect 13 An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.
  • RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.
  • Aspect 17 An oligomeric compound according to any of aspects 1 to 16, wherein the first region of linked nucleosides consists essentially of 18 to 20 linked nucleosides.
  • Aspect 18 An oligomeric compound according to any of aspects 2 to 17, wherein the second region of linked nucleosides consists essentially of 11 to 16, advantageously 12 to 15 or 13 to 16 linked nucleosides.
  • An oligomeric compound according to aspect 20 wherein the 5’ region of the first nucleoside region is directly or indirectly linked to the 3’ region of the second nucleoside region, for example by complementary base pairing, and / or wherein the 3’ region of the first nucleoside region is directly or indirectly linked to the 5’ region of the second nucleoside region.
  • Aspect 22 An oligomeric compound according to any of aspects 1 to 21, which further comprises one or more ligands.
  • An oligomeric compound according to aspect 25, wherein the one or more ligands comprise one or more carbohydrates.
  • an oligomeric compound according to aspect 26 wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.
  • Aspect 28 An oligomeric compound according to aspect 27, wherein the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and / or one or more mannose moieties.
  • Aspect 29 An oligomeric compound according to aspect 28, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.
  • Aspect 30 An oligomeric compound according to aspect 26, wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.
  • Aspect 28
  • Aspect 31. An oligomeric compound according to any of aspects 22 to 30, wherein the one or more ligands are attached to the oligomeric compound, preferably to the second nucleoside region thereof, in a linear configuration, or in a branched configuration. Preferred is that the ligand has the following structure, also referred to as "toothbrush” herein: A particularly preferred embodiment of "GalNAc" (as used herein) is the above structure.
  • Aspect 33. An oligomeric compound according to aspect 19, wherein the oligomeric compound comprises a single strand comprising the first and second nucleoside regions, wherein the single strand dimerises whereby at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region.
  • An oligomeric compound according to aspect 33 wherein the first nucleoside region has a greater number of linked nucleosides compared to the second nucleoside region, whereby the additional number of linked nucleosides of the first nucleoside region form a hairpin loop linking the first and second nucleoside regions.
  • Aspect 35 An oligomeric compound according to aspect 34, as dependent on aspect 20, whereby the hairpin loop is present at the 3' region of the first nucleoside region.
  • Aspect 36 An oligomeric compound according to aspect 34 or 35, wherein the hairpin loop comprises 4 or 5 linked nucleosides.
  • Aspect 40 An oligomeric compound according to aspect 39, which comprises 7, 8, 9 or 10 phosphorothioate or phosphorodithioate internucleoside linkages.
  • Aspect 41 An oligomeric compound according to any of aspects 38 to 40, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the first nucleoside region.
  • Aspect 42 An oligomeric compound according to any of aspects 38 to 41, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the second nucleoside region.
  • Aspect 43 An oligomeric compound according to any of aspects 38 to 40, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the second nucleoside region.
  • An oligomeric compound according to aspect 43 which comprises a phosphorothioate or phosphorodithioate internucleoside linkage between each adjacent nucleoside that is present in the hairpin loop.
  • Aspect 45 An oligomeric compound according to any of aspects 1 to 44, wherein at least one nucleoside comprises a modified sugar.
  • modified sugar is selected from 2' modified sugars; conformationally restricted nucleotides (CRN) sugar such as locked nucleic acid (LNA), (S)-constrained ethyl bicyclic nucleic acid, and constrained ethyl (cEt), tricyclo- DNA; morpholino, unlocked nucleic acid (UNA), glycol nucleic acid (GNA), D-hexitol nucleic acid (HNA), and cyclohexene nucleic acid (CeNA), and preferably is a 2'-O-methyl modified sugar.
  • CRN conformationally restricted nucleotides
  • LNA locked nucleic acid
  • S locked nucleic acid
  • cEt constrained ethyl
  • tricyclo- DNA tricyclo- DNA
  • morpholino unlocked nucleic acid
  • GNA glycol nucleic acid
  • HNA D-hexitol nucleic acid
  • CeNA cyclohexene nucleic acid
  • 2' modified sugars include 2'-O-alkyl modified sugar, 2'-O-methoxyethyl modified sugar, 2'-O- allyl modified sugar, 2'-C-allyl modified sugar, 2'-deoxy modified sugar such as 2'-deoxy ribose, 2'-F modified sugar, 2'-arabino-fluoro modified sugar, 2'-O-benzyl modified sugar, 2'-amino modified sugar, and 2'-O-methyl-4-pyridine modified sugar.
  • Aspect 47 An oligomeric compound according to aspect 45 or 46, wherein the modified sugar is a 2'-F modified sugar.
  • Aspect 50 Aspect 50.
  • An oligomeric compound according to aspect 48 or 49 wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications.
  • Aspect 51 An oligomeric compound according to any of aspects 48 to 50, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications.
  • An oligomeric compound according to aspect 52 wherein one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of odd numbered nucleosides of the first nucleoside region.
  • Aspect 54 An oligomeric compound according to aspect 52 or 53, wherein one or more of the even numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of even numbered nucleosides of the first nucleoside region according to aspect 53.
  • Aspect 55 is provided.
  • An oligomeric compound according to any of aspects 52 to 54 wherein at least one or more of the modified even numbered nucleosides of the first nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the first nucleoside region.
  • Aspect 56 An oligomeric compound according to any of aspects 52 to 55, wherein at least one or more of the modified even numbered nucleosides of the second nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the second nucleoside region.
  • An oligomeric compound according to any of aspects 52 to 56 wherein sugars of one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-O-methyl modified sugars.
  • Aspect 58 An oligomeric compound according to any of aspects 52 to 57, wherein one or more of the even numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-F modified sugars.
  • An oligomeric compound according to any of aspects 52 to 58 wherein sugars of one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are 2'-F modified sugars.
  • Aspect 60 An oligomeric compound according to any of aspects 52 to 56, wherein sugars of one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-O-methyl modified sugars.
  • Aspect 61. An oligomeric compound according to any of aspects 45 to 60, wherein sugars of a plurality of adjacent nucleosides of the first nucleoside region are modified by a common modification.
  • An oligomeric compound according to aspect 65 wherein the plurality of adjacent 2'- O-methyl modified sugars are present in three or four adjacent nucleosides of the hairpin loop.
  • Aspect 68. An oligomeric compound according to aspect 45, as dependent on aspect 34, wherein the hairpin loop comprises at least one nucleoside having a modified sugar.
  • Aspect 69. An oligomeric compound according to aspect 68, wherein the at least one nucleoside is adjacent a nucleoside with a differently modified sugar.
  • Aspect 70 An oligomeric compound according to aspect 69, wherein the modified sugar is a 2'- O-methyl modified sugar, and the differently modifies sugar is a 2'-F modified sugar.
  • An oligomeric compound according to any of aspects 1 to 70 which comprises one or more nucleosides having an un-modified sugar moiety.
  • Aspect 72 An oligomeric compound according to aspect 71, wherein the unmodified sugar is present in the 5' region of the second nucleoside region.
  • Aspect 73 An oligomeric compound according to aspect 71 or 72, as dependent on aspect 34, wherein the unmodified sugar is present in the hairpin loop.
  • An oligomeric compound according to any of aspects 1 to 73 wherein one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3' carbon of its sugar and the 3' carbon of the sugar of the adjacent nucleoside, and / or one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5' carbon of its sugar and the 5' carbon of the sugar of the adjacent nucleoside.
  • Aspect 75 An oligomeric compound according to any of aspects 1 to 74, which is blunt ended.
  • Aspect 77. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 501 to 750, or construct NOs 1751 to 2000.
  • An oligomeric compound according to aspect 77 which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence, wherein the second nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 751 to 1000, or construct NOs 2001 to 2250.
  • an oligomeric compound according to aspect 77 or 78 wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 513, 527, 539, 546, 591, 598, 603, 605, 609, 620, 640, 646, 651, 652, 663, 682, 683, 699, 707, 710, 718, 720, 723, 724, 738, or construct NOs 1758, 1763,1777, 1789, 1796, 1841, 1848, 1853, 1855, 1859, 1870, 1890, 1896, 1901, 1902, 1913, 1932, 1933, 1949, 1957, 1960, 1968, 1970, 1973, 1974, 1988.
  • Aspect 80 Aspect 80.
  • an oligomeric compound according to aspect 79 wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 763, 777, 789, 796, 841, 848, 853, 855, 859, 870, 890, 896, 901, 902, 913, 932, 933, 949, 957, 960, 968, 970, 973, 974, 988, or construct NOs 2008, 2013, 2027, 2039, 2046, 2091, 2098, 2103, 2105, 2109, 2120, 2140, 2146, 2151, 2152, 2163, 2182, 2183, 2199, 2207, 2210, 2218, 2220, 2223, 2224, 2238.
  • Aspect 81 An oligomeric compound according to any of aspects 77 to 80, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 546, 591, 646, 652, 707, or construct NOs 1758, 1796, 1841, 1896, 1902, 1957.
  • Aspect 82 An oligomeric compound according to aspect 81, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 796, 841, 896, 902, 957, or construct NOs 2008, 2046, 2091, 2146, 2152, 2207.
  • Aspect 83 An oligomeric compound according to any of aspects 77 to 80, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 546, 591, 646, 652, 707, or construct NOs 1758, 1796, 1841, 1896, 1902, 1957.
  • Aspect 82 An
  • An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI which is selected from the following sequences: SEQ ID NOs 2251 to 2253, or SEQ ID NOs 2284 to 2288, preferably SEQ ID NO: 2287.
  • An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI which is selected from the following sequences: construct NOs 2254 to 2283.
  • An oligomeric compound according to aspect 88 wherein the one or more ligands are conjugated at the 3 ' region of the sequences, preferably at the 3' terminal nucleoside.
  • Aspect 90 An oligomeric compound according to aspect 88, wherein the one or more ligands are conjugated at non-terminal positions.
  • Aspect 91 An oligomeric compound according to any of aspects 88 to 90, wherein the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and / or peptides that bind cellular membrane or a specific target on cellular surface.
  • Aspect 92 Aspect 92.
  • Aspect 95 An oligomeric compound according to aspect 94, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.
  • Aspect 96 An oligomeric compound according to aspect 95, which comprises two or three N-Acetyl- Galactosamine moieties, preferably three.
  • Aspect 97 An oligomeric compound according to any of aspects 88 to 96, wherein the one or more ligands are attached to the oligomeric compound in a linear configuration, or in a branched configuration.
  • Aspect 98 An oligomeric compound according to any of aspects 88 to 96, wherein the one or more ligands are attached to the oligomeric compound in a linear configuration, or in a branched configuration.
  • An oligomeric compound according to aspect 97 wherein the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration.
  • Aspect 99 An oligomeric compound according to any of aspects 86 to aspect 98, wherein the sequences self dimerise so as to form an at least partially complementary duplex region.
  • Aspect 100 An oligomeric compound according to aspect 99, having a nucleobase sequence and structure as shown in any of Figures 15 to 17 or 18 to 20, construct NOs: 2290 to 2292 being preferred, construct NO: 2290 being particularly preferred.
  • Aspect 101 A composition comprising an oligomeric compound according to any of aspects 1 to 100, and a physiologically acceptable excipient.
  • Aspect 102 A composition comprising an oligomeric compound according to any of aspects 1 to 100, and a physiologically acceptable excipient.
  • An oligomeric compound according to any of aspects 1 to 100 for use in therapy.
  • Aspect 103 An oligomeric compound according to any of aspects 1 to 100, for use in the treatment of a disease or disorder.
  • Aspect 104. A method of treating a disease or disorder comprising administration of an oligomeric compound according to any of aspects 1 to 100, to an individual in need of treatment.
  • Aspect 105. A method according to aspect 104, wherein the oligomeric compound is administered subcutaneously or intravenously to the individual.
  • thromboembolic disease is selected from the group consisting of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end- stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.
  • ESRD end-stage renal disease
  • Aspect 109 Use or method according to aspect 108, wherein the thromboembolic disease is deep vein thrombosis, pulmonary embolism, or a combination thereof.
  • Aspect 110 is a combination thereof.
  • oligomeric compound according to any of items 1 to 100 in the manufacture of a medicament for a treatment of a disease or disorder.
  • the diseases and disorders are advantageously the same as set forth herein above.
  • the molecules disclosed herein, including, but not limited to, the hairpin RNAs as shown in Tables 6 and 7 and Figures 15 to 18, 20 and 22 are characterized by surprisingly outstanding performance, including in an in vivo setting; see, for example, the evidence shown in Figures 24 and 25. These data show a long-lasting down-regulation of Factor XI in response to administration of constructs as described herein. Further evidence of surprising performance of a plurality of constructs can be seen in the in vitro data provided in the Examples, including the data shown in Figure 19.
  • the syntheses of the RNAi constructs disclosed herein may be carried out using synthesis methods known to the person skilled in the art, such as synthesis methods disclosed in https://en.wikipedia.org/wiki/Oligonucleotide_synthesis ⁇ retrieved on 16 February 2022 ⁇ , wherein the methods disclosed on this website are incorporated by reference herein in their entirety .
  • Table 1a A represents adenine; U represents uracil; C represents cytosine; G represents guanine.
  • Table 1b Summary sequence table for active nucleobase sequences with chemical modifications:
  • Table 1b A represents adenine; U represents uracil; C represents cytosine; G represents guanine; P represents a terminal phosphate group; m represents a methyl modification at the 2' position of the sugar of the underlying nucleoside; f represents a fluoro modification at the 2' position of the sugar of the underlying nucleoside.
  • Table 1c Summary sequence table for the nucleobases of the target gene: In above Table 1c: A represents adenine; U represents uracil; C represents cytosine; G represents guanine.
  • the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1b, and wherein the 5' nucleoside of the antisense (guide) strand (first region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C).
  • A adenine
  • U uracil
  • C cytosine
  • the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1b, and wherein the 3' nucleoside of the sense (passenger) strand (second region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C), preferably however a nucleobase that is complementary to the 5' nucleobase of the antisense (guide) strand (first region as defined herein).
  • A adenine
  • U uracil
  • C cytosine
  • N and N' respectively represent any RNA nucleobase that can be present in the 5' terminal position of the antisense (guide) strand (first region as defined herein) and in the 3' terminal position of the sense (passenger) strand (second region as defined herein).
