Methods and compositions for reducing diacyglycerol acyltransferase 2 (DGAT2)

Abstract

Provided herein are methods of treating, preventing, or ameliorating a liver disease comprising administering a composition comprising about 75 mg to about 175 mg of an oligomeric compound comprising a modified antisense oligonucleotide inhibitor of diacylglycerol acyltransferase 2 (DGAT2). Additionally provided are unit doses and dosing regimens useful in the methods for treating, preventing, or ameliorating a liver disease, including MASLD and MASH, and complications thereof.

Description

METHODS AND COMPOSITIONS FOR REDUCING DIACYGLYCEROL ACYLTRANSFERASE 2 (DGAT2)SEQUENCE LISTING

[0001] The present application is being filed concurrently with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0486SEQ.xml, created on May 30, 2025, which is 21 KB in size. The contents of the electronic format of the sequence listing are incorporated herein by reference in their entirety.SUMMARY OF THE INVENTION

[0002] Described herein are methods for reducing the amount of diacylglycerol acyltransferase 2 (DGAT2) RNA and / or DGAT2 protein in a subject. In certain embodiments, the subject has, or is at risk for, liver disease, e.g., metabolic-dysfunction associated steatotic liver disease (MASLD), including metabolic-dysfunction associated steatohepatitis (MASH). In certain embodiments, methods include administering to the subject about 75 mg to about 175 mg of an oligomeric agent comprising a modified oligonucleotide SEQ ID NO: 1 , or salt thereof, to a subject having or at risk for liver disease. In certain embodiments the subject has or is at risk for metabolic-dysfunction associated steatotic liver disease (MASLD), including metabolic-dysfunction associated steatohepatitis (MASH). Also provided are uses of an oligomeric compound or a salt thereof for reducing DGAT2 RNA and / or DGAT2 protein). Also described herein are uses of an oligomeric agent or salt thereof in the manufacture of a medicament for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for liver disease or for treating and / or ameliorating one or more symptoms of liver disease. In certain embodiments the subject has or is at risk for metabolic-dysfunction associated steatotic liver disease (MASLD), including metabolic-dysfunction associated steatohepatitis (MASH). Additionally described are unit doses useful in the provided methods. Described are unit doses comprising about 75 mg to about 125 mg of an oligomeric compound comprising a GalNAc-conjugated modified oligonucleotide represented SEQ ID NO: 1. Unit doses described comprise an amount of oligomeric compound or salt thereof within the range of about 75 mg to 175 mg, 75 mg to 165 mg, 75 mg to 160 mg, 75 mg to 150 mg, 75 mg to 140 mg, 75 mg to 130 mg, 75 mg to 125 mg, 75 mg to 120 mg, 75 mg to 1 15 mg, 75 mg to 1 10 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85 mg, 75 mg to 80 mg, 80 mg to 85 mg, 80 mg to 125 mg, 85 mg to 125 mg, 90 mg to 125mg, 95 mg to 125 mg, 100 mg to 125 mg, 105 mg to 125 mg, 110 mg to 125 mg, 1 15 mg to 125 mg, 120 mg to 125 mg, 115 mg to 120 mg, 90 mg to 120 mg, 95 mg to 1 15 mg, 95 mg to 110 mg, 95 mg to 105 mg, 95 mg to 100 mg, 100 mg to 120 mg, 100 mg to 115 mg, 100 mg to 1 10 mg, 100 mg to 105 mg, 105 mg to 120 mg, 105 mg to 1 15 mg, 105 mg to 1 10 mg, 1 10 mg to 120 mg, 1 10 mg to 1 15 mg, 115 mg to 120 mg, 80 mg to 120 mg, 80 mg to 110 mg, 80 mg to 105 mg, 80 mg to 100 mg, 80 mg to 95 mg, 80 mg to 90 mg, 85 mg to 90 mg, 90 mg to 95 mg, 85 mg to 120 mg, 90 mg to 95 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 115 mg, 85 mg to 90 mg, 85 mg to 95 mg, 90 mg to 175 mg, 95 mg to 175 mg, 100 mg to 175 mg, 105 mg to 175 mg, 1 10 mg to 175 mg, 115 mg to 175 mg, 120 mg to 175 mg, 120 mg to 165 mg, 120 mg to 160 mg, 130 mg to 160 mg, 140 mg to 160 mg, 150 mg to 160 mg, 155 mg to 165 mg, 160 mg to 165 mg, or 155 mg to 160 mg,. Unit doses described comprise an amount of oligomeric compound or salt thereof within the range of about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg, about 75 mg to about 1 15 mg, about 75 mg to about 1 10 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 80 mg to about 95 mg, about 85 mg to about 95 mg, about 90 mg to about 95 mg, about 80 mg to about 125 mg, about 85 mg to about 125 mg, about 85 mg to about 125 mg, about 90 mg to about 125 mg, about 95 mg to about 125 mg, about 100 mg to about 125 mg, about 1 15 mg to about 125 mg, about 1 15 mg to about 120 mg, about 120 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 1 15 mg, about 95 mg to about 110 mg, about 95 mg to about 105 mg, about 95 mg to about 100 mg, about 100 mg to about 120 mg, about 100 mg to about 1 15 mg, about 100 mg to about 1 10 mg, about 100 mg to about 105 mg, about 105 mg to about 120 mg, about 105 mg to about 1 15 mg, about 105 mg to about 1 10 mg, about 1 10 mg to about 120 mg, about 110 mg to about 1 15 mg, about 1 15 mg to about 120 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 105 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 85 mg to about 120 mg, about 90 mg to about 95 mg, about 85 mg to about 105 mg, about 85 mg to 100 mg, 85 mg to about 95 mg, about 85 mg to about 115 mg, about 85 mg to about 90 mg, or about 85 mg to about 95 mg. Unit doses are formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier, adjuvant or excipient. Certain compositions comprise an oligomeric agent or salt thereof and a pharmaceutically acceptable carrier or excipient. Certain compositions comprise a pharmaceutically acceptable carrier or excipient which is sterile water or sterile saline or phosphate buffered saline. Certain compositions are formulated for parenteral administration. Certain compositions are formulated for subcutaneous, intramuscular, or intravenousadministration. Described unit doses and compositions are useful in the methods and uses described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIGURE 1 depicts the Phase 2 study design described in Example 2.

[0004] FIGURE 2 depicts results of Phase 2 study following treatment withION224: FIG2A depicts proportion of patients with greater than 2 point reduction in NAS, with greater than 1 point improvement in hepatocellular ballooning or lobular inflammation, without worsening of fibrosis; and data in the combined expanded treatments arms vs placebo is shown in FIG2A-C, where FIG2A shows the primary endpoint was met (p<0.001), FIG2B shows a greater proportion of subjects achieving MASH resolution without worsening fibrosis (p=0.019) and FIG2C depicts a 20% numerical improvement in fibrosis improvement without worsening of steatohepatitis.

[0005] FIGURE 3 depicts additional results of Phase 2 study following treatment with ION224: FIG3A-3B depicts improvement in biopsy endpoints in patients with Stage F2 and F3 fibrosis; FIG3C depicts results of improvement of ballooning and inflammation; FIG3D-3E depicts results demonstrating dose dependent increases in improvement of liver steatosis overtime; and FIG3F depict results demonstrating reduction in ALT and AST in subjects that had elevated baseline liver enzymes at the outset of the study who were treated with 120 mg ION224 as compared with placebo.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0006] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0007] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Definitions

[0008] The following definitions are provided, along with additional definitions throughout the specification, for a complete understanding of the instant invention. Unless specific definitions are provided, nomenclature used in connection with, and procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those well-known and commonly used in the art. Unless otherwise indicated, the following terms have the following meanings.

[0009] As used herein, “2'-deoxynucleoside” means a nucleoside comprising a 2 -deoxyfuranosyl sugar moiety. Unless otherwise indicated, a 2'-deoxynucleoside is a 2 -p-D-deoxynucleoside which comprises a 2'-p-D-deoxyribosyl sugar moiety, which is in the p-D configuration in naturally occurring deoxyribonucleic acid (DNA). A 2'- deoxynucleoside or a nucleoside comprising an unmodified 2'-deoxyribosyl sugar moiety may be abasic, comprise a modified nucleobase, or may comprise an RNA nucleobase (uracil).

[0010] As used herein, “2'-deoxy sugar moiety” means a 2'-H(H) deoxyfuranosyl sugar moiety. Unless otherwise indicated, a 2'-deoxy sugar moiety is a 2'- P-D-deoxyribosyl sugar moiety, which has the p-D ribosyl configuration in naturally occurring deoxyribonucleic acid (DNA).

[0011] As used herein, “2'-MOE” means a 2'-OCH2CH2OCH3group at the 2'- position of a furanosyl sugar moiety. A “2'-MOE sugar moiety” means a sugar moiety with a 2 -OCH2CH2OCH3 group at the 2'-position of a furanosyl sugar moiety. Unless otherwise indicated, a 2'-MOE sugar moiety is in the p-D-ribosyl stereochemical configuration. “MOE” means O-methoxyethyl.

[0012] As used herein, “2 -MOE nucleoside” or “2 - OCH2CH2OCH3 nucleoside” means a nucleoside comprising a 2 -MOE sugar moiety (or 2'-OCH2CH2OCH3 furanosyl sugar moiety).

[0013] As used herein, “2'-substituted nucleoside” means a modified nucleoside comprising a 2'-substituted furanosyl sugar moiety. 2'-substituted nucleosides include, but are not limited to, e.g., a 2'-MOE nucleoside, a 2'-F nucleoside.

[0014] As used herein, “2’-substitution” or “2'-substituted sugar moiety” means a modified furanosyl sugar moiety wherein the 2 -position is attached to at least one substituent other than H or OH. A 2'-substituted sugar moiety includes a bicyclic sugar moiety wherein the second ring is joined to the furanosyl ring at the 2 -position. 2'- substituted sugar moieties include, but are not limited to, 2'-MOE sugar moieties.

[0015] As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methyl cytosine is a modified nucleobase.

[0016] As used herein, “abasic nucleoside” means a modified nucleoside in which the sugar moiety is not attached to a nucleobase.

[0017] As used herein, “about” means plus or minus 7% of the provided value.

[0018] As used herein, “active agent” refers to a composition or compound that has measurable specified activity when administered to a subject. An active agent maybe, for example, an oligomeric agent, e.g., an antisense oligonucleotide. In certain embodiments an active agent is other than an oligomeric agent or an antisense oligonucleotide.

[0019] As used herein, “ameliorate” with reference to a symptom of a disease, disorder or condition means improvement in, or lessening of, at least one symptom of a disease, disorder or condition. Amelioration may be reduction in severity or frequency of a symptom or the delayed onset, or slowing of progression in the severity or frequency of, a symptom. Progression, frequency, or severity indicators may be determined by subjective or objective measures known in the art and / or described herein.

[0020] As used herein, “antisense activity” means any detectable and / or measurable change attributable (whether directly and / or indirectly) to hybridization of an antisense oligonucleotide to a target nucleic acid. For example, compounds have antisense activity when they alter the amount or activity of a target nucleic acid by 25% or more in an in vitro assay; or, for example compounds have antisense activity when they alter the amount or activity of a target nucleic acid by 25% or more in an in vivo assay. Antisense activity may be assessed in a standard assay. Herein, antisense activity is a decrease in the amount or expression of a target nucleic acid, e.g., a target RNA, or a protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the oligonucleotide.

[0021] As used herein, “antisense agent” means an oligomeric agent comprising an antisense oligonucleotide.

[0022] As used herein, “antisense oligonucleotide” means an oligonucleotide having at least one nucleobase sequence that is complementary to a target nucleic acid (e.g., a nucleobase sequence of a target nucleic acid). An antisense oligonucleotide may be an unpaired antisense oligonucleotide (herein, a single-stranded antisense oligonucleotide), or may be a “hairpin oligonucleotide” that has at least one region that is self-complementary.

[0023] As used herein, “cell-targeting moiety” means a conjugate moiety or portion of a conjugate moiety that has affinity for a particular cell type or particular cell types. For example, a cell-targeting moiety may have affinity for a cell surface moiety, such as a cell surface receptor on a particular cell type.

[0024] As used herein, “cleavable moiety” means a group of atoms comprising at least one bond that is cleaved under physiological conditions, e.g., in a cell, in a subject, such as a cleavable moiety cleaved inside a cell or sub-cellular compartment, e.g., an endosome or lysosome. In certain embodiments, a cleavable moiety may be cleaved by endogenous enzymes, such as nucleases, or under certain conditions, e.g., a certain pH.

[0025] As used herein, “complementary nucleobase(s)” or “complementary” in reference to a nucleobase(s) means nucleobases that form hydrogen bonds with one another. Complementary nucleobase pairs include, but are not limited to, adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methylcytosine (mC) and guanine (G). Certain modified nucleobases that are complementary to unmodified nucleobases or to other modified nucleobases are known in the art. For example, hypoxanthine, the nucleobase of the nucleoside inosine (I), can pair with adenine, cytosine, thymine, or uracil. Herein, hypoxanthine (I) is considered a complementary nucleobase to thymine (T), adenine (A), uracil (U), and cytosine (C).

[0026] As used herein, “complementary sequence(s)” or “complementary” in reference to a sequence(s) refers to two nucleobase sequences in which some, a majority, or all of the nucleobases in the two sequences are complementary nucleobases when the sequences are aligned. A “nucleobase sequence” means the order of contiguous nucleobases in a strand of linked nucleosides or a region thereof (e.g., an oligonucleotide or region thereof, or a target nucleic acid or region thereof) independent of any sugar or internucleoside linkage modification. Complementary nucleobase sequences may be nucleobase sequences of two separate strands of linked nucleosides or region thereof (e.g., an oligonucleotide and a region of a target nucleic acid, or an antisense oligonucleotide and its paired sense oligonucleotide) or complementary nucleobase sequences may be two regions of a single strand of linked nucleosides (e.g., self- complementary regions of a hairpin oligonucleotide). As used herein, when a first strand of linked nucleosides (e.g., an oligonucleotide), or region thereof, is described as being complementary to a second strand of linked nucleosides (e.g., a target nucleic acid or another oligonucleotide), it means that the nucleobase sequence of the first strand of linked nucleosides or region thereof is complementary to the nucleobase sequence of the second strand of linked nucleosides or region thereof when aligned. Not every pair of nucleobases in the aligned nucleobase sequences needs to be a base pair match for the two sequences to be “complementary.” Rather, some mismatches are tolerated. Where complementarity is expressed as a percent, such percent represents the percent of nucleobases within one nucleobase sequence that are complementary to nucleobases within an equal length second sequence when the sequences are aligned. Unless otherwise specified, “complementary” is assumed to be at least 70%. Complementary nucleobase sequences may be 75%, 80%, 85%, 90%, 95%, or 100% complementary. For example, if a nucleobase sequence of an oligonucleotide consisting of 20 nucleosides is 80% complementary to another nucleobase sequence, then 16 of the nucleobase pairs are complementary nucleobases, and there are 4 mismatches when the sequences are aligned. If a nucleobase sequence of an oligonucleotide consisting of 20 nucleosides is atleast 80% complementary to another nucleobase sequence, then 16, 17, 18, 19, or 20 of the nucleobase pairs are complementary nucleobases, and there are 0-4 mismatches when the sequences are aligned. As used herein, “fully complementary” or “100% complementary” means that each nucleobase pair of the two nucleobase sequences is complementary when the equal length sequences are aligned.

[0027] As used herein, “conjugate group” means a group of atoms that is directly or indirectly attached to an oligonucleotide. A conjugate group comprises as conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

[0028] As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

[0029] As used herein, “conjugate moiety" means a group of atoms that when covalently bound to a molecule (e.g., an oligonucleotide) modifies one or more properties of such molecule compared to the same molecule lacking the conjugate moiety, wherein such properties include, but are not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance.

[0030] As used herein, “complementary region” in reference to a strand of linked nucleosides (e.g., an oligonucleotide or a target nucleic acid) is a region of the strand of linked nucleosides in which the nucleobase sequence of the region is complementary with the nucleobase sequence of an equal-length region of a separate strand of linked nucleosides (e.g., an oligonucleotide and a target nucleic acid, or an antisense oligonucleotide and a sense oligonucleotide), or the nucleobase sequence of an equal-length region within the strand of linked nucleosides (e.g., in a “hairpin oligonucleotide”). A complementary region of a strand of linked nucleosides may be a portion of a strand of linked nucleosides or may include the entire strand of linked nucleosides. A complementary region may include a mismatch, but the nucleobases of the terminal nucleosides of a complementary region are complementary to the nucleobases of the terminal nucleosides of the equal-length region of the separate strand of linked nucleosides or to the nucleobases of the terminal nucleosides of the equal-length region within the strand of linked nucleosides.

[0031] As used herein, “deoxy region” means a region of 5-12 contiguous nucleosides, wherein at least 70% of the nucleosides are DNA nucleosides. Each nucleoside of a deoxy region is selected from a 2'-deoxynucleoside and 2'-substituted nucleoside. A deoxy region supports RNase H activity.

[0032] As used herein, “DNA nucleoside” means a nucleoside comprising an unmodified DNA sugar moiety. A DNA nucleoside may comprise a modified or unmodified nucleobase. A DNA nucleoside may comprise a uracil nucleobase or a modified nucleobase, or may be an abasic nucleoside.

[0033] As used herein, “DNA sugar moiety” means an unmodified DNA sugar moiety.

[0034] As used herein, “dose” means a specified quantity of active agent, e.g., a compound, oligomeric agent, for example, in a pharmaceutical composition, typically measured in metric mass units, such as milligrams (mg). A “fixed dose” refers to a quantity of active agent that is provided to each subject to whom the agent is administered, regardless of subject-specific factors, for example, weight. Typically, a fixed dose is indicated as an amount, e.g., milligrams (mg). A “weight-based dose” refers to a quantity of active agent based on weight, or body mass index of a subject to whom the active agent is administered. Typically, a weight-based dose is indicated in amount per unit of measure of body weight, such as kilograms or pounds (e.g., milligrams / kilogram, or mg / kg). As used herein, “unit dose” refers to a physically discrete composition containing a predetermined quantity of active agent (e.g., compound, oligomeric agent) intended for single administration to a subject. For example, a unit dose may be a single dose for a subject, e.g., an injection or a tablet comprising a dose for a human subject. A unit dose may contain active agent (e.g., a compound, oligomeric agent) and a pharmaceutical diluent, carrier, excipient, and / or vehicle. A unit dose may be in a container, such as a vial, ampule, autoinjector device, capsule, or syringe. In certain embodiments, a unit dose is included in a single dose container, e.g., a single-dose pre-filled syringe. In certain embodiments, a unit dose is included in a multidose container, e.g., multiple single-dose pre-filled syringes supplied in a container. In certain embodiments a fixed dose and / or a weight-based dose comprises one or more unit dose(s), e.g., a fixed dose comprises administration of one or two or three unit doses.

[0035] As used herein, a “dosing regimen” refers to specific dose(s), number of dose(s), method of administration, timing of administration of doses and / or frequency of administration of doses (dosing interval) to a subject, and, if relevant, over a specific time period or treatment duration. In certain embodiments, a dosing regimen also includes additional aspects, e.g., administration in conjunction with food and / or drink, administration in conjunction with additional agent(s), administration in conjunction with other lifestyle adjustments (e.g., diet).

[0036] As used herein, “double-stranded” refers to hybridized or bound complementary regions, including those between two separate strands of linked nucleosides (e.g., an antisense oligonucleotide and a sense oligonucleotide) and thosewithin a single strand of linked nucleosides (e.g., a hairpin oligonucleotide). Paired complementary regions of two separate strands of linked nucleosides form a “duplex” of the separate strands. Paired complementary regions of a single strand of linked nucleosides (i.e., a first region of the strand of linked nucleosides and a second region of the strand of linked nucleosides) form a “hairpin”.

[0037] As used herein, “duplex” means a structure formed by two separate strands of linked nucleosides or regions thereof (e.g., two separate oligonucleotides), at least a portion of which are complementary to and hybridize to each other. For clarity, herein a “hairpin oligonucleotide” is a single strand of linked nucleosides that comprises a region that is double-stranded and is not a duplex. A hairpin oligonucleotide that comprises at least one region that is complementary to a target nucleic acid is an antisense oligonucleotide.

[0038] As used herein, a “furanosyl sugar moiety" is a group of atoms that comprises a furanose ring and optional substituents, and is numbered according to the following structure below, with optional additional substituents at any of the 1 ', 2’, 3', 4', and 5' positions.

[0039] As used herein, “hybridize” or “hybridization” means the act or process of two complementary regions of linked nucleosides (e.g., oligonucleotides, nucleic acids) annealing together to form a double-stranded region. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

[0040] As used herein, “internucleoside linkage” means the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “unmodified internucleoside linkage” means a phosphodiester internucleoside linkage. As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. A “phosphorothioate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom. A “mesyl phosphoramidate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with NS(=O)2CH3. Unless otherwise indicated, and in the context of linkednucleosides each comprising a furanosyl sugar moiety, an internucleoside linkage joins the 3'-carbon of one furanosyl sugar moiety to the 5'-carbon of the other furanosyl sugar moiety.

[0041] As used herein, “inverted nucleoside” means a nucleoside having a 3' to 3' and / or 5' to 5' internucleoside linkage.

[0042] As used herein, “linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., nucleosides immediately adjacent to one another, no additional nucleosides are presented between those that are linked).

[0043] As used herein, “loading dose” refers to one or more dose(s) of active agent (e.g., a compound, oligomeric agent) administered to a subject during an initial phase of a dosing regimen. In certain embodiments, a loading dose is administered to achieve a desired condition in a subject, for example, a desired initial concentration of active agent, a steady state concentration of active agent, or a desired effect in the subject. In certain embodiments a single loading dose achieves the desired state (e.g., concentration of active agent). In certain embodiments multiple loading doses achieve the desired state (e.g., concentration of active agent), wherein an “initial loading dose” means a first loading dose, and a “.ast loading dose” means the dose administered most recently prior to a first maintenance dose.

[0044] As used herein, “maintenance dose” refers to one or more dose(s) of active agent (e.g., a compound, oligomeric agent) administered to a subject after a loading dose. For example, a maintenance dose may be administered during a dosing phase after steady state concentration of active substance has been achieved (e.g., through administration of one or more loading dose). A maintenance dose may be administered to maintain a desired condition that results from administration of the loading dose. “Maintenance period” refers to a time period after a desired condition is achieved in a subject during which one or more maintenance doses are administered to the subject.

[0045] As used herein, a “mismatch” between two aligned strands of linked nucleosides means that the two nucleobases at a specified position of the aligned nucleobase sequences are not complementary nucleobases as defined herein.

[0046] As used herein, “modified nucleoside” means a compound or subunit comprising a sugar moiety and optionally a nucleobase, wherein the sugar moiety is modified and / or the nucleobase is modified or absent.

[0047] As used herein, “modified sugar moiety” means a group of atoms other than an unmodified sugar moiety that forms the portion of a nucleoside corresponding to a p-D-ribosyl sugar moiety in RNA or a p-D-deoxyribosyl sugar moiety in DNA. A modified sugar moiety is selected from a modified furanosyl sugar moiety, a sugar surrogate (e.g., a cyclic sugar surrogate, an acyclic sugar surrogate), or a sugar mimic.

[0048] As used herein, a “modified nucleobase” means a group of atoms other than unmodified A, T, C, U or G capable of pairing with at least one unmodified nucleobase. A “5-methylcytosine” is a modified nucleobase. Inosine (I) is a nucleoside comprising the modified nucleobase hypoxanthine.

[0049] As used herein, “motif means a pattern of independently unmodified and / or independently modified sugar moieties, nucleobases, and / or internucleoside linkages in an oligonucleotide.

[0050] As used herein, “non-bicyclic modified sugar moiety’’ means a modified furanosyl sugar moiety comprising a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

[0051] As used herein, “nucleobase” means an unmodified nucleobase or modified nucleobase.

[0052] As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a strand of linked nucleosides independent of any sugar or internucleoside linkage modification. As used herein, “the nucleobase sequence of’ a reference SEQ ID NO refers only to the order of contiguous nucleobases provided in such SEQ ID NO, independent of any sugar or internucleoside linkage modification(s), and therefore, unless otherwise indicated, includes compounds wherein each sugar moiety and each internucleoside linkage, independently, is modified or unmodified, irrespective of the presence or absence of modifications indicated in the referenced SEQ ID NO.

[0053] As used herein, “nucleoside” means an “unmodified nucleoside” or a “modified nucleoside.”

[0054] As used herein, "oligomeric agent" means a compound or complex comprising or consisting of at least one modified oligonucleotide and optionally one or more additional associated features selected from: (a) one or more additional modified or unmodified oligonucleotides, each of which may be hybridized to or covalently linked to the at least one modified oligonucleotide and / or to each other; (b) one or more conjugate groups, which may be covalently attached directly or indirectly to any oligonucleotide of such oligomeric agent; and (c) one or more terminal groups. Herein, where two oligonucleotides are described as being covalently attached to one another, such attachment is other than through a direct internucleoside linkage. Thus, a single, unbranched oligonucleotide comprising only direct internucleoside linkages cannot be described as two separate covalently linked oligonucleotides.

[0055] As used herein, “oligomeric compound” means a compound comprising an oligonucleotide and optionally one or more covalently linked, directly or indirectly, chemical features selected from one or more conjugate group and one or more terminal group.

[0056] As used herein, “oligonucleotide” means a strand of linked nucleosides, wherein each nucleoside and / or each internucleoside linkage of the strand of linked nucleosides may independently be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 12-80 linked nucleosides. Unless otherwise indicated, no more than 10% of the nucleosides of an oligonucleotide are abasic nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside and / or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide consisting of unmodified nucleosides linked by phosphodiester internucleoside linkages. An oligonucleotide may be paired with a second oligonucleotide that is complementary to the oligonucleotide to form an oligomeric duplex, or it may be unpaired.

[0057] As used herein, “pharmaceutical composition” means a mixture of substances suitable for administration to a subject. For example, a pharmaceutical composition may comprise an oligomeric agent and a sterile aqueous solution. A pharmaceutical composition may show activity in certain cell lines.

[0058] As used herein, “pharmaceutically acceptable” in reference to a substance, element, material, compound, or composition means that the substance, element, material, compound, or composition is, within the scope of sound medical judgment, suitable for use in subjects without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, “pharmaceutically acceptable carrier” means an ingredient, e.g., a filler, diluent, preservative, stabilizing agent or excipient, in a pharmaceutical composition suitable for use in administering to a subject. Typically, a pharmaceutically acceptable carrier lacks pharmacological activity but is desirable in preparing a pharmaceutical composition.

[0060] As used herein, “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0061] As used herein, “RNA nucleoside” means a nucleoside comprising an unmodified RNA sugar moiety. An RNA nucleoside may comprise a modified or unmodified nucleobase. An RNA nucleoside may comprise a thymine nucleobase or a modified nucleobase, or may be an abasic nucleoside.

[0062] As used herein, “RNA sugar moiety” means an unmodified RNA sugar moiety.

[0063] As used herein, “RNAi agent” means an antisense agent that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and / or a protein encoded by a target nucleic acid. RNAi agents include, but are not limited to doublestranded siRNA, single-stranded RNAi (ssRNAi), and microRNA, including microRNA mimics. RNAi agents may comprise conjugate groups and / or terminal groups. In certain embodiments, an RNAi agent modulates the amount and / or activity of a target nucleic acid. The term RNAi agent excludes antisense agents that act through RNase H.

[0064] As used herein, “RNase H agent” means an antisense agent that acts, at least in part, through RNase H to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. RNase H agents may be single-stranded or RNase H agents may be double-stranded. RNase H compounds may comprise conjugate groups and / or terminal groups. RNase H agents may modulate the amount and / or activity of a target nucleic acid. The term RNase H agent excludes antisense agents that act principally through RISC / Ago2.

[0065] As used herein, “single-stranded” in reference to a strand of linked nucleosides (e.g., an oligonucleotide) means that the strand is unpaired; that is, the strand of linked nucleosides is not part of a duplex or part of a double-stranded region. For clarity, herein a “hairpin oligonucleotide” is not a single-stranded oligonucleotide, though it may comprise a portion that is unpaired (e.g., a loop or terminal region) as well as portions that are double-stranded. Single-stranded nucleic acids (e.g., single-stranded oligonucleotides) are capable of hybridizing with complementary nucleic acids to form duplexes, at which point they are no longer single-stranded.