  • Table 1d Summary sequence table for active nucleobase sequences:
  • Table 1e Summary sequence table for active nucleobase sequences with chemical modifications:
  • Example 2 Oligonucleotides as set out in Tables 1a / 1b above that target FXI mRNA in human hepatoma cells were screened as follows.
  • Example 3 Dose response curves for the 26 FXI lead compounds as identified in Example 2 are shown in Figure 13. Dose response curves for the 5 FXI lead compounds are shown in Figure 14.
  • Example 4 IC50 values are shown for the 26 FXI lead compounds as identified in Example 2 in following Table 4. Table 4:
  • Example 5 Species cross-reactivity of the 26 FXI lead compounds as identified in Example 2 are shown in following Table 5. Table 5:
  • Example 6 Further to the data as provided in Examples 3 to 5, oligonucleotides F11-46 / SEQ ID NO: 46, F11-91 / SEQ ID NO: 91 and F11-152 / SEQ ID NO: 152 have been identified as particularly preferred antisense oligonucleotide sequences to be used in oligomeric compounds as described herein. On this basis, these sequences have been incorporated into overall oligomeric compounds as described herein of the following sequences SEQ ID NOs 2251 to 2253 as set out in following Table 6. Furthermore, selected modifications have been applied to SEQ ID NOs 2251 to 2253 as shown in SEQ ID NOs 2254 to 2286 in following Table 6. All sequences as provided below in Table 6 are set out in the 5' to 3' directionality. Table 6:
  • a ligand such as a galnac ligand, is preferably attached at the 3' end of the sequence.
  • Galnac can represent any arrangement of Galnac attachment, preferably however a triantennary galnac attachment:
  • the ligand, preferably Galnac, attachment can be to an internal non-terminal nucleoside, such as attachment to the nucleosides in the above sequences where the nucleobase is not shown as modified.
  • Example 7 This Example describes a structure-function relationship study of constructs comprising the nucleobase sequence of SEQ ID NO: 91.
  • Figure 18 shows the constructs comprising the nucleobase sequence of SEQ ID NO: 91 which have been tested. Tests have been performed in primary hepatocytes.
  • Human plateable 5 donor hepatocytes (Sekisui XenoTech, HPCH05+) are thawed in 45 mL of Human OptiThaw Hepatocyte media (Sekisui Xenotech, K8000), spun down at 200g for 5 minutes, and resuspended in 2x WEM complete (5% FBS, 2uM Dexamethasone, Pen/Strep, 8 ug/mL human insulin, 4 mM GlutaMAX, 30 mM HEPES pH 7.4).
  • 2x WEM complete consists of WEM (Gibco, A1217601) and 2x the Hepatocyte Plating Supplement Pack (Gibco, CM3000) with only 1x FBS.
  • the hepatocytes are then plated on 6 well Collagen 1 coated plates (Gibco, A1142803) at 25,000 cell/well at 50 uL per well and allowed to recover and adhere for 4 hours at 37C. After 4 hours, GalNac conjugated complexes are diluted to 2 uM in basal WEM and used to make a 2x, 7 step, 5 fold dilution series. 50 uL of each dilution is added to corresponding wells of the plated hepatocytes to make a final dilution series of 1 - 0.000064 uM in 1x WEM complete.
  • Example 19 The cells are allowed to culture for 72 hours at 37 degrees without disruption before harvest and RNA isolation using the PureLink Pro 96 total RNA Purification Kit (Invitrogen, 12173011A) according to the manufacturer's protocol. Results are shown in Figure 19. Based on these results, 7 molecules have been designed which are to be subjected to further analysis (see following Examples). These molecules are shown in Figure 20. Performance data in primary hepatocytes are shown in Figure 21. Based on these data, three molecules have been tested in humanized mice; see Example 8 below. Example 8: This Examples describes testing of the three molecules identified in Example 7 in humanized mice. Table 7 below shows nucleobase sequences (SEQ ID NOs) and full modification information (construct NOs) of these three molecules.
  • Figure 22 also shows the structures of these molecules.
  • Figure 23 shows performance of these molecules 5 days after administration.
  • Example 9 This Example describes a Pharmacodynamics Study of construct designated "91-Conv-31" (structure displayed in Figure 22) Following Single/Repeat Subcutaneous Injection to Cynomolgus Monkeys. Material and Methods For an overview of the study protocol, see Figure 24. A more detailed account is given below. STUDY PROTOCOL Table 8. Study Design
  • Test Article and Vehicle Information 2.1 Test Article Compounds as specified further above. Desiccate at room temperature, protected from light Storage Conditions: Handling Standard laboratory precautions as defined in WuXi SOPs Instructions: Doses will be prepared according to instructions provided by the Dose Preparation: sponsor. A copy of the instructions, as well as details of preparation, will be maintained in the study records. Dose Solution Analysis Samples: Disposition of Remaining Remaining formulations will be stored at 4°C. Test Article Formulations: Disposition of
  • Remaining Remaining test article will be shipped back to sponsor or discarded
  • Test Article dry 6 months after the final report is signed or at approval of Sponsor, powder or solid: Test System Identification
  • the number of animals in each group is the minimum
  • the room(s) will be controlled and monitored for relative humidity (targeted mean range 40% to 70%, and any excursion from this range for more than 3 hours will be documented as a deviation) and temperature (targeted mean range 18°C to 26°C, and any excursion from this range will be documented as a deviation) with 10 to 20 air changes/hour.
  • the room will be on a 12-hour light/dark cycle except when interruptions are necessitated by study activities.
  • Animals will be pair-housed in cages that are in accordance with applicable animal welfare laws and regulations during acclimation period. The monkeys will be housed individually in cages during experiment. Diet and Feeding
  • RO Reverse osmosis
  • Dose Administration The dose formulations will be administered per facility SOPs.
  • SC ADMINISTRATION SC injection site will be along the dorsal area of the animals’ thoracic regions. For multiple or large doses, different sites will be used. When the injection site is altered, the location must be documented in the record.
  • 4.1 Observations and Examinations 4.1.1 Clinical Observations Twice daily (approximately 9:30 a.m. and 4:00 p.m.), cage-side observations for general health and appearance will be conducted. Animals will be given physical examinations prior to study initiation to confirm animals’ health. On dosing days, the animals will be observed at 2, 4 and 6- hours post-dosing.
  • a blood smear will be prepared from each hematology sample. Blood smears will be labeled, stained, and stored. Blood smears may be read to investigate results of the hematology analyses. If additional examination of blood smears is deemed necessary, the smears may be subsequently evaluated and this evaluation will be described in a study plan amendment.
  • Blood All blood samples will be collected from a peripheral vessel from restrained, non-sedated animals.
  • Protocol and SOP deviations that could impact data interpretation will be included in the final report. 6 Archiving of Materials Test article preparation, test article tracking, in-life data, protocol, protocol amendments (if applicable), and the original final report generated as a result of this study will be archived. 7 STATISTICAL ANALYSIS The following section does not apply to data recorded on unscheduled occasions. Such data will be reported on an individual basis. All numerical data will be subjected to calculation of group means and standard deviations by using Microsoft Excel software, unless otherwise stated hereafter. These descriptive statistics will be presented for each dataset of interest, as determined by the variable to be analyzed and the dataset classification variables (for example: sex, measurement occasion, and any other relevant variable that can be used to specify on which subdivision the descriptive statistics have to be reported).
  • Dunnett’s test When significant differences among the means are indicated by ANOVA test (p ⁇ 0.05), Dunnett’s test will be used to perform the group mean comparisons between the control group and each treated group. If Levene’s test indicates heterogeneous group variances (p ⁇ 0.05) and the data set contains just positive values, log transformation will be performed. If transformed data still fail the test for homogeneity of variance (p ⁇ 0.05) or where the data contain zero and/or negative values, then the non-parametric Kruskal-Wallis test will be used to compare all considered groups. When Kruskal-Wallis test is significant (p ⁇ 0.05), Dunnett’ s test on ranks will be used to perform the pairwise group comparisons of interest.
  • Levene’s test will be performed as described above but a two-sample t-test will replace the one-way ANOVA, a Wilcoxon rank-sum test will be performed instead of the Kruskal-Wallis and, no Dunnett’s tests or Dunnett’s tests on ranks will be performed.
  • Figure 25 shows performance of construct designated "91-Conv-31" (structure displayed in Figure 22) in an in vivo study in terms of Factor XI activity knock-down. The effect of different dosages (expressed in mg/kg) and of single or multiple dosing at the beginning are shown and compared to a negative control (saline).
  • Figure 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study.
  • APTT activated partial thromboplastin time. It measures the activity of intrinsic pathway of clotting that is impacted by factors like FXI.
  • PT stands for prothrombin time which evaluates the integrity of extrinsic pathway of clotting that looks at the presence of factors like VII, V, X, prothrombin and fibrinogen.
  • Figure 27 shows the read-out of the tests illustrated in Figure 26.
  • Figure 28 presents data demonstrating a lack of side effects.
  • a panel liver function and hematology parameters have been assessed. In particular, no elevated levels of liver enzymes and no changes in hematology parameters could be found.

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Abstract

Products, compositions, and their uses are provided. In particular, nucleic acid products that modulate, in particular interfere with or inhibit, Factor XI (FXI) gene expression are provided. The products can be oligomeric compounds that comprise at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250.

Description

Products and compositions Field Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression. Methods, compounds, and compositions are provided for reducing expression of FXI mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate thromboembolic diseases, such as deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition. Background The circulatory system requires mechanisms that prevent blood loss, as well as those that counteract inappropriate intravascular obstructions. Generally, coagulation comprises a cascade of reactions culminating in the conversion of soluble fibrinogen to an insoluble fibrin gel. The steps of the cascade involve the conversion of an inactive zymogen to an activated enzyme. The active enzyme then catalyzes the next step in the cascade. Coagulation Cascade The coagulation cascade may be initiated through two branches, the tissue factor pathway (also “extrinsic pathway”), which is the primary pathway, and the contact activation pathway (also “intrinsic pathway”). The tissue factor pathway is initiated by the cell surface receptor tissue factor (TF, also referred to as Factor III), which is expressed constitutively by extravascular cells (pericytes, cardiomyocytes, smooth muscle cells, and keratinocytes) and expressed by vascular monocytes and endothelial cells upon induction by inflammatory cytokines or endotoxin. (Drake et al., Am J Pathol 1989, 134: 1087-1097). TF is the high affinity cellular receptor for coagulation Factor VIIa, a serine protease. In the absence of TF, VIIa has very low catalytic activity, and binding to TF is necessary to render VIIa functional through an allosteric mechanism (Drake et al., Am J Pathol 1989, 134: 1087-1097). The TF-VIIa complex activates Factor X to Xa. Xa in turn associates with its co-factor Factor Va into a prothrombinase complex which in turn activates prothrombin, (also known as Factor II or Factor 2) to thrombin (also known as Factor Ila, or Factor 2a). Thrombin activates platelets, converts fibrinogen to fibrin and promotes fibrin cross-linking by activating Factor XIII, thus forming a stable plug at sites where TF is exposed on extravascular cells. In addition, thrombin reinforces the coagulation cascade response by activating Factors V and VIII. The contact activation pathway is triggered by activation of Factor XII to Xlla. Factor Xlla converts XI to XIa, and XIa converts IX to IXa. IXa associates with its cofactor VIIIa to convert X to Xa. The two pathways converge at this point as Factor Xa associates with Factor Va to activate prothrombin (Factor II) to thrombin (Factor Ila). Factor XI enhances both the formation and stability of clots in vitro, but is not thought to be involved in the initiation of clotting. Rather, Factor XI is important in the propagation phase of clot growth (von de Borne, et al., Blood Coagulation and Fibrinolysis, 2006, 17:251-257). Additionally, Factor XI-dependent amplification of thrombin formation leads to activation of TAFI (thrombin activatable fibrinolysis inhibitor), which renders clots less sensitive to fibrinolysis (Bouma et al, J Thromb Haemost 1999; 82: 1703-1708). Inhibition of coagulation At least three mechanisms keep the coagulation cascade in check, namely the action of activated protein C, antithrombin, and tissue factor pathway inhibitor. Activated protein C is a serine protease that degrades cofactors Va and VIIIa. Protein C is activated by thrombin with thrombomodulin, and requires coenzyme Protein S to function. Antithrombin is a serine protease inhibitor (serpin) that inhibits serine proteases: thrombin, Xa, Xlla, XIa and IXa. Tissue factor pathway inhibitor inhibits the action of Xa and the TF-VIIa complex. (Schwartz AL et al., Trends Cardiovasc Med.1997; 7:234 - 239.) Disease Thrombosis is the pathological development of blood clots, and an embolism occurs when a blood clot migrates to another part of the body and interferes with organ function. Thromboembolism may cause conditions such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke. While most cases of thrombosis are due to acquired extrinsic problems, for example, surgery, cancer, immobility, some cases are due to a genetic predisposition, for example, antiphospholipid syndrome and the autosomal dominant condition, Factor V Leiden. (Bertina RM et al. Nature 1994; 369:64-67.) Treatment The most commonly used anticoagulants, warfarin, heparin, low molecular weight heparin (LMWH), and newer direct oral anticoagulants (DOAC), all possess significant drawbacks. Warfarin is typically used to treat patients suffering from atrial fibrillation. The drug interacts with vitamin K-dependent coagulation factors which include Factors II, VII, IX and X. Anticoagulant proteins C and S are also inhibited by warfarin. Drug therapy using warfarin is further complicated by the fact that warfarin interacts with other medications, including drugs used to treat atrial fibrillation, such as amiodarone. Because therapy with warfarin is difficult to predict, patients must be carefully monitored in order to detect any signs of anomalous bleeding. Heparin functions by activating antithrombin which inhibits both thrombin and Factor X (Bjork I, Lindahl U. Mol Cell Biochem.198248: 161-182). Treatment with heparin may cause an immunological reaction that makes platelets aggregate within blood vessels that can lead to thrombosis. This side effect is known as heparin-induced thrombocytopenia (HIT) resulting in increased bleeding and requires patient monitoring. Prolonged treatment with heparin may also lead to osteoporosis. LMWH can also inhibit Factor II, but to a lesser degree than unfractioned heparin (UFH). LMWH has been implicated in the development of HIT. Several direct oral anticoagulants have been FDA-approved for the treatment of thrombotic disease, including four Factor Xa inhibitors Betrixaban, Apixaban, Rivaroxaban and Edoxaban and one direct thrombin inhibitor Dabigatran. (Smith, M., Surg Clin N Am 201898:219-238). Rivaroxaban, Dabigatran and Edoxaban all exhibit increased bleeding, especially increased GI bleeding risk compared to warfarin. There therefore remains a need for therapies to treat thromboembolic diseases without risk of increased bleeding. We, therefore, aim to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases. Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression (Fire et a.l, 1998, Nature.1998 Feb 19;391 (6669):806-11 and Elbashir et at., 2001 , Nature.2001 May 24;411 (6836):494-8) by a mechanism that has been termed RNA interference (RNAi). Short dsRNAs direct gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and have become a useful tool for studying gene function. RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger loaded into the RISC complex. Interfering RNA (iRNA) such as siRNAs, antisense RNA, and micro-RNA are oligonucleotides that prevent the formation of proteins by gene-silencing i.e. inhibiting gene translation of the protein through degradation of mRNA molecules. Gene-silencing agents are becoming increasingly important for therapeutic applications in medicine. According to Watts and Corey in the Journal of Pathology (2012; Vol 226, p 365-379) there are algorithms that can be used to design nucleic acid silencing triggers, but all of these have severe limitations. It may take various experimental methods to identify potent siRNAs, as algorithms do not take into account factors such as tertiary structure of the target mRNA or the involvement of RNA binding proteins. Therefore the discovery of a potent nucleic acid silencing trigger with minimal off- target effects is a complex process. For the pharmaceutical development of these highly charged molecules it is necessary that they can be synthesised economically, distributed to target tissues, enter cells and function within acceptable limits of toxicity. An aim is to, therefore, provide compounds, methods, and pharmaceutical compositions for the treatment of thromboembolic diseases as described herein, which comprise oligomeric compounds that modulate and inhibit, gene expression by RNAi. Summary Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression, and associated therapeutic uses. Specific oligomeric compounds and sequences are described herein. This summary is not intended to identify key features or essential features of the subject matter as described herein, nor is it intended to be used to determine the scope of that subject matter. Detailed Description and Embodiments The embodiments described below are exemplary but the skilled artisan will recognize that additional embodiments may be achieved. It will be understood that the benefits and advantages described herein may relate to one embodiment or may relate to several embodiments. The embodiments are not limited to those that solve any or all of the stated problems or those that have any or all of the stated benefits and advantages. Features of different aspects and embodiments may be combined as appropriate, as would be apparent to a skilled person, and may be combined with any of the aspects as described herein. Brief Description of the Drawings The embodiments described below are by way of example only and with reference to the following non-limiting drawings, in which: Figure 1 illustrates the stability of the duplexes of Table 2 in Example 2. Figure 2 illustrates the linear dose response of the two independent F11 qPCR assays as described in Example 2. Figures 3 to 12 show the screening results for FXI gene expression as a percentage of gene expression in non-treated cells for oligomeric compounds including oligonucleotides of Table 1a / 1b of Example 1. Figure 13 provides dose response curves for the 26 FXI lead compounds as identified in Example 2. Figure 14 provides dose response curves for the 5 FXI lead compounds as identified further to the results of Figure 13. Figures 15 to 17 show the overall sequences for oligomeric compounds F11-91, F11-46, F11-152. Figure 18 shows compounds which have been selected for medicinal chemistry. Figure 19 shows performance of the compounds shown in Figure 18. Figure 20 show compounds which have been designed on the basis of the results shown in Figure 19. Figure 21 shows data for the compounds displayed in Figure 20. Figure 22 shows the structure of compounds tested in humanized mice. Figure 23 shows the data obtained from testing in humanized mice. Figure 24 shows the design of an in vivo study with compound 91-Conv-31. Figure 25 shows performance of a compound in an in vivo study in terms of Factor XI activity knock- down. Figure 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study. Figure 27 shows the read-out of the tests illustrated in Figure 26. Figure 28 presents data demonstrating a lack of side effects. Definitions Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in "Carbohydrate Modifications in Antisense Research" Edited by Sangvi and Cook, American Chemical Society , Washington D.C., 1994; "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 21st edition, 2005; and "Antisense Drug Technology, Principles, Strategies, and Applications" Edited by Stanley T. Crooke, CRC Press, Boca Raton, Florida; and Sambrook et al., "Molecular Cloning, A laboratory Manual," 2nd Edition, Cold Spring Harbor Laboratory Press, 1989, which are hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety. Unless otherwise indicated, the following terms have the following meanings: As used herein, "excipient" means any compound or mixture of compounds that is added to a composition as provided herein that is suitable for delivery of an oligomeric compound. As used herein, "nucleoside" means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety, phosphate- linked nucleosides also being referred to as "nucleotides". As used herein, "chemical modification" or "chemically modified" means a chemical difference in a compound when compared to a naturally occurring counterpart. Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and internucleoside linkage modifications. In reference to an oligonucleotide, chemical modification does not include differences only in nucleobase sequence. As used herein, "furanosyl" means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom. As used herein, "naturally occurring sugar moiety" means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA. A "naturally occurring sugar moiety" as referred to herein is also termed as an "unmodified sugar moiety". In particular, such a "naturally occurring sugar moiety" or an "unmodified sugar moiety" as referred to herein has a -H (DNA sugar moiety) or –OH (RNA sugar moiety) at the 2'-position of the sugar moiety, especially a -H (DNA sugar moiety) at the 2'-position of the sugar moiety. As used herein, "sugar moiety" means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside. As used herein, "modified sugar moiety" means a substituted sugar moiety or a sugar surrogate. As used herein, "substituted sugar moiety" means a furanosyl that has been substituted. Substituted sugar moieties include, but are not limited to furanosyls comprising substituents at the 2'-position, the 3'-position, the 5'-position and / or the 4'-position. Certain substituted sugar moieties are bicyclic sugar moieties. As used herein, "2'-substituted sugar moiety" means a furanosyl comprising a substituent at the 2'- position other than H or OH. Unless otherwise indicated, a 2'-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2' -substituent of a 2'-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring). As used herein, "MOE" means -OCH2CH2OCH3. As used herein, "2'-F nucleoside" refers to a nucleoside comprising a sugar comprising fluorine at the 2' position. Unless otherwise indicated, the fluorine in a 2'-F nucleoside is in the ribo position (replacing the OH of a natural ribose). Duplexes of uniformly modified 2′-fluorinated (ribo) oligonucleotides hybridized to RNA strands are not RNase H substrates while the ara analogs retain RNase H activity. As used herein the term "sugar surrogate" means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside sub-units are capable of linking together and / or linking to other nucleosides to form an oligomeric compound which is capable of hybridizing to a complementary oligomeric compound. Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen. Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents). Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid). Sugar surrogates include without limitation morpholinos, cyclohexenyls and cyclohexitols. As used herein, "bicyclic sugar moiety" means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2 '-carbon and the 4 '-carbon of the furanosyl. As used herein, "nucleotide" means a nucleoside further comprising a phosphate linking group. As used herein, "linked nucleosides" may or may not be linked by phosphate linkages and thus includes, but is not limited to "linked nucleotides." As used herein, "linked nucleosides" are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked). As used herein, "nucleobase" means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the group of atoms is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified. As used herein the terms, "unmodified nucleobase" or "naturally occurring nucleobase" means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U). As used herein, "modified nucleobase" means any nucleobase that is not a naturally occurring nucleobase. As used herein, "modified nucleoside" means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides. Modified nucleosides can comprise a modified sugar moiety and / or a modified nucleobase. As used herein, "bicyclic nucleoside" or "BNA" means a nucleoside comprising a bicyclic sugar moiety. As used herein, "locked nucleic acid nucleoside" or "LNA" means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH2-O-2'bridge. As used herein, "2 '-substituted nucleoside" means a nucleoside comprising a substituent at the 2'- position of the sugar moiety other than H or OH. Unless otherwise indicated, a 2 '-substituted nucleoside is not a bicyclic nucleoside. As used herein, "deoxynucleoside" means a nucleoside comprising 2'-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA). In certain embodiments, a 2'- deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil). As used herein, "oligonucleotide" means a compound comprising a plurality of linked nucleosides. In certain embodiments, an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and / or unmodified deoxyribonucleosides (DNA) and / or one or more modified nucleosides. As used herein, "modified oligonucleotide" means an oligonucleotide comprising at least one modified nucleoside and / or at least one modified internucleoside linkage. As used herein, "linkage" or "linking group" means a group of atoms that link together two or more other groups of atoms. As used herein "internucleoside linkage" means a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein "naturally occurring internucleoside linkage" means a 3' to 5' phosphodiester linkage. As used herein, "modified internucleoside linkage" means any internucleoside linkage other than a naturally occurring internucleoside linkage. In particular, a "modified internucleoside linkage" as referred to herein can include a modified phosphorous linking group such as a phosphorothioate or phosphorodithioate internucleoside linkage. As used herein, "terminal internucleoside linkage" means the linkage between the last two nucleosides of an oligonucleotide or defined region thereof. As used herein, "phosphorus linking group" means a linking group comprising a phosphorus atom and can include naturally occurring phosphorous linking groups as present in naturally occurring RNA or DNA, such as phosphodiester linking groups, or modified phosphorous linking groups that are not generally present in naturally occurring RNA or DNA, such as phosphorothioate or phosphorodithioate linking groups. Phosphorus linking groups can therefore include without limitation, phosphodiester, phosphorothioate, phosphorodithioate, phosphonate, methylphosphonate, phosphoramidate, phosphorothioamidate, thionoalkylphosphonate, phosphotriesters, thionoalkylphosphotriester and boranophosphate. As used herein, "internucleoside phosphorus linking group" means a phosphorus linking group that directly links two nucleosides. As used herein, "oligomeric compound" means a polymeric structure comprising two or more substructures. In certain embodiments, an oligomeric compound comprises an oligonucleotide, such as a modified oligonucletide. In certain embodiments, an oligomeric compound further comprises one or more conjugate groups and / or terminal groups and / or ligands. In certain embodiments, an oligomeric compound consists of an oligonucleotide. In certain embodiments, an oligomeric compound comprises a backbone of one or more linked monomeric sugar moieties, where each linked monomeric sugar moiety is directly or indirectly attached to a heterocyclic base moiety. In certain embodiments, oligomeric compounds may also include monomeric sugar moieties that are not linked to a heterocyclic base moiety, thereby providing abasic sites. Oligomeric compounds may be defined in terms of a nucleobase sequence only, i.e., by specifying the sequence of A, G, C, U (or T). In such a case, the structure of the sugar-phosphate backbone is not partictularly limited and may or may not comprise modified sugars and/or modified phosphates. On the other hand, oligomeric compounds may be more comprehensively defined, i.e, by specifying not only the nucleobase sequence, but also the structure of the backbone, in particular the modification status of the sugars (unmodified, 2'-OMe modified, 2'-F modified etc.) and/or of the phosphates. As used herein, "terminal group" means one or more atom attached to either, or both, the 3 ' end or the 5' end of an oligonucleotide. In certain embodiments, a terminal group comprises one or more terminal group nucleosides. As used herein, "conjugate" or "conjugate group" means an atom or group of atoms bound to an oligonucleotide or oligomeric compound. In certain embodiments, a conjugate group links a ligand to a modified oligonucleotide or oligomeric compound. In general, conjugate groups can modify one or more properties of the compound to which they are attached, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and / or clearance properties. As used herein, "conjugate linker" or "linker" in the context of a conjugate group means a portion of a conjugate group comprising any atom or group of atoms and which covalently link an oligonucleotide to another portion of the conjugate group. In certain embodiments, the point of attachment on the oligomeric compound is the 3 '-oxygen atom of the 3'-hydroxyl group of the 3' terminal nucleoside of the oligonucleotide. In certain embodiments the point of attachment on the oligomeric compound is the 5'-oxygen atom of the 5'-hydroxyl group of the 5' terminal nucleoside of the oligonucleotide. In certain embodiments, the bond for forming attachment to the oligomeric compound is a cleavable bond. In certain such embodiments, such cleavable bond constitutes all or part of a cleavable moiety. In certain embodiments, conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and ligand portion that can comprise one or more ligands, such as a carbohydrate cluster portion, such as an N-Acetyl-Galactosamine, also referred to as "GalNAc", cluster portion. In certain embodiments, the carbohydrate cluster portion is identified by the number and identity of the ligand. For example, in certain embodiments, the carbohydrate cluster portion comprises 2 GalNAc groups. For example, in certain embodiments, the carbohydrate cluster portion comprises 3 GalNAc groups and this is particularly preferred. In certain embodiments, the carbohydrate cluster portion comprises 4 GalNAc groups. Such ligand portions are attached to an oligomeric compound via a cleavable moiety, such as a cleavable bond or cleavable nucleoside. The ligands can be arranged in a linear or branched configuration, such as a biantennary or triantennary configurations. As used herein, "cleavable moiety" means a bond or group that is capable of being cleaved under physiological conditions. In certain embodiments, a cleavable moiety is cleaved inside a cell or sub- cellular compartments, such as an endosome or lysosome. In certain embodiments, a cleavable moiety is cleaved by endogenous enzymes, such as nucleases. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is a phosphodiester linkage. As used herein, "cleavable bond" means any chemical bond capable of being broken. As used herein, "carbohydrate cluster" means a compound having one or more carbohydrate residues attached to a linker group. As used herein, "modified carbohydrate" means any carbohydrate having one or more chemical modifications relative to naturally occurring carbohydrates. As used herein, "carbohydrate derivative" means any compound which may be synthesized using a carbohydrate as a starting material or intermediate. As used herein, "carbohydrate" means a naturally occurring carbohydrate, a modified carbohydrate, or a carbohydrate derivative. A carbohydrate is a biomolecule including carbon (C), hydrogen (H) and oxygen (O) atoms. Carbohydrates can include monosaccharide, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides or polysaccharides, such as one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and / or one or more mannose moieties. A particularly preferred carbohydrate is N-Acetyl-Galactosamine moieties. As used herein, "strand" means an oligomeric compound comprising linked nucleosides. The linker is not particularly limited, but includes phosphodiesters and variants thereof as disclosed herein. A strand may also be viewed as a plurality of linked nucleotides in which case the linker would be a covalent bond. The term "construct" means a region of linked nucleosides which is defined in terms of nucleobase sequence and sugar modifications. A construct may coincide with a strand or compound, but may also be part thereof. As used herein, "single strand" or "single-stranded" means an oligomeric compound comprising linked nucleosides that are connected in a continuous sequence without a break therebetween. Such single strands may include regions of sufficient self-complementarity so as to be capable of forming a stable self-duplex in a hairpin structure. As used herein, "hairpin" means a single stranded oligomeric compound that includes a duplex formed by base pairing between sequences in the strand that are self-complementary and opposite in directionality. As used herein, "hairpin loop" means an unpaired loop of linked nucleosides in a hairpin that is created as a result of hybridization of the self-complementary sequences. The resulting structure looks like a loop or a U-shape. In particular, short hairpin RNA, also denoted as shRNA, comprises a duplex region and a loop connecting the regions forming the duplex. The end of the duplex region which does not carry the loop may be blunt-ended or carry (a) 3' and/or (a) 5' overhang(s). Advantageously, the construct is blunt-ended. Such molecules are also referred to as "mxRNAs". As used herein, the term "mxRNA" is in particular understood as defined in WO 2020/044186 A2 which is incorporated by reference herein in its entirety. Particularly preferred hairpin RNAs in accordance with the invention are those shown in Tables 6 and 7 and Figures 15 to 18, 20 and 22. As used herein, "directionality" means the end-to-end chemical orientation of an oligonucleotide based on the chemical convention of numbering of carbon atoms in the sugar moiety meaning that there will be a 5′-end defined by the 5′ carbon of the sugar moiety, and a 3′-end defined by the 3' carbon of the sugar moiety. In a duplex or double stranded oligonucleotide, the respective strands run in opposite 5' to 3' directions to permit base pairing between them. As used herein, "duplex", also abbreviated as "dup", means two or more complementary strand regions, or strands, of an oligonucleotide or oligonucleotides, hybridized together by way of non- covalent, sequence-specific interaction therebetween. Most commonly, the hybridization in the duplex will be between nucleobases adenine (A) and thymine (T), and / or (A) adenine and uracil (U), and / or guanine (G) and cytosine (C). The duplex may be part of a single stranded structure, wherein self-complementarity leads to hybridization, or as a result of hybridization between respective strands in a double stranded molecule. As used herein, "double strand" or "double stranded" means a pair of oligomeric compounds that are hybridized to one another. In certain embodiments, a double-stranded oligomeric compound comprises a first and a second oligomeric compound. As used herein, "expression" means the process by which a gene ultimately results in a protein. Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenlyation, addition of 5 '-cap), and translation. As used herein, "transcription" or "transcribed" refers to the first of several steps of DNA based gene expression in which a target sequence of DNA is copied into RNA (especially mRNA) by the enzyme RNA polymerase. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA sequence called a primary transcript. As used herein, "target sequence" means a sequence to which an oligomeric compound is intended to hybridize to result in a desired activity with respect to Factor XI expression. Oligonucleotides have sufficient complementarity to their target sequences to allow hybridization under physiological conditions. As used herein, "nucleobase complementarity" or "complementarity" when in reference to nucleobases means a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In both DNA and RNA, guanine (G) is complementary to cytosine (C). In certain embodiments, complementary nucleobase means a nucleobase of an oligomeric compound that is capable of base pairing with a nucleobase of its target sequence. For example, if a nucleobase at a certain position of an oligomeric compound is capable of hydrogen bonding with a nucleobase at a certain position of a target sequence, then the position of hydrogen bonding between the oligomeric compound and the target sequence is considered to be complementary at that nucleobase pair. Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity. As used herein, "non-complementary" in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another. As used herein, "complementary" in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides) means the capacity of such oligomeric compounds or regions thereof to hybridize to a target sequence, or to a region of the oligomeric compound itself, through nucleobase complementarity. Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. In certain embodiments, complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary). In certain embodiments, complementary oligomeric compounds or regions are 80%> complementary. In certain embodiments, complementary oligomeric compounds or regions are 90%> complementary. In certain embodiments, complementary oligomeric compounds or regions are 95% complementary. In certain embodiments, complementary oligomeric compounds or regions are 100% complementary. As used herein, "self-complementarity" in reference to oligomeric compounds means a compound that may fold back on itself, creating a duplex as a result of nucleobase hybridization of internal complementary strand regions. Depending on how close together and / or how long the strand regions are, then the compound may form hairpin loops, junctions, bulges or internal loops. As used herein, "mismatch" means a nucleobase of an oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a target sequence, or at a corresponding position of the oligomeric compound itself when the oligomeric compound hybridizes as a result of self-complementarity, when the oligomeric compound and the target sequence and / or self- complementary regions of the oligomeric compound, are aligned. As used herein, "hybridization" means the pairing of complementary oligomeric compounds (e.g., an oligomeric compound and its target sequence). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. As used herein, "specifically hybridizes" means the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site. As used herein, "fully complementary" in reference to an oligomeric compound or region thereof means that each nucleobase of the oligomeric compound or region thereof is capable of pairing with a nucleobase of a complementary nucleic acid target sequence or a self-complementary region of the oligomeric compound. Thus, a fully complementary oligomeric compound or region thereof comprises no mismatches or unhybridized nucleobases with respect to its target sequence or a self- complementary region of the oligomeric compound. As used herein, "percent complementarity" means the percentage of nucleobases of an oligomeric compound that are complementary to an equal-length portion of a target nucleic acid. Percent complementarity is calculated by dividing the number of nucleobases of the oligomeric compound that are complementary to nucleobases at corresponding positions in the target nucleic acid by the total length of the oligomeric compound. As used herein, "percent identity" means the number of nucleobases in a first nucleic acid that are the same type (independent of chemical modification) as nucleobases at corresponding positions in a second nucleic acid, divided by the total number of nucleobases in the first nucleic acid. As used herein, "modulation" means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression. As used herein, "type of modification" in reference to a nucleoside or a nucleoside of a "type" means the chemical modification of a nucleoside and includes modified and unmodified nucleosides. Accordingly, unless otherwise indicated, a "nucleoside having a modification of a first type" may be an unmodified nucleoside. As used herein, "differently modified" mean chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified naturally occurring RNA nucleoside are "differently modified," even though the naturally occurring nucleoside is unmodified. Likewise, DNA and RNA oligonucleotides are "differently modified," even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2'-OMe modified sugar moiety and an unmodified adenine nucleobase and a nucleoside comprising a 2'-OMe modified sugar moiety and an unmodified thymine nucleobase are not differently modified. As used herein, "the same type of modifications" refers to modifications that are the same as one another, including absence of modifications. Thus, for example, two unmodified RNA nucleosides have "the same type of modification," even though the RNA nucleosides are unmodified. Such nucleosides having the same type modification may comprise different nucleobases. As used herein, "region" or "regions", or "portion" or "portions", mean a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the subject-matter and definitions described herein. Typically such regions or portions comprise at least 10, at least 11, at least 12 or at least 13 linked nucleosides. For example, such regions can comprise 13 to 20 linked nucleosides, such as 13 to 16 or 18 to 20 linked nucleosides. Typically a first region as defined herein consists essentially of 18 to 20 nucleosides and a second region as defined herein consists essentially of 13 to 16 linked nucleosides. As used herein, "pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administering to an animal. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile saline. In certain embodiments, such sterile saline is pharmaceutical grade saline. As used herein, "substituent" and "substituent group," means an atom or group that replaces the atom or group of a named parent compound. For example a substituent of a modified nucleoside is any atom or group that differs from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2'- substituent is any atom or group at the 2 '-position of a nucleoside other than H or OH). Substituent groups can be protected or unprotected. In certain embodiments, compounds of the present disclosure have substituents at one or at more than one position of the parent compound. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as oxygen or an alkyl or hydrocarbyl group to a parent compound. Such substituents can be present as the modification on the sugar moiety, in particular a substituent present at the 2'-position of the sugar moiety. Unless otherwise indicated, groups amenable for use as substituents include without limitation, one or more of halo, hydroxyl, alkyl, alkenyl, alkynyl, acyl, carboxyl, alkoxy, alkoxyalkylene and amino substituents. Certain substituents as described herein can represent modifications directly attached to a ring of a sugar moiety (such as a halo, such as fluoro, directly attached to a sugar ring), or a modification indirectly linked to a ring of a sugar moiety by way of an oxygen linking atom that itself is directly linked to the sugar moiety (such as an alkoxyalkylene, such as methoxyethylene, linked to an oxygen atom, overall providing an MOE substituent as described herein attached to the 2'-position of the sugar moiety). As used herein, "alkyl," as used herein, means a saturated straight or branched monovalent C1-6 hydrocarbon radical, with methyl being a most preferred alkyl as a substituent at the 2'-position of the sugar moiety. The alkyl group typically attaches to an oxygen linking atom at the 2' position of the sugar, therefore, overall providing an –O-alkyl substituent, such as an -OCH3 substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. As used herein, "alkylene" means a saturated straight or branched divalent hydrocarbon radical of the general formula -CnH2n- where n is 1-6. Methylene or ethylene are preferred alkylenes. As used herein, "alkenyl" means a straight or branched unsaturated monovalent C2-6 hydrocarbon radical, with ethenyl or propenyl being most preferred alkenyls as a substituent at the 2'-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkenyl radical is the presence of at least one carbon to carbon double bond. The alkenyl group typically attaches to an oxygen linking atom at the 2'-position of the sugar, therefore, overall providing a –Oalkenyl substituent, such as an –OCH2CH=CH2 substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. As used herein, "alkynyl" means a straight or branched unsaturated C2-6 hydrocarbon radical, with ethynyl being a most preferred alkynyl as a substituent at the 2'-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkynyl radical is the presence of at least one carbon to carbon triple bond. The alkynyl group typically attaches to an oxygen linking atom at the 2'-position of the sugar, therefore, overall providing a –Oalkynyl substituent on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. As used herein, "carboxyl" is a radical having a general formula –CO2H. As used herein, "acyl" means a radical formed by removal of a hydroxyl group from a carboxyl radical as defined herein and has the general Formula -C(O)-X where X is typically C1-6 alkyl. As used herein, "alkoxy" means a radical formed between an alkyl group, such as a C1-6 alkyl group, and an oxygen atom wherein the oxygen atom is used to attach the alkoxy group either to a parent molecule (such as at the 2'-position of a sugar moiety), or to another group such as an alkylene group as defined herein. Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Alkoxy groups as used herein may optionally include further substituent groups. As used herein, alkoxyalkylene means an alkoxy group as defined herein that is attached to an alkylene group also as defined herein, and wherein the oxygen atom of the alkoxy group attaches to the alkylene group and the alkylene attaches to a parent molecule. The alkylene group typically attaches to an oxygen linking atom at the 2'-position of the sugar, therefore, overall providing a – Oalkylenealkoxy substituent, such as an –OCH2CH2OCH3 substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood by a person skilled in the art and is generally referred to as an MOE substituent as defined herein and as known in the art. As used herein, "amino" includes primary, secondary and tertiary amino groups. As used herein, "halo" and "halogen," mean an atom selected from fluorine, chlorine, bromine and iodine. It will also be understood that oligomeric compounds as described herein may have one or more non- hybridizing nucleosides at one or both ends of one or both strands (overhangs) and / or one or more internal non-hybridizing nucleosides (mismatches) provided there is sufficient complementarity to maintain hybridization under physiologically relevant conditions. Alternatively, oligomeric compounds as described herein may be blunt ended at at least one end. The term "comprising" is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and as such there may be present additional steps or elements. Further, to the extent that the term "includes" is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in a claim. Each of the constructs of the invention may or may not have a phosphate modification at the 5' end group. Furthermore, and independently, each of the above constructs may or may not have a "3x GalNAc" coupled to the 3' end group. Advantageously, a construct bears a 3x GalNAc ligand, such as a "toothbrush" moiety as disclosed herein. Particularly preferred are constructs which in addition have a 5' phosphate, even though this is not a strict requirement, given that in the absence thereof, mammalian cells will add such phosphate in case it is absent from the molecule as administered. The following are aspects of the present embodiments. Aspect 1. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250, or SEQ ID NOs 1251 to 1500. Aspect 2. An oligomeric compound according to aspect 1, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence and is selected from the following sequences, or a portion thereof: SEQ ID NOs 251 to 500, or SEQ ID NOs 1501 to 1750. Aspect 3. An oligomeric compound according to aspect 1 or 2, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 13, 27, 39, 46, 91, 98, 103, 105, 109, 120, 140, 146, 151, 152, 163, 182, 183, 199, 207, 210, 218, 220, 223, 224, 238, or SEQ ID NOs 1258, 1263, 1277, 1289, 1296, 1341, 1348, 1353, 1355, 1359, 1370, 1390, 1396, 1401, 1402, 1413, 1432, 1433, 1449, 1457, 1460, 1468, 1470, 1473, 1474, 1488. Aspect 4. An oligomeric compound according to aspect 3, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 263, 277, 289, 296, 341, 348, 353, 355, 359, 370, 390, 396, 401, 402, 413, 432, 433, 449, 457, 460, 468, 470, 473, 474, 488, or SEQ ID NOs 1508, 1513, 1527, 1539, 1546, 1591, 1598, 1603, 1605, 1609, 1620, 1640, 1646, 1651, 1652, 1663, 1682, 1683, 1699, 1707, 1710, 1718, 1720, 1723, 1724, 1738. Aspect 5. An oligomeric compound according to any of aspects 1 to 4, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 46, 91, 146, 152, 207, or SEQ ID NOs 1258, 1296, 1341, 1396, 1402, 1457. Aspect 6. An oligomeric compound according to aspect 5, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 296, 341, 396, 402, 457, or SEQ ID NOs 1508, 1546, 1591, 1646, 1652, 1707. Aspect 7. An oligomeric compound according to any of aspects 1 to 6, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 46, 91, 152, or SEQ ID NOs 1296, 1341, 1402. Aspect 8. An oligomeric compound according to aspect 7, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 296, 341, 402, or SEQ ID NOs 1546, 1591, 1652. Aspect 9. An oligomeric compound according to any of aspects 1 to 8, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250. Aspect 10. An oligomeric compound according to aspect 3 and / or 4, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238. Aspect 11. An oligomeric compound according to aspect 5 and / or 6, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207. Aspect 12. An oligomeric compound according to aspect 7 and / or 8, wherein the first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091, 1152. Aspect 13. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250. Aspect 14. An oligomeric compound according to aspect 13, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091, 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151, 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238. Aspect 15. An oligomeric compound according to aspect 13 or 14, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091, 1146, 1152, 1207. Aspect 16. An oligomeric compound according to any of aspects 13 to 15, wherein the RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091, 1152. Aspect 17. An oligomeric compound according to any of aspects 1 to 16, wherein the first region of linked nucleosides consists essentially of 18 to 20 linked nucleosides. Aspect 18. An oligomeric compound according to any of aspects 2 to 17, wherein the second region of linked nucleosides consists essentially of 11 to 16, advantageously 12 to 15 or 13 to 16 linked nucleosides. Aspect 19. An oligomeric compound according to any of aspects 2 to 18, which comprises at least one complementary duplex region that comprises at least a portion of the first nucleoside region directly or indirectly linked to at least a portion of the second nucleoside region. Aspect 20. An oligomeric compound according to aspect 19, wherein each of the first and second nucleoside regions has a 5’ to 3’ directionality thereby defining 5’ and 3’ regions respectively thereof. Aspect 21. An oligomeric compound according to aspect 20, wherein the 5’ region of the first nucleoside region is directly or indirectly linked to the 3’ region of the second nucleoside region, for example by complementary base pairing, and / or wherein the 3’ region of the first nucleoside region is directly or indirectly linked to the 5’ region of the second nucleoside region. Aspect 22. An oligomeric compound according to any of aspects 1 to 21, which further comprises one or more ligands. Aspect 23. An oligomeric compound according to aspect 21, wherein the one or more ligands are conjugated to the second nucleoside region. Aspect 24. An oligomeric compound according to aspect 23, as dependent on aspect 20, wherein the one or more ligands are conjugated at the 3 ' region of the second nucleoside region. Aspect 25. An oligomeric compound according to any of aspects 22 to 24, wherein the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and / or peptides that bind cellular membrane or a specific target on cellular surface. Aspect 26. An oligomeric compound according to aspect 25, wherein the one or more ligands comprise one or more carbohydrates. Aspect 27. An oligomeric compound according to aspect 26, wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide. Aspect 28. An oligomeric compound according to aspect 27, wherein the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and / or one or more mannose moieties. Aspect 29. An oligomeric compound according to aspect 28, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties. Aspect 30. An oligomeric compound according to aspect 29, which comprises two or three N- Acetyl-Galactosamine moieties, preferably three. Aspect 31. An oligomeric compound according to any of aspects 22 to 30, wherein the one or more ligands are attached to the oligomeric compound, preferably to the second nucleoside region thereof, in a linear configuration, or in a branched configuration. Preferred is that the ligand has the following structure, also referred to as "toothbrush" herein:
Figure imgf000021_0001
A particularly preferred embodiment of "GalNAc" (as used herein) is the above structure. Aspect 32. An oligomeric compound according to aspect 31, wherein the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration. Aspect 33. An oligomeric compound according to aspect 19, wherein the oligomeric compound comprises a single strand comprising the first and second nucleoside regions, wherein the single strand dimerises whereby at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region. Aspect 34. An oligomeric compound according to aspect 33, wherein the first nucleoside region has a greater number of linked nucleosides compared to the second nucleoside region, whereby the additional number of linked nucleosides of the first nucleoside region form a hairpin loop linking the first and second nucleoside regions. Aspect 35. An oligomeric compound according to aspect 34, as dependent on aspect 20, whereby the hairpin loop is present at the 3' region of the first nucleoside region. Aspect 36. An oligomeric compound according to aspect 34 or 35, wherein the hairpin loop comprises 4 or 5 linked nucleosides. Aspect 37. An oligomeric compound according to any of aspects 1 to 36, which comprises internucleoside linkages and wherein at least one internucleoside linkage is a modified internucleoside linkage. Aspect 38. An oligomeric compound according to aspect 37, wherein the modified internucleoside linkage is a phosphorothioate or phosphorodithioate internucleoside linkage. Aspect 39. An oligomeric compound according to aspect 38, which comprises 1 to 15 phosphorothioate or phosphorodithioate internucleoside linkages. Aspect 40. An oligomeric compound according to aspect 39, which comprises 7, 8, 9 or 10 phosphorothioate or phosphorodithioate internucleoside linkages. Aspect 41. An oligomeric compound according to any of aspects 38 to 40, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the first nucleoside region. Aspect 42. An oligomeric compound according to any of aspects 38 to 41, as dependent on aspect 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the second nucleoside region. Aspect 43. An oligomeric compound according to any of aspects 38 to 42, as dependent on aspect 34, which comprises phosphorothioate or phosphorodithioate internucleoside linkages between at least two, preferably at least three, preferably at least four, preferably at least five, adjacent nucleosides of the hairpin loop, dependent on the number of nucleotides present in the hairpin loop. Aspect 44. An oligomeric compound according to aspect 43, which comprises a phosphorothioate or phosphorodithioate internucleoside linkage between each adjacent nucleoside that is present in the hairpin loop. Aspect 45. An oligomeric compound according to any of aspects 1 to 44, wherein at least one nucleoside comprises a modified sugar. Aspect 46. An oligomeric compound according to aspect 45, wherein the modified sugar is selected from 2' modified sugars; conformationally restricted nucleotides (CRN) sugar such as locked nucleic acid (LNA), (S)-constrained ethyl bicyclic nucleic acid, and constrained ethyl (cEt), tricyclo- DNA; morpholino, unlocked nucleic acid (UNA), glycol nucleic acid (GNA), D-hexitol nucleic acid (HNA), and cyclohexene nucleic acid (CeNA), and preferably is a 2'-O-methyl modified sugar. Further 2' modified sugars include 2'-O-alkyl modified sugar, 2'-O-methoxyethyl modified sugar, 2'-O- allyl modified sugar, 2'-C-allyl modified sugar, 2'-deoxy modified sugar such as 2'-deoxy ribose, 2'-F modified sugar, 2'-arabino-fluoro modified sugar, 2'-O-benzyl modified sugar, 2'-amino modified sugar, and 2'-O-methyl-4-pyridine modified sugar. Aspect 47. An oligomeric compound according to aspect 45 or 46, wherein the modified sugar is a 2'-F modified sugar. Aspect 48. An oligomeric compound according to any of aspects 45 to 47, as dependent on aspect 20, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5’ region of the first nucleoside region, do not contain 2'-O-methyl modifications. Aspect 49. An oligomeric compound according to any of aspects 45 to 48, as dependent on aspect 20, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleotide of the 5’ region of the first nucleoside region, do not contain 2'-O-methyl modifications. Aspect 50. An oligomeric compound according to aspect 48 or 49, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications. Aspect 51. An oligomeric compound according to any of aspects 48 to 50, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications. Aspect 52. An oligomeric compound according to any of aspects 45 to 51, as dependent on aspect 20, wherein one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are modified, and / or wherein one or more of the even numbered nucleotides starting from the 5’ region of the first nucleoside region are modified, wherein typically the modification of the even numbered nucleotides is a second modification that is different from the modification of odd numbered nucleotides. Aspect 53. An oligomeric compound according to aspect 52, wherein one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of odd numbered nucleosides of the first nucleoside region. Aspect 54. An oligomeric compound according to aspect 52 or 53, wherein one or more of the even numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of even numbered nucleosides of the first nucleoside region according to aspect 53. Aspect 55. An oligomeric compound according to any of aspects 52 to 54, wherein at least one or more of the modified even numbered nucleosides of the first nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the first nucleoside region. Aspect 56. An oligomeric compound according to any of aspects 52 to 55, wherein at least one or more of the modified even numbered nucleosides of the second nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the second nucleoside region. Aspect 57. An oligomeric compound according to any of aspects 52 to 56, wherein sugars of one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-O-methyl modified sugars. Aspect 58. An oligomeric compound according to any of aspects 52 to 57, wherein one or more of the even numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-F modified sugars. Aspect 59. An oligomeric compound according to any of aspects 52 to 58, wherein sugars of one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are 2'-F modified sugars. Aspect 60. An oligomeric compound according to any of aspects 52 to 59, wherein one or more of the even numbered nucleosides starting from the 3’ region of the second nucleoside region are 2'- O-methyl modified sugars. Aspect 61. An oligomeric compound according to any of aspects 45 to 60, wherein sugars of a plurality of adjacent nucleosides of the first nucleoside region are modified by a common modification. Aspect 62. An oligomeric compound according to any of aspects 45 to 61, wherein sugars of a plurality of adjacent nucleosides of the second nucleoside region are modified by a common modification. Aspect 63. An oligomeric compound according to any of aspects 52 to 62, as dependent on aspect 34, wherein sugars of a plurality of adjacent nucleosides of the hairpin loop are modified by a common modification. Aspect 64. An oligomeric compound according to any of aspects 61 to 63, wherein the common modification is a 2'-F modified sugar. Aspect 65. An oligomeric compound according to any of aspects 61 to 63, wherein the common modification is a 2'-O-methyl modified sugar. Aspect 66. An oligomeric compound according to aspect 65, wherein the plurality of adjacent 2'- O-methyl modified sugars are present in at least eight adjacent nucleosides of the first and / or second nucleoside regions. Aspect 67. An oligomeric compound according to aspect 65, wherein the plurality of adjacent 2'- O-methyl modified sugars are present in three or four adjacent nucleosides of the hairpin loop. Aspect 68. An oligomeric compound according to aspect 45, as dependent on aspect 34, wherein the hairpin loop comprises at least one nucleoside having a modified sugar. Aspect 69. An oligomeric compound according to aspect 68, wherein the at least one nucleoside is adjacent a nucleoside with a differently modified sugar. Aspect 70. An oligomeric compound according to aspect 69, wherein the modified sugar is a 2'- O-methyl modified sugar, and the differently modifies sugar is a 2'-F modified sugar. Aspect 71. An oligomeric compound according to any of aspects 1 to 70, which comprises one or more nucleosides having an un-modified sugar moiety. Aspect 72. An oligomeric compound according to aspect 71, wherein the unmodified sugar is present in the 5' region of the second nucleoside region. Aspect 73. An oligomeric compound according to aspect 71 or 72, as dependent on aspect 34, wherein the unmodified sugar is present in the hairpin loop. Aspect 74. An oligomeric compound according to any of aspects 1 to 73, wherein one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3' carbon of its sugar and the 3' carbon of the sugar of the adjacent nucleoside, and / or one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5' carbon of its sugar and the 5' carbon of the sugar of the adjacent nucleoside. Aspect 75. An oligomeric compound according to any of aspects 1 to 74, which is blunt ended. Aspect 76. An oligomeric compound according to any of aspects 1 to 74, wherein either the first or second nucleoside region has an overhang. Aspect 77. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, wherein the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein the first nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 501 to 750, or construct NOs 1751 to 2000. Aspect 78. An oligomeric compound according to aspect 77, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence, wherein the second nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 751 to 1000, or construct NOs 2001 to 2250. Aspect 79. An oligomeric compound according to aspect 77 or 78, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 513, 527, 539, 546, 591, 598, 603, 605, 609, 620, 640, 646, 651, 652, 663, 682, 683, 699, 707, 710, 718, 720, 723, 724, 738, or construct NOs 1758, 1763,1777, 1789, 1796, 1841, 1848, 1853, 1855, 1859, 1870, 1890, 1896, 1901, 1902, 1913, 1932, 1933, 1949, 1957, 1960, 1968, 1970, 1973, 1974, 1988. Aspect 80. An oligomeric compound according to aspect 79, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 763, 777, 789, 796, 841, 848, 853, 855, 859, 870, 890, 896, 901, 902, 913, 932, 933, 949, 957, 960, 968, 970, 973, 974, 988, or construct NOs 2008, 2013, 2027, 2039, 2046, 2091, 2098, 2103, 2105, 2109, 2120, 2140, 2146, 2151, 2152, 2163, 2182, 2183, 2199, 2207, 2210, 2218, 2220, 2223, 2224, 2238. Aspect 81. An oligomeric compound according to any of aspects 77 to 80, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 546, 591, 646, 652, 707, or construct NOs 1758, 1796, 1841, 1896, 1902, 1957. Aspect 82. An oligomeric compound according to aspect 81, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 796, 841, 896, 902, 957, or construct NOs 2008, 2046, 2091, 2146, 2152, 2207. Aspect 83. An oligomeric compound according to any of aspects 77 to 82, wherein the first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 546, 591, 652, or construct NOs 1796, 1841, 1902. Aspect 84. An oligomeric compound according to aspect 83, wherein the second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 796, 841, 902, or construct NOs 2046, 2091, 2152. Aspect 85. An oligomeric compound according to any of aspects 77 to 84, which is further characterised according to any of aspects 17 to 44, or 74 to 76. Aspect 86. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which is selected from the following sequences: SEQ ID NOs 2251 to 2253, or SEQ ID NOs 2284 to 2288, preferably SEQ ID NO: 2287. Aspect 87. An oligomeric compound capable of modulating, preferably inhibiting, expression of FXI, which is selected from the following sequences: construct NOs 2254 to 2283. Aspect 88. An oligomeric compound according to aspect 86 or 87, which further comprises one or more ligands. Aspect 89. An oligomeric compound according to aspect 88, wherein the one or more ligands are conjugated at the 3 ' region of the sequences, preferably at the 3' terminal nucleoside. Aspect 90. An oligomeric compound according to aspect 88, wherein the one or more ligands are conjugated at non-terminal positions. Aspect 91. An oligomeric compound according to any of aspects 88 to 90, wherein the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and / or peptides that bind cellular membrane or a specific target on cellular surface. Aspect 92. An oligomeric compound according to aspect 91, wherein the one or more ligands comprise one or more carbohydrates. Aspect 93. An oligomeric compound according to aspect 92, wherein the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide. A preferred monosaccharide is hexose. Aspect 94. An oligomeric compound according to aspect 93, wherein the one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and / or one or more mannose moieties. Aspect 95. An oligomeric compound according to aspect 94, wherein the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties. Aspect 96. An oligomeric compound according to aspect 95, which comprises two or three N-Acetyl- Galactosamine moieties, preferably three. Aspect 97. An oligomeric compound according to any of aspects 88 to 96, wherein the one or more ligands are attached to the oligomeric compound in a linear configuration, or in a branched configuration. Aspect 98. An oligomeric compound according to aspect 97, wherein the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration. Aspect 99. An oligomeric compound according to any of aspects 86 to aspect 98, wherein the sequences self dimerise so as to form an at least partially complementary duplex region. Aspect 100. An oligomeric compound according to aspect 99, having a nucleobase sequence and structure as shown in any of Figures 15 to 17 or 18 to 20, construct NOs: 2290 to 2292 being preferred, construct NO: 2290 being particularly preferred. Aspect 101. A composition comprising an oligomeric compound according to any of aspects 1 to 100, and a physiologically acceptable excipient. Aspect 102. An oligomeric compound according to any of aspects 1 to 100, for use in therapy. Aspect 103. An oligomeric compound according to any of aspects 1 to 100, for use in the treatment of a disease or disorder. Aspect 104. A method of treating a disease or disorder comprising administration of an oligomeric compound according to any of aspects 1 to 100, to an individual in need of treatment. Aspect 105. A method according to aspect 104, wherein the oligomeric compound is administered subcutaneously or intravenously to the individual. Aspect 106. Use of an oligomeric compound according to any of aspects 1 to 100, for use in research as a gene function analysis tool. Aspect 107. Use according to aspect 103, or a method according to aspect 104, wherein the disease or disorder is a thromboembolic disease. Aspect 108. Use or method according to aspect 107, wherein the thromboembolic disease is selected from the group consisting of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end- stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition. Aspect 109. Use or method according to aspect 108, wherein the thromboembolic disease is deep vein thrombosis, pulmonary embolism, or a combination thereof. Aspect 110. Use of an oligomeric compound according to any of items 1 to 100 in the manufacture of a medicament for a treatment of a disease or disorder. The diseases and disorders are advantageously the same as set forth herein above. The molecules disclosed herein, including, but not limited to, the hairpin RNAs as shown in Tables 6 and 7 and Figures 15 to 18, 20 and 22 are characterized by surprisingly outstanding performance, including in an in vivo setting; see, for example, the evidence shown in Figures 24 and 25. These data show a long-lasting down-regulation of Factor XI in response to administration of constructs as described herein. Further evidence of surprising performance of a plurality of constructs can be seen in the in vitro data provided in the Examples, including the data shown in Figure 19. The Figures as provided herein illustrate exemplary methods and data. While the methods are shown and described as being a series of acts that are performed in a particular sequence, it is to be understood and appreciated that the methods are not limited by the order of the sequence. For example, some acts can occur in a different order than what is described herein. In addition, an act can occur concurrently with another act. Further, in some instances, not all acts may be required to implement a method described herein. The order of the steps of the methods described herein is exemplary, but the steps may be carried out in any suitable order, or simultaneously where appropriate. Additionally, steps may be added or substituted in, or individual steps may be deleted from any of the methods without departing from the scope of the subject matter described herein. Aspects of any of the Examples described above may be combined with aspects of any of the other Examples described to form further Examples. It will be understood that the above description of a preferred embodiment is given by way of example only and that various modifications may be made by those skilled in the art. What has been described above includes Examples of one or more embodiments. It is, of course, not possible to describe every conceivable modification and alteration of the above compounds, compositions or methods for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended claims. Examples The following Examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif or modification patterns provides reasonable support for additional oligonucleotides having the same or similar motif or modification patterns. The syntheses of the RNAi constructs disclosed herein may be carried out using synthesis methods known to the person skilled in the art, such as synthesis methods disclosed in https://en.wikipedia.org/wiki/Oligonucleotide_synthesis {retrieved on 16 February 2022}, wherein the methods disclosed on this website are incorporated by reference herein in their entirety . The only difference to the synthesis method disclosed in this reference is that GalNAc phosphoramidite immobilized on a support is used in the synthesis method during the first synthesis step. The terms "construct number" and "SEQ ID NO" are used equivalently herein, especially with respect to 67 nucleobase sequences. Nucleobase sequences generally do not carry information about modifications of the sugar-phosphate backbone. Example 1: Oligomeric compounds were synthesized using the oligonucleotides as set out in Tables 1a and 1b below. Table 1a: Summary sequence table for active nucleobase sequences:
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
In above Table 1a: A represents adenine; U represents uracil; C represents cytosine; G represents guanine. Table 1b: Summary sequence table for active nucleobase sequences with chemical modifications:
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
In above Table 1b: A represents adenine; U represents uracil; C represents cytosine; G represents guanine; P represents a terminal phosphate group; m represents a methyl modification at the 2' position of the sugar of the underlying nucleoside; f represents a fluoro modification at the 2' position of the sugar of the underlying nucleoside. The target sequences in the Factor XI gene, with which the antisense (guide) sequences of Tables 1a / 1b interact are set out in Table 1c below. Table 1c: Summary sequence table for the nucleobases of the target gene:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
In above Table 1c: A represents adenine; U represents uracil; C represents cytosine; G represents guanine. It should also be noted that the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1b, and wherein the 5' nucleoside of the antisense (guide) strand (first region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C). Additionally, the scope of the present embodiments extends to sequences that correspond to those in Table 1a or Table 1b, and wherein the 3' nucleoside of the sense (passenger) strand (second region as defined herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine or cytosine (C), preferably however a nucleobase that is complementary to the 5' nucleobase of the antisense (guide) strand (first region as defined herein). These further sequences are shown in Tables 1d (unmodified) and 1e (chemically modified), where N and N' respectively represent any RNA nucleobase that can be present in the 5' terminal position of the antisense (guide) strand (first region as defined herein) and in the 3' terminal position of the sense (passenger) strand (second region as defined herein). Table 1d: Summary sequence table for active nucleobase sequences:
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
In above Table 1d: A represents adenine; U represents uracil; C represents cytosine; G represents guanine; N represents any RNA nucleobase; N' represents any RNA nucleobase and is preferably complementary to N. Table 1e: Summary sequence table for active nucleobase sequences with chemical modifications:
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
In above Table 1e: A represents adenine; U represents uracil; C represents cytosine; G represents guanine; P represents a terminal phosphate group; m represents a methyl modification at the 2' position of the sugar of the underlying nucleoside; f represents a fluoro modification at the 2' position of the sugar of the underlying nucleoside N represents any RNA nucleobase; N' represents any RNA nucleobase and is preferably complementary to N. Example 2: Oligonucleotides as set out in Tables 1a / 1b above that target FXI mRNA in human hepatoma cells were screened as follows. Native gel electrophoresis for random FXI oligomeric compounds: Oligomeric compounds including oligonucleotides as set out in Table 1a / 1b above were dissolved in sterile Rnase-, Dnase free water to the final concentration 100 μM. 10 random oligomeric compounds were selected for validation based on following Table 2. Table 2:
Figure imgf000097_0001
20% TBE gel electrophoresis was carried out for the above oligomeric compounds of Table 2, 10 pm oligonucleotide / lane, staining: SybrGold. Figure 1 illustrates the stability of the resulting duplexes. Based on this QC data we used all oligomeric compounds in the following screening. Two independent F11 qPCR assays and were validated for the screening. Both assays produced linear dose response as illustrated in Figure 2 with high sensitivity and efficiency. Due to known qPCR artifacts caused by siRNAs overlapping with qPCR probe regions, two probes from different target gene regions were used. Screening F11 oligomeric compounds in hepatoma cell line: Protocol details: Cell seeding: 10,000 HepG2 cells/well. Lipofectamine RNAiMax mediated transfection. Transfection: 20 nM compounds, antibiotic-free EMEM medium 10% FBS, 72 h incubation. Gene expression was measured by qPCR (Taqman chemistry), adjusted to the standard curve and normalized to the reference gene GAPDH. Data is expressed as the percentage of gene expression in non-treated cells (NT). Results of the screening are shown in Figures 3 to 12. 26 oligomeric compounds with 80% knockdown cut off were selected for the dose response curves. Basis for this selection is as follows in Table 3. Table 3:
Figure imgf000098_0001
Example 3: Dose response curves for the 26 FXI lead compounds as identified in Example 2 are shown in Figure 13. Dose response curves for the 5 FXI lead compounds are shown in Figure 14. Example 4: IC50 values are shown for the 26 FXI lead compounds as identified in Example 2 in following Table 4. Table 4:
Figure imgf000099_0001
Example 5: Species cross-reactivity of the 26 FXI lead compounds as identified in Example 2 are shown in following Table 5. Table 5:
Figure imgf000100_0001
Example 6: Further to the data as provided in Examples 3 to 5, oligonucleotides F11-46 / SEQ ID NO: 46, F11-91 / SEQ ID NO: 91 and F11-152 / SEQ ID NO: 152 have been identified as particularly preferred antisense oligonucleotide sequences to be used in oligomeric compounds as described herein. On this basis, these sequences have been incorporated into overall oligomeric compounds as described herein of the following sequences SEQ ID NOs 2251 to 2253 as set out in following Table 6. Furthermore, selected modifications have been applied to SEQ ID NOs 2251 to 2253 as shown in SEQ ID NOs 2254 to 2286 in following Table 6. All sequences as provided below in Table 6 are set out in the 5' to 3' directionality. Table 6:
Figure imgf000101_0001
1 In case of nucleobase sequences 2 In case of nucleobase and sugar modifications being given
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
In above Table 6: A represents adenine; U represents uracil; C represents cytosine; G represents guanine; m represents a methyl modification at the 2' position of the sugar of the underlying nucleoside; f represents a fluoro modification at the 2' position of the sugar of the underlying nucleoside N / N'' / N''' represents any RNA nucleobase; N' represents any RNA nucleobase and is preferably complementary to N; (ps) represents a phosphorothioate inter-nucleoside linkage; i represents an inverted inter-nucleoside linkage, which can be either 3'-3', or 5'-5'; vp represents vinyl phosphonate; mvp represents methyl vinyl phosphonate. For each of the above constructs of Table 6, a ligand, such as a galnac ligand, is preferably attached at the 3' end of the sequence. Specifically for SEQ ID NOs 2251, 2252, 2253, this can be respectively illustrated as follows, where Galnac can represent any arrangement of Galnac attachment, preferably however a triantennary galnac attachment:
Figure imgf000109_0002
Alternatively for SEQ ID NOs 2272 to 2273 as shown in above Table 6, the ligand, preferably Galnac, attachment can be to an internal non-terminal nucleoside, such as attachment to the nucleosides in the above sequences where the nucleobase is not shown as modified. Example 7: This Example describes a structure-function relationship study of constructs comprising the nucleobase sequence of SEQ ID NO: 91. Figure 18 shows the constructs comprising the nucleobase sequence of SEQ ID NO: 91 which have been tested. Tests have been performed in primary hepatocytes. Human plateable 5 donor hepatocytes (Sekisui XenoTech, HPCH05+) are thawed in 45 mL of Human OptiThaw Hepatocyte media (Sekisui Xenotech, K8000), spun down at 200g for 5 minutes, and resuspended in 2x WEM complete (5% FBS, 2uM Dexamethasone, Pen/Strep, 8 ug/mL human insulin, 4 mM GlutaMAX, 30 mM HEPES pH 7.4). 2x WEM complete consists of WEM (Gibco, A1217601) and 2x the Hepatocyte Plating Supplement Pack (Gibco, CM3000) with only 1x FBS. The hepatocytes are then plated on 6 well Collagen 1 coated plates (Gibco, A1142803) at 25,000 cell/well at 50 uL per well and allowed to recover and adhere for 4 hours at 37C. After 4 hours, GalNac conjugated complexes are diluted to 2 uM in basal WEM and used to make a 2x, 7 step, 5 fold dilution series. 50 uL of each dilution is added to corresponding wells of the plated hepatocytes to make a final dilution series of 1 - 0.000064 uM in 1x WEM complete. The cells are allowed to culture for 72 hours at 37 degrees without disruption before harvest and RNA isolation using the PureLink Pro 96 total RNA Purification Kit (Invitrogen, 12173011A) according to the manufacturer's protocol. Results are shown in Figure 19. Based on these results, 7 molecules have been designed which are to be subjected to further analysis (see following Examples). These molecules are shown in Figure 20. Performance data in primary hepatocytes are shown in Figure 21. Based on these data, three molecules have been tested in humanized mice; see Example 8 below. Example 8: This Examples describes testing of the three molecules identified in Example 7 in humanized mice. Table 7 below shows nucleobase sequences (SEQ ID NOs) and full modification information (construct NOs) of these three molecules.
Figure imgf000110_0001
Figure imgf000111_0001
In above Table 7 A represents adenine; U represents uracil; C represents cytosine; G represents guanine; m represents a methyl modification at the 2' position of the sugar of the underlying nucleoside; f represents a fluoro modification at the 2' position of the sugar of the underlying nucleoside; * represents a phosphorothioate inter-nucleoside linkage; vp represents vinyl phosphonate; phos represents phosphonate; and 3galnac represents the toothbrush ligand defined herein above. Figure 22 also shows the structures of these molecules. Figure 23 shows performance of these molecules 5 days after administration. Based on these results, the construct designated "91-Conv-31" (structure displayed in Figure 22) has been selected for testing in non-human primates; see Example 9 below. Of note, this molecule is particularly short and comprises only a total of 31 nucleotides. Example 9: This Example describes a Pharmacodynamics Study of construct designated "91-Conv-31" (structure displayed in Figure 22) Following Single/Repeat Subcutaneous Injection to Cynomolgus Monkeys. Material and Methods For an overview of the study protocol, see Figure 24. A more detailed account is given below. STUDY PROTOCOL Table 8. Study Design
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
1 Study Information 1.1 Study Objective The objective of this study is to determine the pharmacodynamics (PD) of the compound selected for this study, following a single/repeat subcutaneous (SC) administration in male cynomolgus monkeys. 1.2 Regulatory Compliance This study is conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) standard animal procedures along with the IACUC guidelines that are in compliance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. This study will be conducted in accordance with this protocol and protocol amendments (if applicable) and the associated study-specific procedures, and with applicable Standard Operating Procedures (SOPs) and generally recognized good laboratory practices. This study will not be considered within the scope of the Good Laboratory Practice regulations. 2 Test Article and Vehicle Information 2.1 Test Article Compounds as specified further above. Desiccate at room temperature, protected from light Storage Conditions: Handling Standard laboratory precautions as defined in WuXi SOPs Instructions: Doses will be prepared according to instructions provided by the Dose Preparation: sponsor. A copy of the instructions, as well as details of preparation, will be maintained in the study records. Dose Solution Analysis Samples: Disposition of Remaining Remaining formulations will be stored at 4°C. Test Article Formulations: Disposition of
Remaining Remaining test article will be shipped back to sponsor or discarded
Test Article (dry 6 months after the final report is signed or at approval of Sponsor, powder or solid): Test System Identification
3.1 Animal Specifications
Species Cynomolgus monkeys (Macaca fascicularis)
Justification for Species This is an acceptable species to support PK studies for
Selection compounds intended to use in humans.