[0066] As used herein, “stabilized phosphate moiety” means a 5'-phosphate analog that is metabolically more stable than a 5'-phosphate as naturally occurs on DNA or RNA.

[0067] As used herein, “stereorandom” or “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center that is not intentionally controlled during synthesis, or enriched following synthesis, for a particular absolute stereochemical configuration at that chiral center. It is understood that a stereorandom chiral center may not be racemic because one absolute configuration predominates following synthesis, e.g., due to steric and electronic interactions of reagents with the reactant molecule. The stereorandom chiral center may be at the phosphorous atom of a stereorandom phosphorothioate or stereorandom mesyl phosphoramidate internucleoside linkage.

[0068] As used herein, a “strand” or “strand of linked nucleosides” means contiguous linked nucleosides connected via internucleoside linkages. A strand of linked nucleosides has a nucleobase sequence.

[0069] As used herein, “subject” means a human or non-human animal, e.g., a mammal. In certain embodiments, the subject is a human subject.

[0070] As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety.

[0071] As used herein, “symptom” of a disease means any manifestation, indication, sign, or evidence of a disease. Symptoms include subjective and objective indicia of a disease and may be perceived, experienced, detected, observed, measured, and / or quantified. A symptom may be apparent only upon invasive diagnostic testing, including, but not limited to, post-mortem tests. A symptom may be an absence of a feature, such as failing to reach expected developmental milestones.

[0072] As used herein, “treating,” or “treatment,” with respect to a disease, disorder or condition, means administering a compound or agent to a subject having or at risk for developing such disease, disorder or condition. In certain embodiments, treating a disease, disorder or condition results in amelioration of at least one symptom of such disease, disorder or condition. In certain embodiments, treatment reduces, improves, and / or prevents one or more symptom(s) such that a symptom of the disease, disorder or condition is diminished, is no longer apparent, or is never apparent. In certain embodiments, treatment delays the onset of, slows the progression of, or prevents the disease, disorder or condition.

[0073] As used herein, “unmodified nucleobase” means unmodified adenine (A), unmodified thymine (T), unmodified cytosine (C), unmodified uracil (U), or unmodified guanine (G).

[0074] As used herein, an “unmodified nucleoside” means a compound or subunit comprising an unmodified sugar moiety and an unmodified nucleobase.

[0075] As used herein, “unmodified sugar moiety” means a 2'-OH(H) p-D- ribosyl sugar moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2'-H(H) p-D-deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties are furanosyl or deoxyfuranosyl sugar moieties in the p-D- ribosyl stereochemical configuration, and have one hydrogen at each of the 1', 3', and 4' positions, an oxygen at the 3' position, two hydrogens at the 5' position, and two hydrogens (DNA) or a hydrogen and an OH (RNA) at the 2' position.Certain Embodiments1. A method of treating metabolic dysfunction associated steatotic liver disease (MASLD) in a subject in need thereof comprising administering to the subject about 75 mg to about 150 mg of a DGAT2 oligomeric compound; wherein the oligomericcompound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A - an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.2. Use of about 75 mg to about 150 mg of an oligomeric compound or a salt thereof in the manufacture of a medicament for treating MASLD in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.3. Use of about 75 mg to about 150 mg of an oligomeric compound or a salt thereof for treating MASLD in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.4. A method for reducing DGAT2 RNA and / or DGAT2 protein in a subject, comprising administering 75 mg to 150 mg of an oligomeric compound or salt thereof to a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3- conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.5. Use of 75 mg to 150 mg of an oligomeric compound or a salt thereof for reducing DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, ando = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.6. The method or use of any one of embodiments 1 -5, wherein the oligomeric compound is represented by the following chemical notation (5’ to 3’):GalNAcsO Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1); wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.7. The method or use of any one of embodiments 1 -6, wherein the oligomeric compound is represented by the following Structure 1 :(SEQ ID NO: 1) or a salt thereof.8. The method or use of any one of embodiments 1 -7, wherein the oligomeric compound is a sodium salt or a potassium salt.9. The method or use of any one of embodiments 1 -8, wherein the oligomeric compound is a sodium salt represented by the following Structure 2:(SEQ ID NO: 1).10. The method or use of any one of embodiments 1 -9, wherein the amount of DGAT2 protein in the liver of the subject is reduced compared to the baseline amount of DGAT2 protein in the subject prior to any administration of the oligomeric compound or salt thereof.1 1 . The method or use of any one of embodiments 10, wherein the amount of DGAT2 RNA and / or DGAT2 protein is decreased by at least 70%, at least 75%, at least 80% at least 85% or at least 90% compared to the baseline amount of DGAT2 RNA and / or DGAT2 protein in the subject prior to any administration of the oligomeric compound or salt thereof.12. The method or use of any one of embodiments 1-11 , wherein the subject has or is at risk for metabolic dysfunction associated steatohepatitis (MASH), liver fibrosis, advanced liver fibrosis, or cirrhosis.13. The method or use of embodiment 12, wherein the subject has one or more of: MASH without cirrhosis, MASH with advanced liver fibrosis, liver stiffness, liver fibrosis, and cirrhosis.14. The method or use of embodiment 12, wherein the subject has one or more of: diabetes, high body mass index, obesity, high HbA1 C, dyslipidemia, high cholesterol, high triglycerides, hypertension and inflammation.15. The method or use of any one of embodiments 1-14, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of the oligomeric compound or salt thereof within the range of about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 165 mg, about 75 mg to about 160 mg, about 75 mg to about 155 mg, about 75 mg to about 150 mg, about 75 about 75 mg to about 145 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg, about 75 mg to about 1 15 mg, about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 80 mg to about 95 mg, about 85 mg to about 95 mg, about 90 mg to about 95 mg, about 80 mg to about 125 mg, about 85 mg to about 175 mg, about 85 mg to about 170 mg, about 85 mg to about 165 mg, about 85 mg to about 160 mg, about 85 mg to about 155 mg, about 85 mg to about 150 mg, about 85 to about 145 mg, about 85 mg to about 140 mg, about 85 mg to about 130 mg, about 85 mg to about 125 mg, about 85 mg to about 120 mg, about 85 mg to about 1 15 mg, about 85 mg to about 1 10 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 95 mg, about 85 mg to about 125 mg, about 90 mg to about 125 mg, about 95 mg to about 125 mg, about 100 mg to about 125 mg, about 115 mg to about 125 mg, about 1 15 mg to about 120 mg, about 120 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 115 mg, about 95 mg to about 1 10 mg, about 95 mg to about 105 mg, about 95 mg to about 100 mg, about 100 mg to about 120 mg, about 100 mg to about 1 15 mg, about 100 mg to about 1 10 mg, about 100 mg to about 105 mg, about 105 mg to about 120 mg, about 105 mg to about 115 mg, about 105 mg to about 1 10 mg, about 1 10 mg to about 120 mg, about 1 10 mg to about 1 15 mg, about 115 mg to about 120 mg, about 80 mg to about 120 mg, about 80 mg to about 1 10 mg, about 80 mg to about 105 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 85 mg to about 120 mg, about 90 mg to about 95 mg, about 85 mg to about 105 mg, about 85 mg to 100 mg, 85 mg to about 95 mg, about 85 mg to about 1 15 mg, about 85 mg to about 90 mg, about 85 mg to about 95 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 165 mg, about 90 mg to about 160 mg, about 90 mg to about 155 mg, about 90 mg to about 150 mg, about 90 to about 145 mg .about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 1 15 mg, about 120 mg to about 175 mg, about 125 mg to about 175 mg, about 130 mg to about175 mg, about 140 mg to about 165 mg, about 150 mg to about 165 mg, about 150 mg to about 160 mg, or about 160 mg to about 165 mg.16. The method or use of any one of embodiments 1-14, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of at least about 50 mg and less than about 150 mg, at least about 75 mg and less than about 150 mg, at least about 75 mg and less than about 140 mg, at least about 75 mg and less than about 130 mg, at least about 75 mg and less than about 125 mg, at least about 75 mg and less than about 120 mg, at least about 75 mg and less than about 1 15 mg, at least about 75 mg and less than about 1 10 mg, at least about 75 mg and less than about 100 mg, at least about 75 mg and less than about 95 mg, at least about 80 mg and less than about 95 mg, at least about 85 mg and less than about 95 mg, at least about 90 mg and less than about 95 mg, at least about 80 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 90 mg and less than about 125 mg, at least about 95 mg and less than about 125 mg, at least about 100 mg and less than about 125 mg, at least about 1 15 mg and less than about 125 mg, at least about 1 15 mg and less than about 120 mg, at least about 120 mg and less than about 125 mg, at least about 90 mg and less than about 120 mg, at least about 95 mg and less than about 1 15 mg, at least about 95 mg and less than about 110 mg, at least about 95 mg and less than about 105 mg, at least about 95 mg and less than about 100 mg, at least about 100 mg and less than about 120 mg, at least about 100 mg and less than about 115 mg, at least about 100 mg and less than about 110 mg, at least about 100 mg and less than about 105 mg, at least about 105 mg and less than about 120 mg, at least about 105 mg and less than about 1 15 mg, at least about 105 mg and less than about 1 10 mg, at least about 1 10 mg and less than about 120 mg, at least about 110 mg and less than about 1 15 mg, at least about 1 15 mg and less than about 120 mg, at least about 80 mg and less than about 120 mg, at least about 80 mg and less than about 110 mg, at least about 80 mg and less than about 105 mg, at least about 80 mg and less than about 100 mg, at least about 80 mg and less than about 95 mg, at least about 80 mg and less than about 90 mg, at least about 85 mg and less than about 90 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 120 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 105 mg, at least about 85 mg and less than 100 mg, at least about 85 mg and less than about 95 mg, at least about 85 mg and less than about 1 15 mg, at least about 85 mg and less than about 90 mg, or at least about 85 mg and less than about 95 mg of the oligomeric compound or salt thereof.17. The method or use of embodiment 16, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of 75mg to 150 mg, 75 mg to 140 mg, 75 mg to 130 mg, 75 mg to 125 mg, 75 mg to 120 mg, 75 mg to 1 15 mg, 75 mg to 1 10 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85 mg, 75 mg to 80 mg, 80 mg to 85 mg, 80 mg to 125 mg, 85 mg to 125 mg, 90 mg to 125 mg, 95 mg to 125 mg, 100 mg to 125 mg, 105 mg to 125 mg, 1 10 mg to 125 mg, 115 mg to 125 mg, 120 mg to 125 mg, 1 15 mg to 120 mg, 90 mg to 120 mg, 95 mg to 1 15 mg, 95 mg to 1 10 mg, 95 mg to 105 mg, 95 mg to 100 mg, 100 mg to 120 mg, 100 mg to 115 mg, 100 mg to 1 10 mg, 100 mg to 105 mg, 105 mg to 120 mg, 105 mg to 1 15 mg, 105 mg to 110 mg, 1 10 mg to 120 mg, 110 mg to 115 mg, 115 mg to 120 mg, 80 mg to 120 mg, 80 mg to 1 10 mg, 80 mg to 105 mg, 80 mg to 100 mg, 80 mg to 95 mg, 80 mg to 90 mg, 85 mg to 90 mg, 90 mg to 95 mg, 85 mg to 120 mg, 90 mg to 95 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 115 mg, 85 mg to 90 mg, or 85 mg to 95 mg of the oligomeric compound or salt thereof.18. The method or use of embodiment 15, wherein the administering or use comprises administering or use of a fixed dose of the oligomeric compound or salt thereof within the range of about 80 mg to about 130 mg, about 85 mg to about 130 mg, about 90 mg to about 130 mg, about 110 mg to about 130 mg, about 1 15 mg to about 125 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, or about 85 mg to about 95 mg.19. The method or use of embodiment 16, wherein administering or use comprises administering or use of a fixed dose of about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof.20. The method or use of embodiment 17, wherein the administering or use comprises administering or use of a fixed dose of 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 10 mg, 1 15 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or salt thereof.21 . The method or use of embodiment 19, comprising administering or use of a fixed dose of about 85 mg of the oligomeric compound or salt thereof.22. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 90 mg of the oligomeric compound or salt thereof.23. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 95 mg of the oligomeric compound or salt thereof.24. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 100 mg of the oligomeric compound or salt thereof.25. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 115 mg of the oligomeric compound or salt thereof.26. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 120 mg of the oligomeric compound or salt thereof.27. The method or use of embodiment 19, comprising administering or use of a fixed dose of about 125 mg of the oligomeric compound or salt thereof.28. The method or use of embodiment 20, comprising administering or use of a fixed dose of 80 mg to 125 mg of the oligomeric compound or salt thereof.29. The method or use of embodiment 20, comprising administering or use of a unit dose of 85 mg of the oligomeric compound or salt thereof.30. The method or use of embodiment 20, comprising administering or use of a fixed dose of 90 mg of the oligomeric compound or salt thereof.31 . The method or use of embodiment 20, comprising administering or use of a fixed dose of 95 mg of the oligomeric compound or salt thereof.32. The method or use of embodiment 20, comprising administering or use of a fixed dose of 100 mg of the oligomeric compound or salt thereof.33. The method or use of embodiment 20, comprising administering or use of a fixed dose of 1 10 mg of the oligomeric compound or salt thereof.34. The method or use of embodiment 20, comprising administering or use of a fixed dose of 1 15 mg of the oligomeric compound or salt thereof.35. The method or use of embodiment 20, comprising administering or use of a fixed dose of 120 mg of the oligomeric compound or salt thereof.36. The method or use of embodiment 20, comprising administering or use of a fixed dose of 125 mg of the oligomeric compound or salt thereof.37. The method or use of any one of embodiments 1-36, wherein the oligomeric compound or salt thereof is ION224 or a salt thereof.38. The method of any one of embodiments 1-37, wherein the oligomeric compound or salt thereof is administered once about every 4 weeks or once about every 28 days.39. The method of any one of embodiments 1-37, wherein the oligomeric compound or salt thereof is administered at an interval of about once a month, about once every two months, or about once every three months.40. The method of any one of embodiments 1-37, wherein the oligomeric compound or salt thereof is administered about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, or about once every 10 weeks.41. The method or use of any one of embodiments 1-40, wherein administering or use comprises administering or use of a fixed dose of 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 10 mg, 115 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or saltthereof once every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks.42. The method or use of any one of embodiments 1 -40, wherein administering or use comprises administering or use of a fixed dose of about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof once about every 3 weeks, once about every 4 weeks, once about every 5 weeks or once about every 6 weeks, wherein the oligomeric compound is formulated for parenteral administration.43. The method or use of embodiment 42, wherein administering or use comprises administering or use of a fixed dose of 90 mg or about 90 mg, or 120 mg or about 120 mg of the oligomeric compound or salt thereof once every 28 days or about every 28 days, or once every 4 weeks or about every 4 weeks, or once a month or about once a month, wherein the oligomeric compound is formulated for subcutaneous administration.44. The method or use of embodiment 42, wherein administering or use comprises administering or use of a fixed dose of about 90 mg or about 120 mg of the oligomeric compound or salt thereof once about every 28 days or once about every 4 weeks, or once about every month, wherein the oligomeric compound is formulated for subcutaneous administration.45. The method or use of any one of embodiments 1-44, wherein the oligomeric compound or salt thereof comprises administering or use of a loading dose.46. The method or use of embodiment 45, wherein the administering or use comprises one or more maintenance doses of the oligomeric compound or salt thereof.47. The method or use of embodiment 46, wherein the loading dose comprises a greater amount of the oligomeric compound or salt thereof than a maintenance dose.48. The method or use of embodiment 46, wherein the loading dose and the maintenance dose comprises the same amount of the oligomeric compound or salt thereof.49. The method or use of any one of embodiments 1-48, wherein the administration or use of the oligomeric compound or salt thereof is effective to decrease the amount of DGAT2 RNA and / or DGAT2 protein in the subject by at least 70%, at least 75%, at least 80%, or at least 85% compared to the baseline amount of DGAT2 RNA and / or DGAT2 protein in the subject prior to any administration or use of the oligomeric compound or salt thereof.50. The method or use of any one of embodiments 1-49, wherein the oligomeric compound or salt thereof is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.51. The method or use of embodiment 50, wherein the pharmaceutical composition comprises water, saline, or phosphate buffered isotonic saline, pH 7.4.52. The method or use of any one of embodiments 1-51 , wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered parenterally.53. The method or use of embodiment 52, wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered subcutaneously or intravenously.54. The method or use of embodiment 53, wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered by a syringe, optionally by an autoinjector device.55. The method or use of any one of embodiments 1-54, wherein such method or use is effective to treat MASH and / or ameliorate one or more symptoms of MASH, but does not significantly increase fibrosis and / or worsen steatohepatitis in a subject having, or at risk for, MASH.56. The method or use of embodiment 55, wherein such method or use improves hepatocellular ballooning or lobular inflammation, reduces at least one stage in the fibrosis score, reduces liver steatosis, reverses or attenuates MASH histologic features, improves liver biochemistry tests, improves plasma lipid profile, improves indices of glycemic control, improves HbA1c, improves BMI, and / or improves quality of life in the subject having, or at risk for, MASH.57. A method of treating MASH in a subject, comprising administering a fixed dose of 80 mg to 130 mg of an oligomeric compound or a salt thereof to a subject; wherein administering the oligomeric compound results in amelioration of one or more symptoms and / or lack of progression of MASH, without worsening of fibrosis; wherein the oligomeric compound is represented by the following Structure 2:(SEQ ID NO: 1), wherein the oligomeric compound is formulated with a pharmaceutically acceptable carrier or excipient selected from sterile water or sterile saline or phosphate buffered saline, formulated for parenteral administration.58. The method of embodiment 57, wherein the fixed dose is formulated for subcutaneous administration and contained in a single use vial, pre-filled syringe or an autoinjector device.59. The method of embodiment 57, wherein administering the oligomeric compound or salt thereof comprises administering or use of a loading dose.60. The method or use of embodiment 59, wherein the administering or use comprises one or more maintenance doses of the oligomeric compound or salt thereof once about every 28 days or once about every 4 weeks, or once about every month.61. A unit dose comprising 75 mg to 150 mg of an oligomeric compound comprising a GalNAc-conjugated modified oligonucleotide represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase,e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAcs is a trishexylamino N-acetyl galactosamine conjugate moiety.62. A unit dose comprising 75 mg to 150 mg of an oligomeric compound represented by the following Structure 1 :(SEQ ID NO: 1) or a salt thereof.63. A unit dose comprising 75 mg to 150 mg an oligomeric compound represented by the following sodium salt Structure 2:(SEQ ID NO: 1).64. The unit dose of any one of embodiments 61-63, comprising an amount of the oligomeric compound or salt thereof within the range of about 75 mg to about 150 mg, about 75 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg, about 75 mg to about 1 15 mg, about 75 mg to about 1 10 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 80 mg to about 95 mg, about 85 mg to about 95 mg, about 90 mg to about 95 mg, about 80 mg to about 125 mg, about 85 mg to about 125 mg, about 85 mg to about 125 mg, about 90 mg to about 125 mg, about 95 mg to about 125 mg, about 100 mg to about 125 mg, about 1 15 mg to about 125 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 115 mg, about 95 mg to about 110 mg, about 95 mg to about 105 mg, about 95 mg to about 100 mg, about 100 mg to about 120 mg, about 100 mg to about 115 mg, about 100 mg to about 1 10 mg, about 100 mg to about 105 mg, about 105 mg to about 120 mg, about 105 mg to about 1 15 mg, about 105 mg to about 110 mg, about 110 mg to about 120 mg, about 1 10 mg to about 1 15 mg, about 1 15 mg to about 120 mg, about 80 mg to about 120 mg, about 80 mg to about 1 10 mg, about 80 mg to about 105 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 85 mg to about 120 mg, about 90 mg to about 95 mg, about 85 mg to about 105 mg, about85 mg to 100 mg, 85 mg to about 95 mg, about 85 mg to about 1 15 mg, about 85 mg to about 90 mg, or about 85 mg to about 95 mg.65. The unit dose of any one of embodiments 61-63, comprising an amount of the oligomeric compound or salt thereof of at least about 50 mg and less than about 150 mg, at least about 75 mg and less than about 150 mg, at least about 75 mg and less than about 140 mg, at least about 75 mg and less than about 130 mg, at least about 75 mg and less than about 125 mg, at least about 75 mg and less than about 120 mg, at least about 75 mg and less than about 115 mg, at least about 75 mg and less than about 1 10 mg, at least about 75 mg and less than about 100 mg, at least about 75 mg and less than about 95 mg, at least about 80 mg and less than about 95 mg, at least about 85 mg and less than about 95 mg, at least about 90 mg and less than about 95 mg, at least about 80 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 90 mg and less than about 125 mg, at least about 95 mg and less than about 125 mg, at least about 100 mg and less than about 125 mg, at least about 1 15 mg and less than about 125 mg, at least about 1 15 mg and less than about 120 mg, at least about 120 mg and less than about 125 mg, at least about 90 mg and less than about 120 mg, at least about 95 mg and less than about 1 15 mg, at least about 95 mg and less than about 1 10 mg, at least about 95 mg and less than about 105 mg, at least about 95 mg and less than about 100 mg, at least about 100 mg and less than about 120 mg, at least about 100 mg and less than about 115 mg, at least about 100 mg and less than about 1 10 mg, at least about 100 mg and less than about 105 mg, at least about 105 mg and less than about 120 mg, at least about 105 mg and less than about 1 15 mg, at least about 105 mg and less than about 1 10 mg, at least about 1 10 mg and less than about 120 mg, at least about 1 10 mg and less than about 1 15 mg, at least about 115 mg and less than about 120 mg, at least about 80 mg and less than about 120 mg, at least about 80 mg and less than about 1 10 mg, at least about 80 mg and less than about 105 mg, at least about 80 mg and less than about 100 mg, at least about 80 mg and less than about 95 mg, at least about 80 mg and less than about 90 mg, at least about 85 mg and less than about 90 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 120 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 105 mg, at least about 85 mg and less than 100 mg, at least about 85 mg and less than about 95 mg, at least about 85 mg and less than about 115 mg, at least about 85 mg and less than about 90 mg, or at least about 85 mg and less than about 95 mg.66. The unit dose of embodiment 65, comprising a fixed dose of 75 mg to 150 mg, 75 mg to 140 mg, 75 mg to 130 mg, 75 mg to 125 mg, 75 mg to 120 mg, 75 mg to 1 15 mg, 75 mg to 1 10 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85mg, 75 mg to 80 mg, 80 mg to 85 mg, 80 mg to 125 mg, 85 mg to 125 mg, 90 mg to 125 mg, 95 mg to 125 mg, 100 mg to 125 mg, 105 mg to 125 mg, 110 mg to 125 mg, 1 15 mg to 125 mg, 120 mg to 125 mg, 115 mg to 120 mg, 90 mg to 120 mg, 95 mg to 1 15 mg, 95 mg to 110 mg, 95 mg to 105 mg, 95 mg to 100 mg, 100 mg to 120 mg, 100 mg to 115 mg, 100 mg to 1 10 mg, 100 mg to 105 mg, 105 mg to 120 mg, 105 mg to 1 15 mg, 105 mg to 1 10 mg, 1 10 mg to 120 mg, 1 10 mg to 1 15 mg, 115 mg to 120 mg, 80 mg to 120 mg, 80 mg to 110 mg, 80 mg to 105 mg, 80 mg to 100 mg, 80 mg to 95 mg, 80 mg to 90 mg, 85 mg to 90 mg, 90 mg to 95 mg, 85 mg to 120 mg, 90 mg to 95 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 1 15 mg, 85 mg to 90 mg, or 85 mg to 95 mg of the oligomeric compound or salt thereof.67. The unit dose of embodiment 65, comprising a fixed dose of the oligomeric compound or salt thereof within the range of about 80 mg to about 130 mg, about 85 mg to about 130 mg, about 90 mg to about 130 mg, about 110 mg to about 130 mg, about 1 15 mg to about 125 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, or about 85 mg to about 95 mg.68. The unit dose of embodiment 66, comprising about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof.69. The unit dose of embodiment 67, comprising a fixed dose of 80 mg, 85 mg,90 mg, 95 mg, 100 mg, 1 10 mg, 1 15 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or salt thereof.70. The unit dose of embodiment 69, comprising about 85 mg of the oligomeric compound or salt thereof.71 . The unit dose of embodiment 69, comprising about 90 mg of the oligomeric compound or salt thereof.72. The unit dose of embodiment 69, comprising about 95 mg of the oligomeric compound or salt thereof.73. The unit dose of embodiment 69, comprising about 100 mg of the oligomeric compound or salt thereof.74. The unit dose of embodiment 69, comprising about 115 mg of the oligomeric compound or salt thereof.75. The unit dose of embodiment 69, comprising about 120 mg of the oligomeric compound or salt thereof.76. The unit dose of embodiment 69, comprising about 125 mg of the oligomeric compound or salt thereof.77. The unit dose of embodiment 70, comprising a fixed dose of 80 mg to 125 mg of the oligomeric compound or salt thereof.78. The unit dose of embodiment 70, comprising a unit dose of 85 mg of the oligomeric compound or salt thereof.79. The unit dose of embodiment 70, comprising a unit dose of 90 mg of the oligomeric compound or salt thereof.80. The unit dose of embodiment 70, comprising a unit dose of 95 mg of the oligomeric compound or salt thereof.The unit dose of embodiment 70, comprising a unit dose of 100 mg of the oligomeric compound or salt thereof.The unit dose of embodiment 70, comprising a unit dose of 110 mg of the oligomeric compound or salt thereof.The unit dose of embodiment 70, comprising a unit dose of 115 mg of the oligomeric compound or salt thereof.The unit dose of embodiment 70, comprising a unit dose of 120 mg of the oligomeric compound or salt thereof.The unit dose of embodiment 70, comprising a unit dose of 125 mg of the oligomeric compound or salt thereof.86. The unit dose of any one of embodiments 61-85, wherein the unit dose wherein the oligomeric compound or salt thereof is ION224 or a salt thereof.87. The unit dose of any one of embodiments 61-86, further comprising a pharmaceutically acceptable carrier, adjuvant or excipient.88. The unit dose of embodiments 87, consisting of the oligomeric compound or salt thereof and a pharmaceutically acceptable carrier or excipient.89. The unit dose of embodiment 88, wherein the pharmaceutically acceptable carrier or excipient is sterile water or sterile saline or phosphate buffered saline.90. The unit dose of embodiment 89, consisting of the oligomeric compound or salt thereof and sterile water or sterile saline or phosphate buffered saline.91 . The unit dose of any one of embodiments 61-90, formulated for parenteral administration.92. The unit dose of embodiment 91 , formulated for subcutaneous, intramuscular, or intravenous administration.93. The unit dose of embodiment 91 , formulated for subcutaneous administration.94. The unit dose of any one of embodiments 61-93, contained in a single-dose vial.95. The unit dose of any one of embodiments 61-93, provided in multi-dose vials.96. The unit dose of any one of embodiments 61-93, contained in a prefilled syringe.97. The unit dose of any one of embodiments 61-93, contained in a single-dose prefilled syringe.98. The unit dose of any one of embodiments 61-93, contained in an autoinjector device.99. A kit, comprising:(a) the unit dose of any one of embodiments 61-98, and(b) instructions for use, and, optionally,(c) means for administering the unit dose.100. The kit of embodiment 99, wherein the instructions are for use in reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASH.101. A unit dose comprising 85 mg to 125 mg of an oligomeric compound represented by the following sodium salt:(SEQ ID NO: 1), and a pharmaceutically acceptable carrier or excipient selected from sterile water or sterile saline or phosphate buffered saline, formulated for parenteral administration.102. The unit dose of embodiment 101 , formulated for subcutaneous administration and contained in a single use vial, pre-filled syringe or an autoinjector device.I. Diacylglycerol acyltransferase 2 (DGAT2)

[0076] Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of addition of acyl-CoA to diacylglycerol in de novo triglyceride synthesis. DGAT2 been proposed as a genetic target for treating MASLD and MASH because MASLD is characterized by accumulation of triglycerides (TGs) in hepatocytes, and excess liver TG accumulation in subjects with MASLD is believed to lead to development of MASH. The nucleobase sequence for a human DGAT2 gene (encoding human DGAT2 RNA, wherein diacylglycerol O-acyltranferase 2 protein is the expression product) is RefSeq No. NC_000011.10 at nucleotides 75768778..75801534 (GRCh38p14 assembly), which is incorporated herein by reference. DGAT2 expression has been shown to be important in the development of hepatic steatosis, and DGAT2 inhibitors in clinical trials have shown promise as DGAT2 inhibition in combination with inhibition of acetyl coA carboxylase (ACC, another enzyme in de novo lipogenesis) improved liver steatosis as well as liver function (as measured by liver enzymes). Thus, inhibition of DGAT2 is proposed to treat MASLD and mitigate or prevent advancement of to MASH, steatosis, fibrosis and cirrhosis of the liver.