History of Dosing 18 naive animals and 6 non-na'ive animals
Body Weight Range 2-7 kg
Age Si 2.0 years old
Sex Male
Hainan Jingang Laboratory Animal Co. Ltd and other
Source permitted vendor
Nayangxintan Fucheng Town, Qiongshan District,
Address of Supplier Haikou Hainan Province, P.R. China
Method of Identification Unique skin tattoo on chest
The number of animals in each group is the minimum
Justification for number of number of animals necessary for assessment of Animals interanimal variability.
24 males will be selected. Animals will have undergone a physical examination for general health by a staff
Selection of Animals veterinarian. 24 males confirmed as being healthy, will be assigned to study.
Acclimation Period Selected animals will be acclimated prior to the study.
3.2 Animal Care
3.2.1 Environmental Conditions
The room(s) will be controlled and monitored for relative humidity (targeted mean range 40% to 70%, and any excursion from this range for more than 3 hours will be documented as a deviation) and temperature (targeted mean range 18°C to 26°C, and any excursion from this range will be documented as a deviation) with 10 to 20 air changes/hour. The room will be on a 12-hour light/dark cycle except when interruptions are necessitated by study activities. 3.2.2 Housing
Animals will be pair-housed in cages that are in accordance with applicable animal welfare laws and regulations during acclimation period. The monkeys will be housed individually in cages during experiment. Diet and Feeding
Animals will be fed twice daily. Stock monkeys will be fed approximately 120 grams of Certified Monkey Diet daily. These amounts can be adjusted as necessary based on food consumption of the group or body weight changes of an individual and/or changes in the certified diet.
Animals will be fasted overnight prior to blood collections for serum chemistry.
Drinking Water
Reverse osmosis (RO) water will be available to all animals, ad libitum.
3.2.3 Feed and Water Analyses RO water is analyzed every three months and every batch of feed will be analyzed before use. Feed and water analyses will be maintained in the facility records.
3.2.4 Environmental Enrichment
Enrichment toys will be provided. Administration of Dose Formulation
Administration Route: Subcutaneous injection via the dorsal area of the animals’ thoracic regions.
Justification for the Dose Dose levels chosen to characterize the Level: pharmacodynamics of test article in monkeys over the desired dose range and dosing frequencies.
Justification for the This administration route is consistent with the Administration Route: proposed initial route of human administration. Dose Administration: The dose formulations will be administered per facility SOPs. SC ADMINISTRATION: SC injection site will be along the dorsal area of the animals’ thoracic regions. For multiple or large doses, different sites will be used. When the injection site is altered, the location must be documented in the record. 4.1 Observations and Examinations 4.1.1 Clinical Observations Twice daily (approximately 9:30 a.m. and 4:00 p.m.), cage-side observations for general health and appearance will be conducted. Animals will be given physical examinations prior to study initiation to confirm animals’ health. On dosing days, the animals will be observed at 2, 4 and 6- hours post-dosing. General condition, injection site, behavior, activity, excretion, respiration or other unusual observations noted throughout the study will be recorded in the raw data. When necessary, additional clinical observations will be performed and recorded. A staff veterinarian or veterinary technician will evaluate each animal if clinical observations demonstrate declining animal condition and the Study Director will be notified. The Study Director, or designee, will notify the Sponsor if warranted by the evaluation. 4.1.2 Body Weight All animals will be weighted weekly. On dosing days, animals will be weighed on prior to dosing to determine the dose volume to be administered. 4.1.3 Blood Collection for Clinical Pathology All blood samples will be collected from a peripheral vessel from restrained, non- sedated animals.
Table 10 Clinical Pathology Schedule
Figure imgf000119_0001
a Blood sample may be collected from animals subjected to unscheduled euthanasia. Animals may not be fasted under that circumstance.
(1) Blood Collection for Hematology: Whole blood (at least 1.0 mL) will be collected from the animals into commercially available tubes with Potassium (K2) EDTA at room temperature (RT). The blood samples will be sent to clinical pathology lab in RT and tested for hematology parameters listed in the Table 9.
A blood smear will be prepared from each hematology sample. Blood smears will be labeled, stained, and stored. Blood smears may be read to investigate results of the hematology analyses. If additional examination of blood smears is deemed necessary, the smears may be subsequently evaluated and this evaluation will be described in a study plan amendment.
(2) Blood Collection for Coagulation Test: Approximately 1.7 mL blood will be collected into sodium citrate anticoagulation tubes at RT and sent to clinical pathology lab., The parameters listed in Table 9 will be performed to test coagulation function.
(3) Blood Collection for Clinical Chemistry: Whole blood samples (approximately 1 .2 mL) without anticoagulant will be collected and held at RT and up-right for at least 30 minutes and sent to clinical pathology lab. The samples will be processed to serum, which will be examined for the parameters listed in Table 9.
4.1.4 Blood Collection for Pharmacodynamics (PD)
Blood: All blood samples will be collected from a peripheral vessel from restrained, non-sedated animals.
Animals: All available, all groups Post-Dose Blood volume: Approximately 5.6 mL Anticoagulant: Sodium citrate Frequency: Refer to Table 9. Actual sample collection times will be recorded in the study records. For samples collected within the first hour of dosing, a ± 1 minute is acceptable. For the remaining time points, samples that are taken within 5% of the scheduled time are acceptable and will not be considered as protocol deviation.
Sample Processing: For FXI ELISA: 2 mL Blood will be collected into a tube
(Purchased from sponsor’s required company) containing sodium citrate on wet ice. Then all the blood will be mixed upside down 4 times. Samples will be centrifuged (1000g for 20 minutes at 4 °C) and approximately 1 mL plasma will be transferred into two tubes quickly (approximately 0.50 mL per tube). One tube (labeled frozen plasma) should be frozen instantly in liquid nitrogen, then stored at -80 °C.
For FXI Activity Assays: 3 mL Blood will be collected into a tube (Purchased from sponsor’s required company) containing sodium citrate on wet ice. Then all the blood will be mixed upside down 4 times. Samples will be centrifuged (1660g for 10 minutes at 4 °C) and approximately 1.5 mL plasma will be transferred into two labeled polypropylene micro-centrifuge tubes quickly (approximately 0.70 mL per tube). One tube (labeled frozen plasma) should be frozen instantly in liquid nitrogen, then stored at -80°C. Another tube should be in a cool set to maintain 2-6°C and shipped within 2-4 hours in 4°C for analysis of Factor XI protein for Activity Assays. For Serum: Whole blood samples (approximately 0.6 mL) without anticoagulant will be collected and held at RT and up-right for at least 30 minutes and then samples will be centrifuged (3200g for 10 minutes at 4°C) and approximately 0.3 mL serum will be transferred into tubes quickly. The tube should be frozen instantly in liquid nitrogen, then stored at -80°C until analysis. Protocol Amendments and Deviations
Changes to the approved protocol will be in the form of amendments approved by the Study Director and the Sponsor. Amendments will describe the protocol changes clearly and will include the effective date of the change and the justification for the change. The Study Director and Study Representative may authorize protocol changes by telephone or electronic means if he/she is not physically present at the time urgent or critical changes are required. Any authorization for such changes made as above must be documented appropriately and followed by a properly prepared written protocol amendment. The amendment must be signed and dated by the Study Director within 45 days of the effective date(s). All deviations from the protocol and SOPs and the reasons of the deviations will be documented and acknowledged by the Study Director. The Sponsor's Representative will be informed promptly of the occurrence of any deviations that might affect the results of the study, and any corrective actions taken. Protocol and SOP deviations that could impact data interpretation will be included in the final report. 6 Archiving of Materials Test article preparation, test article tracking, in-life data, protocol, protocol amendments (if applicable), and the original final report generated as a result of this study will be archived. 7 STATISTICAL ANALYSIS The following section does not apply to data recorded on unscheduled occasions. Such data will be reported on an individual basis. All numerical data will be subjected to calculation of group means and standard deviations by using Microsoft Excel software, unless otherwise stated hereafter. These descriptive statistics will be presented for each dataset of interest, as determined by the variable to be analyzed and the dataset classification variables (for example: sex, measurement occasion, and any other relevant variable that can be used to specify on which subdivision the descriptive statistics have to be reported). If a dataset has less than three non-missing values in each group, then the following inferential data analysis will not be conducted. No inferential data analysis will be conducted on toxicokinetic parameters and semi-quantitative data such as: urine protein, urine pH, urine bilirubin, urine occult blood, urine glucose, and urine ketones. Whenever there are more than two groups, the homogeneity of the group variances will be evaluated using Levene’s test at the 0.05 significance level. If differences between group variances are not found to be significant (p>0.05), then a parametric one-way analysis of variance (ANOVA) will be performed. When significant differences among the means are indicated by ANOVA test (p≤0.05), Dunnett’s test will be used to perform the group mean comparisons between the control group and each treated group. If Levene’s test indicates heterogeneous group variances (p≤0.05) and the data set contains just positive values, log transformation will be performed. If transformed data still fail the test for homogeneity of variance (p≤0.05) or where the data contain zero and/or negative values, then the non-parametric Kruskal-Wallis test will be used to compare all considered groups. When Kruskal-Wallis test is significant (p^0.05), Dunnett’ s test on ranks will be used to perform the pairwise group comparisons of interest.
Whenever there are only two groups to compare, Levene’s test will be performed as described above but a two-sample t-test will replace the one-way ANOVA, a Wilcoxon rank-sum test will be performed instead of the Kruskal-Wallis and, no Dunnett’s tests or Dunnett’s tests on ranks will be performed.
Each pairwise group comparisons of interest will be conducted via a two-sided test at the 5% significance level. Significant results will be reported as either p^O.001 , p^O.01 , or p^0.05, where p represents the observed probability.
Results
The results of the study are depicted in Figures 25, 27 and 28.
Figure 25 shows performance of construct designated "91-Conv-31" (structure displayed in Figure 22) in an in vivo study in terms of Factor XI activity knock-down. The effect of different dosages (expressed in mg/kg) and of single or multiple dosing at the beginning are shown and compared to a negative control (saline).
Efficient and unexpectedly long-lasting knock-down is apparent.
Figure 26 shows the molecular mechanism underlying the tests for targeting specificity as performed in the course of an in vivo study.
APTT stands for activated partial thromboplastin time. It measures the activity of intrinsic pathway of clotting that is impacted by factors like FXI. PT stands for prothrombin time which evaluates the integrity of extrinsic pathway of clotting that looks at the presence of factors like VII, V, X, prothrombin and fibrinogen.
Figure 27 shows the read-out of the tests illustrated in Figure 26.
The % FXI plasma activity (Figure 25), together with APTT and PT data (Figure 27) demonstrate that the molecule specifically targets FXI and does not have any off-target effect on the extrinsic clotting pathway.
Figure 28 presents data demonstrating a lack of side effects. A panel liver function and hematology parameters have been assessed. In particular, no elevated levels of liver enzymes and no changes in hematology parameters could be found.

Claims

Claims
1. An oligomeric compound that inhibits expression of FXI, wherein said compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250, or SEQ ID NOs 1251 to 1500.
2. An oligomeric compound according to claim 1 , which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to said first nucleobase sequence and is selected from the following sequences, or a portion thereof: SEQ ID NOs 251 to 500, or SEQ ID NOs 1501 to 1750.
3. An oligomeric compound according to claim 1 or 2, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 13, 27, 39, 46, 91 , 98, 103, 105, 109, 120, 140, 146, 151 , 152, 163, 182, 183, 199, 207, 210, 218, 220, 223, 224, 238, or SEQ ID NOs 1258, 1263, 1277, 1289, 1296, 1341 , 1348, 1353, 1355, 1359, 1370, 1390, 1396, 1401 , 1402, 1413, 1432, 1433, 1449, 1457, 1460, 1468, 1470, 1473, 1474, 1488.
4. An oligomeric compound according to claim 3, wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 263, 277, 289, 296, 341 , 348, 353, 355, 359, 370, 390, 396, 401 , 402, 413, 432, 433, 449, 457, 460, 468, 470, 473, 474, 488, or SEQ ID NOs 1508, 1513, 1527, 1539, 1546, 1591 , 1598, 1603, 1605, 1609, 1620, 1640,
1646, 1651 , 1652, 1663, 1682, 1683, 1699, 1707, 1710, 1718, 1720, 1723, 1724, 1738.
5. An oligomeric compound according to any of claims 1 to 4, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 8, 46, 91 , 146,
152, 207, or SEQ ID NOs 1258, 1296, 1341 , 1396, 1402, 1457.
6. An oligomeric compound according to claim 5, wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 258, 296, 341 , 396, 402, 457, or SEQ ID NOs 1508, 1546, 1591 , 1646, 1652, 1707.
7. An oligomeric compound according to any of claims 1 to 6, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 46, 91 , 152, or SEQ ID NOs 1296, 1341 , 1402.
8. An oligomeric compound according to claim 7, wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 296, 341 , 402, or SEQ ID NOs 1546, 1591 , 1652.
9. An oligomeric compound according to any of claims 1 to 8, wherein said first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.
10. An oligomeric compound according to claim 3 and / or 4, wherein said first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091 , 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151 , 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.
11. An oligomeric compound according to claim 5 and / or 6, wherein said first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091 , 1146, 1152, 1207.
12. An oligomeric compound according to claim 7 and / or 8, wherein said first nucleobase sequence is at least partially complementary to any of the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091 , 1152.
13. An oligomeric compound that inhibits expression of FXI, which compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1001 to 1250.
14. An oligomeric compound according to claim 13, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1013, 1027, 1039, 1046, 1091 , 1098, 1103, 1105, 1109, 1120, 1140, 1146, 1151 , 1152, 1163, 1182, 1183, 1199, 1207, 1210, 1218, 1220, 1223, 1224, 1238.
15. An oligomeric compound according to claim 13 or 14, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1008, 1046, 1091 , 1146, 1152, 1207.
16. An oligomeric compound according to any of claims 13 to 15, wherein said RNA is selected from the following sequences, or a portion thereof: SEQ ID NOs 1046, 1091 , 1152.