[0077] Thus, provided herein, are compositions and methods for reducing DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD and for treating, or ameliorating at least one symptom of MASLD in, a subject having or at risk for MASLD. In certain embodiments, the MASLD is MASH. In certain embodiments, compositions and methods are provided for reducing DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD (e.g., MASH) and for treating a subject having or at risk for MASLD (e.g., MASH) wherein the subject is, or is at risk of being, susceptible to advanced fibrotic disease, including, but not limited to, stage F4 and cirrhosis. In certain embodiments, a subject has or is at risk of having diabetes, increased body mass index, obesity, or inflammation. In certain embodiments, compositions provided herein, and methods for reducing DGAT2 RNA and / or DGAT2 protein or for treating a subject having or at risk for MASLD or MASH, provide for at least a 70%, at least a 75%, at least an 80%, at least an 85% decrease or at least 90% decrease in the amount or level of DGAT2 RNA and / or DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 liver protein of the subject, or circulating level of DGAT2 protein) compared to the level of DGAT2 RNA and / or DGAT2 protein prior to any treatment with the compositions and methods (i.e., baseline DGAT2 RNA or DGAT2 protein levels). In certain embodimentsof the compositions and methods, the composition contains or consists essentially of, or the method for reducing DGAT2 RNA and / or DGAT2 protein, or for treating a subject having or at risk for MASLD (e.g., MASH) includes administration of, a single-stranded oligomeric agent (such as, for example, a single-stranded modified oligonucleotide, e.g., a single-stranded modified antisense oligonucleotide) having a nucleobase sequence complementary to a target region sequence in a DGAT2 nucleic acid. In certain embodiments, the oligomeric agent is ION224. In certain embodiments, the amount of ION224 is within the range of about 75 mg to about 175 mg, about 80 mg to about 165 mg, about 90 mg to about 160 mg, about 90 mg to about 150 mg, about 90 mg to about 140 mg, or about 90 to about 130 mg, about 85 mg to about 125 mg, about 90 mg to about 120 mg, about 100 mg to about 175 mg, about 1 10 mg to about 165 mg, about 120 mg to about 160 mg, about 130 mg to about 160 mg, about 140 mg to about 160 mg, or about 150 mg to about 160 mg. In certain embodiments, ION224 is administered once every 4 weeks or once a month. In certain embodiments, ION224 or a composition containing ION224 is administered for a period of about 1 month to about 12 months, or about 6 months to about 36 months, or about 12 months to about 60 months or more.II. Oligomeric Agents

[0078] In certain embodiments of compositions and methods described herein, a composition contains, or a method includes administering to a cell or subject, an oligomeric agent comprising or consisting of at least one modified oligonucleotide and optionally one or more additional associated features selected from: (a) one or more additional oligonucleotides, each of which may be modified or unmodified, hybridized to or covalently linked to the at least one modified oligonucleotide and / or to each other; (b) one or more conjugate groups, which may be covalently attached directly or indirectly to an oligonucleotide of such oligomeric agent; and (c) one or more terminal groups. In certain embodiments, an oligomeric agent comprises or consists of a modified oligonucleotide comprising a nucleobase sequence that is complementary to an equal length target region of a target nucleic acid, such as a DGAT2 target nucleic acid (e.g., a human DGAT2 target nucleic acid). In certain embodiments, the DGAT2 oligomeric agent comprises or consists of the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2 or the nucleobase sequence of SEQ ID NO: 3. In certain embodiments, the DGAT2 oligomeric agent is ION224.

[0079] In certain embodiments, an oligomeric agent contains or consists of a modified oligonucleotide, such as, for example, an antisense oligonucleotide, containing a nucleobase sequence complementary to a DGAT2 RNA, e.g., a human DGAT2 RNA, such as a mature DGAT2 mRNA or a DGAT2 pre-mRNA, including intronic, exonic, and untranslated regions. In certain embodiments, the modified oligonucleotide, is single-stranded. In certain embodiments, the modified oligonucleotide, is double-stranded. In certain embodiments, contacting a cell with an oligomeric agent containing a modified oligonucleotide, comprising or consisting of SEQ ID NO: 1 or SEQ ID NO: 2 decreases the amount or level of DGAT2 RNA in the cell, and in certain embodiments decreases the amount or level of DGAT2 protein produced in the cell. In certain embodiments, the oligonucleotide is attached to a conjugate group, e.g., a conjugate group containing a celltargeting moiety that interacts with or binds to a cell surface protein of a hepatic cell. In certain embodiments, the oligonucleotide is attached to a conjugate group containing one or more N-acetyl galactosamine (GalNAc) moieties. In certain embodiments, the oligomeric agent consists of an oligonucleotide attached to a conjugate group, e.g., a conjugate group containing one or more GalNAc moieties. In certain embodiments, the conjugate group is attached to a terminus of the oligonucleotide, e.g., the 5’ terminal nucleobase of the oligonucleotide. In certain embodiments, a modified oligonucleotide of the oligomeric agent is an antisense oligonucleotide. In certain embodiments, the oligomeric agent comprises or consists of an antisense oligonucleotide. In certain embodiments, the oligomeric agent comprises or consists of an antisense oligonucleotide and a conjugate group. In certain embodiments, the oligomeric agent consists of an antisense oligonucleotide attached to a conjugate group, e.g., a conjugate group containing one or more GalNAc moieties. In certain embodiments, the oligomeric agent comprises or consists of an antisense oligonucleotide and one or more terminal group(s). In certain embodiments, an oligomeric agent is an RNase H agent. In certain embodiments, an oligomeric agent is an RNAi agent.

[0080] In certain embodiments of compositions and methods described herein, a composition contains, or a method includes administering to a cell or subject, an oligomeric agent comprising or consisting of a modified oligonucleotide, having the sequence of SEQ ID NO: 1. In certain embodiments, the oligomeric agent contains a conjugate group. In certain embodiments, the oligomeric agent consists of a modified oligonucleotide, having the sequence of SEQ ID NOs: 2 attached to a conjugate group. In certain embodiments, the conjugate group contains a cell-targeting moiety that interacts with or binds to a cell surface protein of a hepatic cell. In certain embodiments, the oligonucleotide is attached to a conjugate group containing one or more GalNAc moieties. In certain embodiments, the conjugate group is attached to a terminus of the oligonucleotide, e.g., the 5’ terminal nucleobase of the oligonucleotide.

[0081] In certain embodiments of compositions and methods described herein, a composition contains or consists of, or a method includes administering to a cell or subject, a compound comprising or consisting of a modified oligonucleotide according to the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2); wherein, A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G - a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

[0082] In certain embodiments of compositions and methods described herein, a composition contains or consists of, or a method includes administering to a cell or subject, ION224. In certain embodiments, ION224 is represented by the following chemical notation (5’ to 3’):GalNAc3o Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1); wherein:A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety. In certain embodiments GalNAc3 is THA-C6-GalNAc3 represented by:(SEQ ID NO: 1) (Structure 1) or a salt thereof. Under certain conditions, an oligomeric agent, e.g., ION224, acts as an acid. For example, although an oligomeric agent such as ION224 may be drawn or described in ionized form or protonated (free acid) form, or and in association with a cation (salt) form, aqueous solutions of the oligomeric agent, e.g., ION224, exist in equilibrium among such forms. For example, a phosphate linkage of ION224 in aqueous solution exists in equilibrium among free acid, anion, and salt forms. Unless otherwise indicated, the term, “ION224,” is intended to include all such forms. Moreover, ION224 has several such linkages, each of which is in equilibrium. Thus, ION224 exists in solution in an ensemble of forms at multiple positions all at equilibrium. The term “ION224” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of ION224 followed by the term “or a salt thereof’ expressly includes all such forms that may be fully or partially protonated / de-protonated / in association with a cation. In certain instances, one or more specific cation is identified. In certain embodiments, ION224 is a pharmaceutically acceptable salt comprising one or more cations selected from sodium, potassium, calcium, and magnesium. In certain embodiments, ION224 is a sodium salt or a potassium salt. In certain embodiments, ION224 is in aqueous solution with sodium. In certain embodiments, ION224 is in aqueous solution with potassium. In certain embodiments, ION224 is in phosphate-buffered saline (PBS). In certain embodiments, ION224 is in water. In certain embodiments, the pH of the solution is adjusted with NaOH and / or HCI to achieve a desired pH. In certain embodiments, the fully sodiated sodium salt of ION224 is represented by the following chemical structure (SEQ ID NO: 1 having the nucleobase sequence of SEQ ID NO: 3) (Structure 2):III. Oligon ucleotides

[0084] In certain embodiments, modified oligonucleotides useful in the methods and compositions described herein are described by their nucleobase sequence. In certain embodiments, oligonucleotides have a nucleobase sequence that is complementary to a nucleobase sequence of a second strand of linked nucleosides (e.g., another oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid) or a region thereof. In certain embodiments of compositions and methods described herein, a composition contains, or a method includes administering, an oligomeric agent comprising or consisting of a modified oligonucleotide, containing a nucleobase sequence that is complementary to an equal length nucleobase sequence of a target nucleic acid. In certain embodiments, the target nucleic acid is a DGAT2 target nucleic acid (e.g., a human DGAT2 target nucleic acid).

[0085] In certain embodiments, the oligonucleotide (e.g., modified oligonucleotide) is complementary to a target region of a DGAT2 nucleic acid over the entire length of the oligonucleotide. In certain embodiments, a modified oligonucleotide) is at least 99%, at least 95%, at least 90%, at least 85%, or at least 80% complementary to an equal length portion of the DGAT2 nucleic acid. In certain embodiments, the modified oligonucleotide is at least 80% complementary to a region of the DGAT2 nucleic acid overthe entire length of the oligonucleotide and comprises a nucleobase sequence that is 100% or fully complementary to a target region of the DGAT2 nucleic acid.

[0086] In certain embodiments, a targeting region nucleobase sequence of a modified oligonucleotide is from 6 to 20, 10 to 18, 14 to 18, 15 to 16, 16 to 17, 16 to 20, or 18 to 20 nucleosides in length. In certain embodiments, the targeting region nucleobase sequence comprises at least 8, at least 9, at least 10, at least 1 1 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 , at least 22, or at least 23 contiguous nucleosides. In certain embodiments, the targeting region nucleobase sequence is 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, or 23 contiguous nucleosides in length. In certain embodiments, the targeting region nucleobase sequence constitutes at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the nucleosides of the oligonucleotide. In certain embodiments, the targeting region nucleobase sequence constitutes all of the nucleosides of the oligonucleotide. In certain embodiments, the targeting region nucleobase sequence of the oligonucleotide is at least 99%, at least 95%, at least 90%, at least 85%, or at least 80% complementary to the DGAT2 nucleic acid. In certain embodiments, the targeting region nucleobase sequence of the oligonucleotide is 100% complementary to a nucleobase sequence of the DGAT2 nucleic acid.

[0087] It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309, a series of oligonucleotides 13-25 nucleosides in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Oligonucleotides 25 nucleosides in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

[0088] In certain embodiments, an oligonucleotide (including modified oligonucleotides, antisense oligonucleotides, oligonucleotides contained in oligomeric agents) has any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain embodiments, X and Y are each independently selected from 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X< Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21 , 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19,13 to 20, 13 to 21 , 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21 , 14 to 22,14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to17, 15 to 18, 15 to 19, 15 to 20, 15 to 21 , 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26,15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21 , 16 to22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18,17 to 19, 17 to 20, 17 to 21 , 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21 , 18 to 22, 18 to 23, 18 to 24, 18 to 25,18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21 , 19 to 22, 19 to 23, 19 to24, 19 to 25, 19 to 26, 19 to 27, 19 to 28, 19 to 29, 19 to 30, 20 to 21 , 20 to 22, 20 to 23,20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25,22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26,25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

[0089] In certain embodiments, modified oligonucleotides consist of 16 linked nucleosides. In certain embodiments, oligonucleotides modified oligonucleotides consist of 14 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 15 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 17 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 18 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 19 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 20 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 21 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 22 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 23 linked nucleosides. In certain embodiments, modified oligonucleotides have no more than 1 to 3 mismatches to a target nucleic acid.

[0090] In certain embodiments, modified oligonucleotides consist of 12-30 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 14-25 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 14-23 linked nucleosides. In certain embodiments modified oligonucleotides consist of 14-20 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 14-18 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 14-17 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 14-16 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 16-23linked nucleosides. In certain embodiments, modified oligonucleotides consist of 16-20 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 16-30 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 19-30 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 23-30 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 18-25 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 16-22 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 18-19 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 21-23 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 23-24 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 16 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 17 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 18 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 19 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 20 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 21 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 22 linked nucleosides. In certain embodiments, modified oligonucleotides consist of 23 linked nucleosides.

[0091] In certain embodiments, a modified oligonucleotide contains one or more mismatches relative to the nucleobase sequence of the target DGAT2 nucleic acid. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, antisense activity against the target nucleic acid is reduced by such a mismatch, and activity against a non-target nucleic acid is reduced. In certain embodiments, activity against the non-target nucleic acid is reduced by a greater amount than activity against the target nucleic acid. Thus, in certain embodiments selectivity of the antisense oligonucleotide is improved. In certain embodiments, the oligonucleotide, e.g., antisense oligonucleotide, is at least 80% complementary to the target region of the DGAT2 nucleic acid over the entire length of the oligonucleotide and comprises no more than one to three mismatches with the DGAT2 nucleic acid. In certain embodiments, the oligonucleotide comprises a nucleobase sequence that is at least 80% complementary to a nucleobase sequence of the DGAT2 nucleic acid over the entire length, and comprises no more than one to three mismatches with the target nucleic acid. In certain embodiments, the oligonucleotide, e.g., an antisense oligonucleotide, comprises a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to a the DGAT2 nucleic acid over the entire length of the nucleobase sequence. In certain embodiments, a mismatch is specifically positioned within an oligonucleotide, e.g., an antisense oligonucleotide. In certain embodiments, a mismatch isat position 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 from the 5'-end of the oligonucleotide. In certain embodiments, a mismatch is at position 11 , 10, 9, 8, 7, 6, 5, 4, 3, or 2 from the 3'-end of the oligonucleotide. In certain embodiments, 1-2 additional mismatches may be present at a terminus or at both termini of the oligonucleotide. In certain embodiments, a mismatch is at position 1 , 2, 3, or 4 from the 5'-end of the oligonucleotide. In certain embodiments, a mismatch is at position 4, 3, 2, or 1 from the 3'-end of the oligonucleotide.

[0092] In certain embodiments, a modified oligonucleotide (such as, for example, a single-stranded modified oligonucleotide), containing a nucleobase sequence complementary to an equal length target region of a DGAT2 target nucleic acid (e.g., a human DGAT2 target nucleic acid), when administered to a cell or subject, decreases the amount of DGAT2 RNA and / or DGAT2 protein in the cell or subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) by at least 70%, at least 75%, at least 80%, at least 85% or at least 90% compared to the amount or level of DGAT2 RNA and / or DGAT2 protein prior to any administration of the oligomeric agent (i.e., the baseline level or amount of DGAT2 RNA and / or DGAT2 protein in the cell or subject).A. Modified Oligonucleotides

[0093] In certain embodiments of compositions and methods described herein comprise an oligomeric agent comprising or consisting of a modified oligonucleotide targeting DGAT2. Modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and / or a modified nucleobase and / or lacking a nucleobase) and / or at least one modified internucleoside linkage. Examples of certain modified nucleosides and modified internucleoside linkages suitable for use in modified oligonucleotides are described herein. In certain embodiments, modified nucleosides comprising the following modified sugar moieties and / or the following modified nucleobases, and internucleoside linkages comprising the following modifications, may be incorporated into modified oligonucleotides described herein.1. Modified Sugar Moieties

[0094] Modified sugar moieties include modified furanosyl sugar moieties, sugar surrogates (e.g., cyclic sugar surrogates, acyclic sugar surrogates), and sugar mimics. In certain embodiments, modified sugar moieties are non-bicyclic modified furanosyl sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic furanosyl sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

[0095] In certain embodiments, modified sugar moieties are non-bicyclic modified furanosyl sugar moieties comprising one or more substituent groups including, but not limited to, substituents at the 2', 3', 4', and / or 5' positions. In certain embodiments, the modified furanosyl sugar moiety is a ribosyl sugar moiety that is not an unmodified sugar moiety ( / .e., an unmodified RNA or unmodified DNA moiety). In certain embodiments, the modified furanosyl sugar moiety is a xylosyl, lyxosyl, or arabinosyl sugar moiety.

[0096] In certain embodiments, non-bicyclic modified sugar moieties are 2'- substituted sugar moieties and comprise a substituent group at the 2'-position. In certain embodiments one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched. Examples of substituent groups suitable for the 2'-position of modified sugar moieties include but are not limited to: 2'-F, 2 -OCH3(“OMe” or “O-methyl”), and 2'- O(CH2)2OCH3(“MOE” or “O-methoxyethyl”). In certain embodiments, 2'-substituent groups are selected from: halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, C1-C10 alkoxy, C1-C10 substituted alkoxy, C1-C10 alkyl, C1-C10 substituted alkyl, S-alkyl, N(Rm)- alkyl, O-alkenyl, S-alkenyl, N(Rm)-alkenyl, O-alkynyl, S-alkynyl, N(Rm)-alkynyl, O-alkylenyl- O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH2)2SCH3, O(CH2)2ON(Rm)(Rn) or OCH2C(=O)-N(Rm)(Rn), where each Rmand Rnis, independently, H, an amino protecting group, or substituted or unsubstituted C1-C10 alkyl, O(CH2)2ON(CH3)2(“DMAOE”), or 2'- O(CH2)2O(CH2)2N(CH3)2(“DMAEOE”). Synthetic methods for some of these 2'-substituent groups may be found, e.g., in Cook et a / ., U.S. 6,531 ,584; Cook et a / ., U.S. 5,859,221 ; and Cook et a / ., U.S. 6,005,087. Certain embodiments of these 2'-substituent groups may be further substituted with one or more substituent groups independently selected from: halo, cyano, ORa2, NO2, NH2, NHRa2, N(Ra2)2, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Ci0cycloalkyl, C6-Ci0aryl, heteroaryl, heterocyclyl, Ci-C5alkylene-NH2, C1- C6alkyl alkyl)RC4alkyl)S(O)Ra3, NHS(O)2Ra3, and N(C C4alkyl)S(O)2Ra3; each Ra2is independently selected from C2-C3alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cio cycloalkyl, Ce-C-io aryl, heteroaryl, and heterocyclyl; each Ra3is independently hydrogen, OH, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-Cio cycloalkyl, Ce-C aryl, heteroaryl, or heterocyclyl. In certain embodiments, a sugar moiety comprises two of the above substituents at the 2'-position. In certain embodiments, a sugar moiety comprises a 2'-fluoro and a second 2'-substituent. In certain embodiments, a 2'-substituted sugar moiety comprises a non-bridging 2'- substituent group selected from: F, NH2, N3, OCF3. OCH3, O(CH2)3NH2, CH2CH=CH2, OCH2CH=CH2, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2)2ON(Rm)(Rn), O(CH2)2O(CH2)2N(CH3)2, and N-substituted acetamide (OCH2C(=O)-N(Rm)(Rn)), whereeach Rmand Rnis, independently, H, an amino protecting group, or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, a 2'-substituted sugar moiety comprises a non-bridging 2'-substituent group selected from: F, OCF3, OCH3, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2)2ON(CH3)2, O(CH2)2O(CH2)2N(CH3)2,O(CH2)2ON(CH3)2 (“DMAOE”), O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”), and OCH2C(=O)- N(H)CH3(“NMA”). In certain embodiments, a 2 -substituted sugar moiety comprises a 2'- substituent group selected from: F, OCH3, and OCH2CH2OCH3.

[0097] In certain embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by stereochemical configuration. For example, a 2'-deoxyfuranosyl sugar moiety ( / .e., 2'-(H)H furanosyl sugar moiety) may be in seven isomeric configurations other than the naturally occurring p-D-deoxyribosyl configuration. Such modified sugar moieties are described in, e.g., WO 2020 / 072991 , incorporated by reference herein. A 2'-modified sugar moiety has an additional stereocenter at the 2'-position relative to a 2'-deoxyfuranosyl sugar moiety; therefore, such sugar moieties have a total of sixteen possible stereochemical configurations. Modified furanosyl sugar moieties described herein are in the [3-D-ribosyl stereochemical configuration unless otherwise specified.

[0098] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 4'-position. Examples of substituent groups suitable for the 4'- position of modified sugar moieties include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128, which is incorporated herein by reference.

[0099] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 3'-position. Examples of substituent groups suitable for the 3'- position of modified sugar moieties include, but are not limited to, alkoxy (e.g., methoxy), alkyl (e.g., methyl, ethyl).

[0100] In certain embodiments, non-bicyclic modified sugar moieties comprise a substituent group at the 5'-position. Examples of substituent groups suitable for the 5'- position of modified sugar moieties include, but are not limited to, vinyl, alkoxy (e.g., methoxy), alkynyl, allyl, and alkyl (e.g., methyl (R or S), ethyl (R or S)).

[0101] In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties, such as described in Migawa et al., US 2010 / 0190837, which is incorporated herein by reference, or alternative 2'- and 5'-modified sugar moieties as described in Rajeev et al., US 2013 / 0203836, which is incorporated herein by reference.

[0102] Certain modified sugar moieties are bicyclic sugar moieties and comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring.In certain embodiments, the bicyclic sugar moiety comprises a bridge between the 4' and the 2' furanose ring atoms. Examples of such 4' to 2' bridging sugar substituents include, but are not limited to: 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' (“LNA”), 4'-CH2-S-2', 4’-(CH2)2-O-2' (“ENA”), 4'-CH(CH3)-O-2' (referred to as “constrained ethyl” or “cEt” when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)-O-2' (“constrained MOE” or “cMOE”) and analogs thereof, 4'-C(CH3)(CH3)-O-2' and analogs thereof, 4'-CH2-N(OCH3)-2' and analogs thereof, 4'-CH2-O-N(CH3)-2', 4'-CH2-C(H)(CH3)- 2', 4'-CH2-C(=CH2)-2' and analogs thereof, 4’-C(RaRb)-N(R)-O-2’, 4'-C(RaRb)-O-N(R)-2', 4'- CH2-O-N(R)-2', and 4'-CH2-N(R)-O-2', wherein each R, Ra, and Rbis, independently, H, a protecting group, or Ci-Ci2alkyl. Representative U.S. patents that teach the preparation of such bicyclic sugar moieties include, but are not limited to: Imanishi et al., U.S. 7,427,672; Swayze et al., U.S. 7,741 ,457; Swayze et al., U.S. 8,022,193; Seth et al., U.S. 8,278,283; Prakash et al., U.S. 8,278,425; and Seth et al., U.S. 8,278,426, each of which are incorporated herein by reference.

[0103] In certain embodiments, such 4' to 2' bridges independently comprise from 1 to 4 linked groups independently selected from: -[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]n-O-, - C(Ra)=C(Rb)-, -C(Ra)=N-, -C(=NRa)-, -C(=O)-, -C(=S)-, -O-, -Si(Ra)2-, -S(=O)X-, and -N(Ra)- ; wherein x is 0, 1 , or 2; n is 1 , 2, 3, or 4; each Raand Rbis, independently, halo, cyano, ORa2, NO2, NH2, NHRa2, N(Ra2)2, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cio cycloalkyl, C6-io aryl, heteroaryl, heterocyclyl, Ci-C6alkylene-NH2, Ci-C6alkylene- NHRa2, Ci-C6alkylene-N(Ra2)2, C(O)Ra3, C(O)ORa3, C(O)NHRa3, C(O)N(CI-C4alkyl)Ra3, SRa3, S(O)2Ra3, S(O)Ra3, NHC(O)Ra3, N(CI-C4alkyl)C(O)Ra3, NHS(O)Ra3, N(CI-C4alkyl)S(O)Ra3, NHS(O)2Ra3, and N(CI-C4alkyl)S(O)2Ra3; each Ra2is independently selected from Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Ci0cycloalkyl, C5-Ci0aryl, heteroaryl, and heterocyclyl; each Ra3is independently hydrogen, OH, Ci-C6alkyl, Ci-C6haloalkyl, C3-C10 cycloalkyl, C6-Ci0aryl, heteroaryl, or heterocyclyl.

[0104] In certain embodiments, the bicyclic sugar moiety comprises a bridge between the 5' and the 3' furanose ring atoms. Examples of such 5' to 3' bridging sugar substituents include, but are not limited to, 5'-(CH2)2-3' (bcDNA), 5'-(CH2)3-3' (bc43DNA), 5'-C(F)=CH-CH2-3', and 5'-CH2-CHQ-3', wherein Q is an attachment to an internucleoside linkage. Additional bicyclic sugar moieties are known in the art, see, for example: Wan, et al., J. Medicinal Chemistry, 2016, 59, 9645-9667; Wengel et al., U.S. 8,080,644; Ramasamy et al., U.S. 6,525,191 ; Seth et al., U.S. 7,547,684; and Seth et al., U.S. 7,666,854, which are each incorporated herein by reference. In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by stereochemical configuration. For example, an LNA nucleoside (described herein) may be in the a-L configuration or in the p-D configuration. a-L-methyleneoxy (4'-CH2-O-2') or a-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al. Nucleic Acids Res. 2003, 21, 6365-6372). The addition of locked nucleic acids to siRNAs has been shown, in certain studies, to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al. Nucleic Acids Res. 2005, 33(1), 439-447; Mook, O. R. et al. Mol. Cane. Ther. 2007, 6(3), 833-843; Grunweller, A. et al. Nucleic Acids Res. 2003, 37(12), 3185-3193). Herein, general descriptions of bicyclic nucleosides include both stereochemical configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the p-D stereochemical configuration, unless otherwise specified.

[0105] In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5'- substituted and 4'-2' bridged sugars).

[0106] In certain embodiments, modified sugar moieties are sugar surrogates, selected from cyclic sugar surrogates and acyclic sugar surrogates.

[0107] In certain embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom (X is S, C(RIR2), or N(R3)). In certain such embodiments, such modified sugar moieties also comprise bridging and / or nonbridging substituents as described herein. For example, certain sugar surrogates comprise a 4-sulfur atom and a substitution at the 2'-position and / or the 5' position.

[0108] In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a sixmembered tetrahydropyran (“THP”), where X is O-C(RIR2), p is 1 , Q is CH, Z is C(GIG2), and m is 0. Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), altritol nucleic acid (Gi=OH; G2=H; “ANA”), and fluoro HNA “FHNA”, see e.g., Egli, M. et al. J. Am. Chem. Soc. 2011 , 133(41), 16642-16649; Swayze et al., U.S. 8,088,904; and Swayze et al., U.S. 8,440,803); FHNA can also be referred to as a F-THP or 3'-fluoro tetrahydropyran or 3'-FHNA) , which are each incorporated herein by reference.

[0109] In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported. As used here, the term “morpholino” means a sugar surrogate having Formula la, above, wherein X is O, Y and Z are each CH2, and Q is N. In certain embodiments, a morpholino is modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholines. ”

[0110] In certain embodiments, sugar surrogates are acyclic sugar surrogates In certain embodiments, acyclic sugar surrogates are the “unlocked” sugar structure of UNA (“unlocked nucleic acid”) nucleosides. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent Publication No. 2011 / 0313020. In certain embodiments, acyclic sugar surrogates are the glycerol as found in GNA (“glycol nucleic acid”) nucleosides. Further acyclic sugar surrogates include those described in Manoharan et al., U.S. 10,913,767; US patent publication US 2021 / 0238595; and PCT publication WO 2023 / 109940.