17. An oligomeric compound according to any of claims 1 to 16, wherein said first region of linked nucleosides consists essentially of 18 to 20 linked nucleosides.
18. An oligomeric compound according to any of claims 2 to 17, wherein said second region of linked nucleosides consists essentially of 11 to 16, 12 to 15, or 13 to 16 linked nucleosides.
19. An oligomeric compound according to any of claims 2 to 18, which comprises at least one complementary duplex region that comprises at least a portion of said first nucleoside region directly or indirectly linked to at least a portion of said second nucleoside region.
20. An oligomeric compound according to claim 19, wherein each of said first and second nucleoside regions has a 5’ to 3’ directionality thereby defining 5’ and 3’ regions respectively thereof.
21 . An oligomeric compound according to claim 20, wherein the 5’ region of said first nucleoside region is directly or indirectly linked to the 3’ region of said second nucleoside region, for example by complementary base pairing, and / or wherein the 3’ region of said first nucleoside region is directly or indirectly linked to the 5’ region of said second nucleoside region.
22. An oligomeric compound according to any of claims 1 to 21 , which further comprises one or more ligands.
23. An oligomeric compound according to claim 21 , wherein said one or more ligands are conjugated to said second nucleoside region.
24. An oligomeric compound according to claim 23, as dependent on claim 20, wherein said one or more ligands are conjugated at the 3 ' region of the second nucleoside region.
25. An oligomeric compound according to any of claims 22 to 24, wherein said one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and / or peptides that bind cellular membrane or a specific target on cellular surface.
26. An oligomeric compound according to claim 25, wherein said one or more ligands comprise one or more carbohydrates.
27. An oligomeric compound according to claim 26, wherein said one or more carbohydrates is a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.
28. An oligomeric compound according to claim 27, wherein said one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl- Galactosamine moieties, and / or one or more mannose moieties.
29. An oligomeric compound according to claim 28, wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.
30. An oligomeric compound according to claim 29, which comprises two or three N-Acetyl- Galactosamine moieties, preferably three.
31 . An oligomeric compound according to any of claims 22 to 30, wherein said one or more ligands are attached to said oligomeric compound, preferably to the second nucleoside region thereof, in a linear configuration, or in a branched configuration.
32. An oligomeric compound according to claim 31 , wherein said one or more ligands are attached to said oligomeric compound as a biantennary ortriantennary configuration.
33. An oligomeric compound according to claim 19, wherein said oligomeric compound comprises a single strand comprising said first and second nucleoside regions, wherein said single strand dimerises whereby at least a portion of said first nucleoside region is directly or indirectly linked to at least a portion of said second nucleoside region so as to form said at least partially complementary duplex region.
34. An oligomeric compound according to claim 33, wherein said first nucleoside region has a greater number of linked nucleosides compared to the second nucleoside region, whereby the additional number of linked nucleosides of the first nucleoside region form a hairpin loop linking the first and second nucleoside regions.
35. An oligomeric compound according to claim 34, as dependent on claim 20, whereby said hairpin loop is present at the 3' region of said first nucleoside region.
36. An oligomeric compound according to claim 34 or 35, wherein said hairpin loop comprises 4 or 5 linked nucleosides.
37. An oligomeric compound according to any of claims 1 to 36, which comprises internucleoside linkages and wherein at least one internucleoside linkage is a modified internucleoside linkage.
38. An oligomeric compound according to claim 37, wherein said modified internucleoside linkage is a phosphorothioate or phosphorodithioate internucleoside linkage.
39. An oligomeric compound according to claim 38, which comprises 1 to 15 phosphorothioate or phosphorodithioate internucleoside linkages.
40. An oligomeric compound according to claim 39, which comprises 7, 8, 9 or 10 phosphorothioate or phosphorodithioate internucleoside linkages.
41 . An oligomeric compound according to any of claims 38 to 40, as dependent on claim 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the first nucleoside region.
42. An oligomeric compound according to any of claims 38 to 41 , as dependent on claim 20, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5’ region of the second nucleoside region.
43. An oligomeric compound according to any of claims 38 to 42, as dependent on claim 34, which comprises phosphorothioate or phosphorodithioate internucleoside linkages between at least two, preferably at least three, preferably at least four, preferably at least five, adjacent nucleosides of the hairpin loop, dependent on the number of nucleotides present in the hairpin loop.
44. An oligomeric compound according to claim 43, which comprises a phosphorothioate or phosphorodithioate internucleoside linkage between each adjacent nucleoside that is present in said hairpin loop.
45. An oligomeric compound according to any of claims 1 to 44, wherein at least one nucleoside comprises a modified sugar.
46. An oligomeric compound according to claim 45, wherein said modified sugar is a 2'-0-methyl modified sugar.
47. An oligomeric compound according to claim 45 or 46, wherein said modified sugar is a 2'-F modified sugar.
48. An oligomeric compound according to any of claims 45 to 47, as dependent on claim 20, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5’ region of the first nucleoside region, do not contain 2'-0-methyl modifications.
49. An oligomeric compound according to any of claims 45 to 48, as dependent on claim 20, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleotide of the 5’ region of the first nucleoside region, do not contain 2'-0-methyl modifications.
50. An oligomeric compound according to claim 48 or 49, wherein sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications.
51 . An oligomeric compound according to any of claims 48 to 50, wherein sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleoside of the 5’ region of the first nucleoside region, contain 2'-F modifications.
52. An oligomeric compound according to any of claims 45 to 51 , as dependent on claim 20, wherein one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are modified, and / or wherein one or more of the even numbered nucleotides starting from the 5’ region of the first nucleoside region are modified, wherein typically the modification of the even numbered nucleotides is a second modification that is different from the modification of odd numbered nucleotides.
53. An oligomeric compound according to claim 52, wherein one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of odd numbered nucleosides of the first nucleoside region.
54. An oligomeric compound according to claim 52 or 53, wherein one or more of the even numbered nucleosides starting from the 3’ region of the second nucleoside region are modified by a modification that is different from the modification of even numbered nucleosides of the first nucleoside region according to claim 53.
55. An oligomeric compound according to any of claims 52 to 54, wherein at least one or more of the modified even numbered nucleosides of the first nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the first nucleoside region.
56. An oligomeric compound according to any of claims 52 to 55, wherein at least one or more of the modified even numbered nucleosides of the second nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the second nucleoside region.
57. An oligomeric compound according to any of claims 52 to 56, wherein sugars of one or more of the odd numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-0- methyl modified sugars.
58. An oligomeric compound according to any of claims 52 to 57, wherein one or more of the even numbered nucleosides starting from the 5’ region of the first nucleoside region are 2'-F modified sugars.
59. An oligomeric compound according to any of claims 52 to 58, wherein sugars of one or more of the odd numbered nucleosides starting from the 3’ region of the second nucleoside region are 2'-F modified sugars.
60. An oligomeric compound according to any of claims 52 to 59, wherein one or more of the even numbered nucleosides starting from the 3’ region of the second nucleoside region are 2-0- methyl modified sugars.
61 . An oligomeric compound according to any of claims 45 to 60, wherein sugars of a plurality of adjacent nucleosides of the first nucleoside region are modified by a common modification.
62. An oligomeric compound according to any of claims 45 to 61 , wherein sugars of a plurality of adjacent nucleosides of the second nucleoside region are modified by a common modification.
63. An oligomeric compound according to any of claims 52 to 62, as dependent on claim 34, wherein sugars of a plurality of adjacent nucleosides of the hairpin loop are modified by a common modification.
64. An oligomeric compound according to any of claims 61 to 63, wherein said common modification is a 2'-F modified sugar.
65. An oligomeric compound according to any of claims 61 to 63, wherein said common modification is a 2'-0-methyl modified sugar.
66. An oligomeric compound according to claim 65, wherein said plurality of adjacent 2'-0-methyl modified sugars are present in at least eight adjacent nucleosides of said first and / or second nucleoside regions.
67. An oligomeric compound according to claim 65, wherein said plurality of adjacent 2'-0-methyl modified sugars are present in three or four adjacent nucleosides of said hairpin loop.
68. An oligomeric compound according to claim 45, as dependent on claim 34, wherein said hairpin loop comprises at least one nucleoside having a modified sugar.
69. An oligomeric compound according to claim 68, wherein said at least one nucleoside is adjacent a nucleoside with a differently modified sugar.
70. An oligomeric compound according to claim 69, wherein said modified sugar is a 2'-0-methyl modified sugar, and said differently modifies sugar is a 2'-F modified sugar.
71 . An oligomeric compound according to any of claims 1 to 70, which comprises one or more nucleosides having an un-modified sugar moiety.
72. An oligomeric compound according to claim 71 , wherein said unmodified sugar is present in the 5' region of the second nucleoside region.
73. An oligomeric compound according to claim 71 or 72, as dependent on claim 34, wherein said unmodified sugar is present in the hairpin loop.
74. An oligomeric compound according to any of claims 1 to 73, wherein one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3' carbon of its sugar and the 3' carbon of the sugar of the adjacent nucleoside, and / or one or more nucleosides of the first nucleoside region and / or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5' carbon of its sugar and the 5' carbon of the sugar of the adjacent nucleoside.
75. An oligomeric compound according to any of claims 1 to 74, which is blunt ended.
76. An oligomeric compound according to any of claims 1 to 74, wherein either the first or second nucleoside region has an overhang.
77. An oligomeric compound that inhibits expression of FXI, wherein said compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 501 to 750, or construct NOs 1751 to 2000.
78. An oligomeric compound according to claim 77, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to said first nucleobase sequence, wherein said second nucleobase sequence is a modified sequence and is selected from the following sequences, or a portion thereof: construct NOs 751 to 1000, or construct NOs 2001 to 2250.
79. An oligomeric compound according to claim 77 or 78, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 513, 527, 539,
546, 591 , 598, 603, 605, 609, 620, 640, 646, 651 , 652, 663, 682, 683, 699, 707, 710, 718, 720, 723, 724, 738, or construct NOs 1758, 1763,1777, 1789, 1796, 1841 , 1848, 1853, 1855, 1859, 1870, 1890, 1896, 1901 , 1902, 1913, 1932, 1933, 1949, 1957, 1960, 1968, 1970, 1973, 1974, 1988.
80. An oligomeric compound according to claim 79, wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 763, 777, 789, 796, 841 , 848, 853, 855, 859, 870, 890, 896, 901 , 902, 913, 932, 933, 949, 957, 960, 968, 970, 973, 974, 988, or construct NOs 2008, 2013, 2027, 2039, 2046, 2091 , 2098, 2103, 2105, 2109, 2120, 2140,
2146, 2151 , 2152, 2163, 2182, 2183, 2199, 2207, 2210, 2218, 2220, 2223, 2224, 2238.
81 . An oligomeric compound according to any of claims 77 to 80, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 508, 546,
591 , 646, 652, 707, or construct NOs 1758, 1796, 1841 , 1896, 1902, 1957.
82. An oligomeric compound according to claim 81 , wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 758, 796, 841 , 896, 902, 957, or construct NOs 2008, 2046, 2091 , 2146, 2152, 2207.
83. An oligomeric compound according to any of claims 77 to 82, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 546, 591 ,
652, or construct NOs 1796, 1841 , 1902.
84. An oligomeric compound according to claim 83, wherein said second nucleobase sequence is selected from the following sequences, or a portion thereof: construct NOs 796, 841 , 902, or construct NOs 2046, 2091 , 2152.
85. An oligomeric compound according to any of claims 77 to 84, which is further characterised according to any of claims 17 to 44, or 74 to 76.
86. An oligomeric compound that inhibits expression of FXI, which is selected from the following sequences: SEQ ID NOs 2251 to 2253, or SEQ ID NOs 2284 to 2288, preferably SEQ ID NO: 2287.
87. An oligomeric compound that inhibits expression of FXI, which is selected from the following sequences: construct NOs 2254 to 2283.
88. An oligomeric compound according to claim 86 or 87, which further comprises one or more ligands.
89. An oligomeric compound according to claim 88, wherein said one or more ligands are conjugated at the 3 ' region of said sequences, preferably at the 3' terminal nucleoside.
90. An oligomeric compound according to claim 88, wherein said one or more ligands are conjugated at non-terminal positions.
91 . An oligomeric compound according to any of claims 88 to 90, wherein said one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and / or peptides that bind cellular membrane or a specific target on cellular surface.
92. An oligomeric compound according to claim 91 , wherein said one or more ligands comprise one or more carbohydrates.
93. An oligomeric compound according to claim 92, wherein said one or more carbohydrates is a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide.
94. An oligomeric compound according to claim 93, wherein said one or more carbohydrates comprise one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl- Galactosamine moieties, and / or one or more mannose moieties.
95. An oligomeric compound according to claim 94, wherein said one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties.
96. An oligomeric compound according to claim 95, which comprises two or three N-Acetyl- Galactosamine moieties, preferably three.
97. An oligomeric compound according to any of claims 88 to 96, wherein said one or more ligands are attached to said oligomeric compound in a linear configuration, or in a branched configuration.
98. An oligomeric compound according to claim 97, wherein said one or more ligands are attached to said oligomeric compound as a biantennary ortriantennary configuration.
99. An oligomeric compound according to any of claims 86 to claim 98, wherein said sequences self dimerise so as to form an at least partially complementary duplex region.
100. An oligomeric compound according to claim 99, having a nucleobase sequence and structure as shown in any of Figures 15 to 17 or 18 and 20, construct NOs: 2290 to 2292 being preferred, construct NO: 2290 being particularly preferred.
101. A composition comprising an oligomeric compound according to any of claims 1 to 100, and a physiologically acceptable excipient.
102. An oligomeric compound according to any of claims 1 to 100, for use in therapy.
103. An oligomeric compound according to any of claims 1 to 100, for use in the treatment of a disease or disorder.
104. A method of treating a disease or disorder comprising administration of an oligomeric compound according to any of claims 1 to 100, to an individual in need of treatment.
105. A method according to claim 104, wherein the oligomeric compound is administered subcutaneously or intravenously to the individual.
106. Use of an oligomeric compound according to any of claims 1 to 100, for use in research as a gene function analysis tool.
107. Use according to claim 103, or a method according to claim 104, wherein the disease or disorder is a thromboembolic disease.
108. Use or method according to claim 107, wherein the thromboembolic disease is selected from the group consisting of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition.
109. Use or method according to claim 108, wherein the thromboembolic disease is deep vein thrombosis, pulmonary embolism, or a combination thereof.
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