[0111] In certain embodiments, modified oligonucleotides include one or more sugar mimic, in which a group of atoms other than a “furanosyl sugar moiety” or a “sugar surrogate” form the portion of a nucleoside corresponding to the p-D-ribosyl sugar in RNA. In certain embodiments, a sugar mimic is a portion of the backbone of a peptide nucleic acid, while the remainder of the backbone of the peptide nucleic acid is an internucleoside linkage. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patent Nos. 5,539,082; 5,714,331 ; and 5,719,262.2. Modified Nucleobases

[0112] In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside. In certain embodiments, modified oligonucleotides contain no abasic nucleosides. In certain embodiments, modified oligonucleotides comprise one or more inosine nucleosides ( / .e., nucleosides comprising a hypoxanthine nucleobase). An “unmodified nucleobase” is unmodified adenine (A), unmodified thymine (T), unmodified cytosine (C), unmodified uracil (U), or unmodified guanine (G). A modified nucleobase is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one other nucleobase. A 5-methylcytosine is an example of a modified nucleobase. A universal base is a modified nucleobase that can pairwith any one of the five unmodified nucleobases, e.g., inosine (I).

[0113] In certain embodiments, modified nucleobases of a modified oligonucleotide are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6, and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 5- methylcytosine, hypoxanthine, 1-methylpseudouridine, 2-aminopropyladenine, 5- hydroxymethyl cytosine, xanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (-C°C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo (particularly 5-bromo), 5-trifluoromethyl, 5- halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2- aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N- benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1 ,3-diazaphenoxazine-2-one, 1 ,3- diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1 ,3-diazaphenoxazine-2-one (G- clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7- deazaguanosine, 2-aminopyridine, and 2-pyridone. Further nucleobases include those disclosed in Englisch, U. et al., Angew. Chem. Int. Ed. 1991 , 30, 613; Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S T., Ed., CRC Press, 2008, 163-166 and 442-443.

[0114] Preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases are known in the art and can be readily identified in publications that include without limitation, Rogers et al., U.S. 5,134,066 ; Benner et al., U.S. 5,432,272; Matteucci et al., U.S. 5,502,177 ; Froehler et al., U.S. 5,594,121 ; and Cook et al., U.S. 5,681 ,941.

[0115] In certain embodiments, each nucleobase of a modified oligonucleotide is selected from unmodified A, unmodified G, unmodified C, unmodified T, unmodified U, andmC. In certain embodiments, each nucleobase of a modified oligonucleotide is selected from unmodified A, unmodified G, unmodified C, unmodified T, unmodified U,mC, or hypoxanthine. In certain embodiments, there are no modified nucleobases in a modified oligonucleotide and each nucleobase of a modified oligonucleotide is selected from unmodified A, unmodified G, unmodified C, unmodified T, and unmodified U.3. Modified Internucleoside Linkages

[0116] In In certain embodiments, oligomeric agents provided herein comprise or consist of a modified oligonucleotide comprising at least one modified internucleoside linkage. The naturally occurring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodiester linkage. Herein, all internucleoside linkages between furanosyl sugar moieties are 3' to 5' internucleoside linkages unless otherwise indicated. In certain embodiments, nucleosides of modified oligonucleotides are linked together using one ormore modified internucleoside linkages. The two main classes of internucleoside linkages are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphates, which contain a phosphodiester bond (“P=O”) (also referred to as unmodified linkages), phosphotriesters, methylphosphonates, phosphoramidates, phosphorothioates (“P=S”), and phosphorodithioates (“HS-P=S”). Representative non-phosphorus containing internucleoside linkages include but are not limited to methylenemethylimino (-CH2- N(CH3)-O-CH2-), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-), siloxane (-O-SiH2-O-), and N,N'-dimethylhydrazine (-CH2-N(CH3)-N(CH3)-). Modified internucleoside linkages, compared to naturally occurring phosphodiester linkages, may be used to alter, typically increase, nuclease resistance of the oligonucleotide.

[0117] In certain embodiments, a modified internucleoside linkage is any of those described in WO 2021 / 030778, incorporated by reference herein. Certain internucleoside linkages having reduced charge (referred to as “neutral internucleoside linkages”) have been described. Such neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3- CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl (MOP) (see US 9,926,556), and thioformacetal (3'-S-CH2-O-5'). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2component parts.

[0118] In certain embodiments, a modified oligonucleotide comprises an internucleoside linkage comprising a triazole, alkyne, or cyclic guanidine moiety. In certain embodiments, internucleoside linkages are not 3'-to-5' internucleoside linkages.

[0119] In certain embodiments, modified oligonucleotides comprise one or more inverted nucleoside. In certain embodiments, an inverted nucleoside is terminal ( / .e., the last nucleoside on one end of an oligonucleotide) and so only one internucleoside linkage depicted above will be present. In certain embodiments, additional features (e.g., a conjugate group) are attached to the inverted nucleoside. Such terminal inverted nucleosides may be attached to either or both ends of an oligonucleotide. In certain embodiments, inverted nucleosides lack a nucleobase (are abasic nucleosides). In certain such embodiments, additional features (e.g., a conjugate group) are attached to the inverted abasic nucleoside. A terminal inverted nucleoside may be attached to either or both ends of an oligonucleotide.

[0120] In certain embodiments, internucleoside linkages have at least one chiral center. In such embodiments, a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Representative internucleoside linkages having a chiral center include but are not limited to phosphorothioates.B. Motifs

[0121] In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In certain embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and / or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif, and / or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the nucleobase sequence).1. Sugar Motifs

[0122] In certain embodiments, oligonucleotides comprise one or more type of modified sugar and / or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, a sugar motif includes but is not limited to any of the sugar modifications discussed herein. In certain embodiments, the sugar moiety of at least one nucleoside of a modified oligonucleotide is a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety and the oligonucleotide is referred to as a fully modified oligonucleotide. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, each nucleoside of a uniformly modified oligonucleotide is a 2'-substituted nucleoside comprising the same 2'-substituent. In certain embodiments, a sugar moiety of an antisense oligonucleotide is modified, wherein the modified nucleoside comprises a 2'- MOE sugar moiety.

[0123] In certain embodiments, at least one nucleoside of a modified oligonucleotide comprises a 2'-deoxy sugar moiety. In certain embodiments, a modified oligonucleotide comprises a deoxy region. In certain embodiments, the deoxy region consists of 5-12 or 7-12 linked nucleosides. In certain embodiments, the deoxy region consists of 6, 7, 8, 9, 10, or 6-10 linked nucleosides. In certain embodiments, at least one nucleoside within the deoxy region comprises a modified sugar moiety. In certain embodiments, each nucleoside of the deoxy region is a deoxynucleoside. In certain embodiments, each nucleoside of the deoxy region is a 2'-p-D-deoxynucleoside. In certain embodiments, the deoxy region is flanked on the 5'-side by a 5'-region consisting of linked 5-region nucleosides and on the 3'-side by a 3'-region consisting of linked 3 -region nucleosides; wherein the 3'-most nucleoside of the 5-region comprises a modified sugar moiety and the 5'-most nucleoside of the 3'-region is comprises a modified sugar moiety. In certain embodiments, the sugar moiety of the 3'-most nucleoside of the 5'-region and the sugar moiety of the 5'-most nucleoside of the 3'-region each differ from the sugar moiety of the respective adjacent nucleoside of the deoxy region, thus defining the boundary between the 5'-region, the deoxy region, and the 3'-region. In certain embodiments, each nucleoside of the 5'-region and each nucleoside of the 3-region comprises a modified sugar moiety.2. Nucleobase Motifs

[0124] In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, at least one nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, at least one purine and / or at least pyrimidine is modified. In certain embodiments, at least one adenine is modified. In certain embodiments, at least one guanine is modified. In certain embodiments, at least one thymine is modified. In certain embodiments, at least one uracil is modified. In certain embodiments, at least one cytosine is modified. In certain embodiments, at least one of the cytosine nucleobases in a modified oligonucleotide is 5- methylcytosine. In certain embodiments, all of the cytosine nucleobases are 5- methylcytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases. In certain embodiments, one ortwo of the cytosine nucleobases are 5-methylcytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.3. Internucleoside Linkage Motifs

[0125] In certain embodiments, oligonucleotides comprise modified and unmodified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each internucleoside linkage is a phosphodiester internucleoside linkage. In certain embodiments, each internucleoside linkage of a modified oligonucleotide is a phosphorothioate internucleoside linkage. In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and a phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, a (Sp) phosphorothioate, and a (Rp) phosphorothioate. In certain embodiments an antisense oligonucleotide has an internucleoside linkage motif (from 5' to 3') of: soossssssssssos, wherein each ‘o’ represents a phosphodiester internucleoside linkage and each ‘s’ represents a phosphorothioate internucleoside linkage.

[0126] In certain embodiments, a modified oligonucleotide is characterized by sequence, modification motif(s) and overall length. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of a modified oligonucleotide having one or more modified sugar moiety and / or sugar motif, independently, is modified or unmodified and may or may not follow the modification pattern of the sugar modifications or sugar motif. For example, internucleoside linkages within a region of a modified oligonucleotide comprising certain sugar modifications may be the same or different from one another and may be the same or different from the internucleoside linkages of the region of the modified oligonucleotide comprising different sugar modifications. Likewise, such modified oligonucleotides may comprise one or more modified nucleobase independent of the pattern of the sugar modifications or sugar motif and independent of the internucleoside linkages or internucleoside linkage motif. Unless specifically indicated, all modifications are independent of nucleobase sequence. Furthermore, each modification, whether internucleoside linkage, modified sugar moiety, or modified nucleobase, of a modified oligonucleotide, e.g., a modified antisense oligonucleotide, is independent of each modification of a paired oligonucleotide, e.g., sense oligonucleotide, unless specifically indicated otherwise.C. Antisense Oligonucleotides

[0127] In certain embodiments, an oligomeric agent comprises a modified oligonucleotide that is an antisense oligonucleotide, e.g., modified antisense oligonucleotide; wherein such oligomeric agent is an antisense agent. In certainembodiments, an oligomeric agent comprises a modified single-stranded antisense oligonucleotide. In certain embodiments, the oligomeric agent is an RNase H agent. In certain embodiments, a single-stranded oligonucleotide, e.g., modified oligonucleotide, comprises at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleosides within SEQ ID NO: 1 or within SEQ ID NO: 2. In certain embodiments, the single-stranded oligonucleotide, e.g., modified oligonucleotide, consists of 16 to 25, 16 to 23, 16 to 20, 16 to 18, 16 to 17, or 16 linked nucleosides, wherein at least 12, at least 13, at least 14, at least 15, or at least 16 contiguous nucleosides of SEQ ID NO: 1 or SEQ ID NO: 2.D. Antisense Activity

[0128] Antisense activities may be observed directly or indirectly. In certain embodiments, antisense activity involves a decrease in an amount or level of DGAT2 RNA and / or DGAT2 protein (e.g., human DGAT2 RNA and / or human DGAT2 protein) in a cell or subject. Methods for detecting a change in an amount or level of DGAT2 RNA and / or DGAT2 protein in a cell or subject include, for example, measuring the amount of DGAT2 RNA and / or DGAT2 protein in a cell or in a sample from a subject (e.g., blood, plasma, or serum) at different times or under different conditions and comparing the amounts, which, if different, indicates a change in the amount or level or DGAT2 RNA and / or DGAT2 protein. For example, the amount or level of DGAT2 RNA and / or DGAT2 protein in a cell or a sample from a subject may be measured before administering an oligomeric agent described herein, e.g., ION224 (e.g., baseline amount or level of DGAT2 RNA and / or DGAT2 protein), and the amount compared to the level or amount of DGAT2 RNA and / or DGAT2 protein measured after administering an oligomeric agent described herein, e.g., ION224. For example, DGAT2 RNA (e.g., human DGAT2 RNA) can be measured by extracting RNA from cells or tissues and performing real-time PCR analysis using a primer probe set (e.g., human DGAT2 primer probe) Results can be normalized to total RNA content, for example, measure by RIBOGREEN® and / or to a control, e.g., GAPDH (e.g., human GAPDH) using PCR. DGAT2 protein (e.g., human DGAT2 protein) in a sample, e.g., plasma, can be measured, e.g., using an ELISA method according to the manufacturer’s instructions.IV. Conjugate and Terminal Groups

[0129] In certain embodiments, provided herein are oligomeric compounds comprising one or more modified oligonucleotide and one or more conjugate groups. In certain embodiments, an oligomeric compound optionally further comprises one or more terminal groups. Conjugate groups comprise or consist of a conjugate moiety and aconjugate linker. A conjugate group may be attached at the 3' end and / or the 5' end of an oligonucleotide and / or at any internal position. In certain embodiments, conjugate groups are attached through a modified sugar moiety or a modified internucleoside linkage. In certain embodiments, oligomeric compounds comprise a modified oligonucleotide, a celltargeting moiety, and a conjugate linker.A. Conjugate Groups

[0130] In certain embodiments, a conjugate group comprises a conjugate moiety and a conjugate linker.Conjugate Moieties

[0131] In certain embodiments, a conjugate moiety modifies one or more properties of an attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, a conjugate moiety imparts a new property on the attached oligonucleotide.

[0132] In certain embodiments, a conjugate moiety comprises or consists of a cell-targeting moiety. In certain embodiments, a cell-targeting moiety is capable of binding the cell-surface receptor or the cell-surface moiety. In certain embodiments, an agent comprising a cell-targeting moiety is capable of being internalized when it interacts with or binds the cell-surface receptor or the cell-surface moiety. In certain embodiments, a celltargeting moiety comprises a liver cell targeting moiety or a liver cell ligand. In certain embodiments, a liver cell-targeting moiety consists of a cell-targeting moiety having affinity for the hepatic asialoglycoprotein receptor (ASGP-R). In certain embodiments, the celltargeting moiety comprises more than one ligand, and each ligand has affinity for the ASGP-R. In certain embodiments, each ligand is a carbohydrate. In certain embodiments, each ligand is independently selected from galactose, N-acetyl galactosamine (GalNAc), mannose, glucose, glucosamine, and fucose.

[0133] In certain embodiments, each ligand of a cell-targeting moiety is a carbohydrate, carbohydrate derivative, modified carbohydrate, polysaccharide, modified polysaccharide, or polysaccharide derivative. In certain embodiments, the conjugate group comprises a carbohydrate cluster (see, e.g., Maier et al., “Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Clusterfor Cellular Targeting,” Bioconjugate Chemistry, 2003, 14, 18-29 or Rensen et al., “Design and Synthesis of Novel A / -Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein Receptor,” J. Med. Chem. 2004, 47, 5798-5808). In certain embodiments, each ligand is an amino sugar or a thio sugar. For example, amino sugarsmay be selected from any number of compounds known in the art, such as sialic acid, a- D-galactosamine, p-muramic acid, 2-deoxy-2-methylamino-L-glucopyranose, 4,6- dideoxy-4-formamido-2,3-di-0-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D- glucopyranose and A / -sulfo-D-glucosamine, and A / -glycoloyl-a-neuraminic acid. For example, thio sugars may be selected from 5-Thio-p-D-glucopyranose, methyl 2,3,4-tri-O- acetyl-1-thio-6-0-trityl-a-D-glucopyranoside, 4-thio-p-D-galactopyranose, and ethyl 3,4,6,7-tetra-0-acetyl-2-deoxy-1 ,5-dithio-a-D-g / uco-heptopyranoside.

[0134] In certain embodiments, each ligand is N-acetyl galactosamine (GalNAc). In certain embodiments, the cell-targeting moiety comprises one GalNAc ligand. In certain embodiments, the cell-targeting moiety comprises two GalNAc ligands. In certain embodiments, the cell-targeting moiety comprises three GalNAc ligands. In certain embodiments, the cell-targeting moiety comprises a GalNAc ligand cluster. In certain embodiments, the cell-targeting moiety comprises a three GalNAc ligand cluster. In certain embodiments, the cell-targeting moiety is any one of those described in US 9,127,276, the entire contents of which is incorporated herein by reference. In certain embodiments, a conjugate group comprises a cell-targeting moiety selected from any one of the formula set forth in TABLE A:Conjugate Linkers

[0135] In certain embodiments, oligomeric compounds comprise an oligonucleotide and a conjugate group, wherein the conjugate group comprises a conjugate moiety and a conjugate linker. In certain embodiments, the conjugate linker links the conjugate moiety to the oligonucleotide. In certain embodiments, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain embodiments, the conjugate linker comprises one or more atoms. In certain embodiments, the conjugate linker comprises achemical group. In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0136] In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

[0137] In certain embodiments, conjugate linkers, including the conjugate linkers described herein, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate moieties to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to react with a particular site on a parent compound and the other is selected to react with a peptide extender. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

[0138] In certain embodiments, conjugate linkers comprise chemical groups that are formed upon a reaction between a first functional group and a second functional group. In certain embodiments, a modified oligonucleotide is attached to the first functional group during synthesis, and a conjugate moiety is attached to a second functional group during synthesis. Then, the two compounds are mixed under specific conditions to yield the final oligomeric compound. Such reactions that are compatible with both oligonucleotide and peptide chemistry have been previously described and are often called “bioconjugation” reactions. Such reactions include strain promoted azido-alkyne cycloaddition (SPAAC), copper-catalyzed click reaction (CuAAC), active ester conjugation to an amino modified oligonucleotide, maleimide-thiol Michael addition, ketol / hydroxylamine ligation, the Staudinger ligation, reductive amination, thio ether formation, disulfide formation, reductive alkylation, catalyst-free N-arylation, sulfur fluorideexchange click reaction (SuFEx), and inverse demand Diels Alder reaction. Certain such reactions are described in, e.g., Jbara, et al., “Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents’’, Angew. Chem. Int. Ed. 2021, 60(21)12109-12115; Dong, et al., “Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry,” Angew. Chem. Int. Ed. 2014, 53(36):9430-9448.4; Zhang, et al., “Arylation Chemistry for Bioconjugation,” Angew. Chem. Int. Ed. Engl. 2019; 58(15): 4810-4839; Walsh, et al., “Site-selective modification strategies in antibody-drug conjugates” Chem. Soc. Rev., 2021 , 50: 1305-1353; Tiefenbrunn, et al., “Chemoselective ligation techniques: modern applications of time-honored chemistry”, Biopolymers, 2010, 94(1 ):95- 106; Drake, et al., Bioconjug. Chem. 2014, 25(7): 1331 -1341 ; Bode, Acc. Chem. Res., 2017, 50, 9, 2104-2115; J. Magano, B. Bock, et al, Org. Proc. Res. Dev. 2014, 18:142-151 ; Craig S. McKay and M.G. Finn, “Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation”, Chemistry & Biology 2014; Mitchell P. Christy et al., Org. Lett. 2020, 22: 2365; Ren et al., Angew. Chem. Int. Ed. Engl. 2009, 48, 9658-9662; Rohrbacher, F. et al., Helv. Chim. Acta. 2018, 101 ; Baalmaan, et al, “A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well-Defined Protein-Protein Conjugates”, Angew. Chem. Int. Ed.2020 (59): 12885-12893; Lang, et al, “Biorthogonal Reactions for Labeling Proteins”, J. Am. Chem. Soc, 2014, 9(1): 16-20; Nair, et al., “The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry”, Chem. Mater. 2013 26(1):724-744; Kalia and Raines, “Hydrolytic Stability of Hydrazones and Oximes”, Angew. Chem. Int. Ed., 2008, 47:7523-7526.

[0139] Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or substituted or unsubstituted C2-C10 alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

[0140] In certain embodiments, conjugate linkers comprise 1-5 linker- nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. In certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker- nucleosides comprise a modified sugar moiety. In certain embodiments, linker- nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is anucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine, guanine and 2-N- isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

[0141] Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and / or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1) an oligonucleotide consisting of 18-30 nucleosides and (2) a conjugate linker comprising 1- 10 linker-nucleosides that are contiguous with the nucleosides of the oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise an oligonucleotide consisting of 18-30 nucleosides and no conjugate linker. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

[0142] In certain embodiments, it is desirable for a conjugate moiety to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate moiety be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. 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 selectively cleaved inside a cell or subcellular compartment, such as a lysosome. Incertain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

[0143] In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphodiester linkage between an oligonucleotide and a conjugate moiety.

[0144] In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain embodiments, the one or more linker- nucleosides are linked to one another and / or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2'-deoxy nucleoside that is attached to either the 3' or 5'-terminal nucleoside of an oligonucleotide by a phosphate internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage. In certain embodiments, the cleavable moiety is 2'-deoxyadenosine.

[0145] In certain embodiments, oligomeric compounds described herein comprise an oligonucleotide linked to a conjugate moiety by a conjugate linker, wherein the oligomeric compound is prepared using Click chemistry known in the art. Compounds have been prepared using Click chemistry wherein alkynyl phosphonate internucleoside linkages on an oligomeric compound attached to a solid support are converted into the 1 ,2,3-triazolylphosphonate internucleoside linkages and then cleaved from the solid support (Krishna et al., J. Am. Chem. Soc. 2012, 134(28), 11618-11631), which is incorporated by reference herein in its entirety. Additional conjugate linkers suitable for use in several embodiments are prepared by Click chemistry described in “Click Chemistry for Biotechnology and Materials Science” Ed. Joerg Laham, Wiley 2009, which is incorporated by reference herein in its entirety.

[0146] In certain embodiments, compounds comprise an oligonucleotide, a cell-targeting moiety, and a conjugate linker. In certain embodiments, oligomeric compounds comprise an oligonucleotide, a hepatic asialoglycoprotein receptor (ASGP-R) ligand, and a conjugate linker. In certain embodiments, oligomeric compounds comprise an oligonucleotide, a N-acetyl galactosamine (GalNAc) ligand, and a conjugate linker. In certain embodiments, oligomeric compounds comprise an oligonucleotide, a GalNAc trimer, a branching group, a conjugate linker, and optionally modifications to the GalNAc ligands. In certain embodiments, oligomeric compounds comprise an oligonucleotide, two or more GalNAc ligands, a branching group, a conjugate linker, and optionallymodifications to the GalNAc ligands. In certain embodiments, a conjugate linker connects GalNAc ligand to an oligonucleotide.

[0147] In certain embodiments, two or more GalNAc ligands are covalently connected to a conjugate linker, and the conjugate linker is covalently connected to the 3’ end of an oligonucleotide. In certain embodiments, a three GalNAc cluster is covalently connected to a conjugate linker, and the conjugate linker is covalently connected to the 3’ end of an oligonucleotide. In certain embodiments, two or more GalNAc ligands are covalently connected to a conjugate linker, and the conjugate linker is covalently connected to the 5’ end of an oligonucleotide. In certain embodiments, a three GalNAc cluster is covalently connected to a conjugate linker, and the conjugate linker is covalently connected to the 5’ end of an oligonucleotide. In certain embodiments, two or more GalNAc ligands are covalently connected to a conjugate linker, and the conjugate linker is covalently connected to an internal position of an oligonucleotide. In certain embodiments, a three GalNAc cluster is covalently connected to a conjugate linker, and the conjugate linker is covalently connected to an internal position of an oligonucleotide. In certain embodiments, an internal position of an oligonucleotide is a 2’-position of a modified sugar moiety of a nucleoside within the internal region of an oligonucleotide that is not the 5’ terminal nucleoside or the 3’ terminal nucleoside. In certain embodiments, an internal position of an oligonucleotide is a modified internucleoside linkage of the oligonucleotide.

[0148] In certain embodiments, a conjugate group comprises a conjugate trishexylamino (THA)-C6 linker. In certain embodiments, a conjugate group comprises GalNAc is trishexylamino-(THA)-C6 GalNAc3. In certain embodiments, the trishexylamino- (THA)-C6 GalNAc3is attached to the 5’-terminal nucleoside of an oligonucleotide. In certain embodiments, a 5'-Trishexylamino-(THA)-C6 GalNAc3conjugate group has the formula:

[0149] In certain embodiments, a modified oligonucleotide is linked to the Trishexylamino-(THA)-C6 GalNAc3conjugate by a cleavable moiety. In certain embodiments, the cleavable moiety is a phosphate group. In certain embodiments, the phosphate group is attached to the 5’-oxygen atom of the 5’-nucleoside of the oligonucleotide. In certain embodiments, a 5'-Trishexylamino-(THA)-C6 GalNAc3conjugate group containing a cleavable moiety has the formula:

[0150] In certain embodiments, a GalNAc-containing conjugate group is HPPO-GalNAc. In certain embodiments, the HPPO-GalNAc-containing conjugate group is attached to the 3’-terminal nucleoside of an oligonucleotide. In certain embodiments, HPPO-GalNAc conjugate group containing a cleavable moiety has the formula:B. Terminal Groups

[0151] As used herein, “terminal group” means a group of atoms that is covalently linked to a terminus of an oligonucleotide. Examples of a terminal group include, but are not limited to, a capping group, a phosphate moiety, a stabilized phosphate group, and a protecting group, wherein one or more groups is attached to either or both ends ofan oligonucleotide. In certain embodiments, one or more terminal groups is attached to either or both ends of an oligonucleotide. In certain embodiments, an oligonucleotide is linked to a terminal group comprising a stabilized 5’-phosphate. In certain embodiments, one or more terminal groups is attached at the 3' and / or 5'-end of the oligonucleotide. In certain embodiments, one or more terminal groups is attached at the 3'-end of the oligonucleotide. In certain embodiments, one or more terminal groups is attached at the 5 -end of the oligonucleotide. In certain embodiments, one or more terminal groups is attached at the 3'-end of the oligonucleotide and one or more terminal groups is attached at the 5'-end of the oligonucleotide. In certain embodiments, a terminal group is attached at the 3' and / or 5'-end of the oligonucleotide. In certain embodiments, a terminal group is attached at the 3'-end of the oligonucleotide. In certain embodiments, a terminal group is attached near the 3'-end of the oligonucleotide. In certain embodiments, a terminal group is attached at the 5'-end of the oligonucleotide. In certain embodiments, a terminal group is attached near the 5'-end of the oligonucleotide. In certain embodiments, a terminal group is attached at the 3'-end of the oligonucleotide and a terminal group is attached at the 5'- end of the oligonucleotide.

[0152] In certain embodiments, amodified oligonucleotide is linked to a terminal group comprising a stabilized phosphate moiety attached to the 5’-end of the oligonucleotide. The stabilized phosphate moiety results in stabilization of a 5’-phosphate moiety of the 5’-terminal nucleoside of an oligonucleotide, relative to the stability of an unmodified 5’-phosphate of an unmodified nucleoside under biologic conditions. Such stabilization of a 5’-phosphate group includes but is not limited to resistance to removal by phosphatases. Stabilized phosphate moieties, but are not limited to 5’-phosphonates, including, but not limited to 5’-vinylphosphonate, 5’-methylphosphonate, and 5’- cyclopropyl phosphonate. In certain embodiments, the stabilized phosphate moiety is a cyclopropyl phosphonate or an (E) -vinyl phosphonate.V. CompositionsA. Pharmaceutical Compositions

[0153] In certain embodiments, described herein are compositions comprising or consisting of, or consisting essentially of, an oligomeric agent. In certain embodiments, an oligomeric agent (e.g., a unit dose) contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) having a nucleobase sequence complementary to a DGAT2 nucleic acid targeted by ION224, e.g., a human DGAT2 targeting oligomeric agent ION224 such as, e.g., SEQ ID NO: 1 or 2. In certain embodiments, the oligomeric agent is any such oligomeric agent described herein and / orcontaining any such oligonucleotide described herein. In certain embodiments, a composition containing an oligomeric agent is a pharmaceutical composition, e.g., a pharmaceutical formulation. In certain embodiments, the composition contains a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition consists of the oligomeric agent and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the oligonucleotide of the oligomeric agent is single-stranded. In certain embodiments, the oligonucleotide of the oligomeric agent is a single-stranded antisense agent, and in certain embodiments is a single-stranded RNase H agent. In certain embodiments, the composition is a pharmaceutical composition consisting of an oligomeric agent consisting of a singlestranded antisense agent, and optionally a conjugate group, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the nucleobase sequence of the modified oligonucleotide includes at least 16 contiguous nucleobases of SEQ ID NO: 1 or SEQ ID NO: 2. In certain embodiments of the oligomeric agent-containing compositions provided herein, the nucleobase sequence of the modified oligonucleotide is SEQ ID NO: 1 or 2. In certain embodiments, the oligomeric agent contains a conjugate group attached to the modified oligonucleotide. In certain embodiments, the conjugate group includes one or more GalNAc moieties (e.g., trishexylamino-(THA)-C6 GalNAc3). In certain embodiments, the oligomeric agent consists of, or consists essentially of, the modified oligonucleotide and the conjugate group. In certain embodiments, the oligomeric agent comprises or consists of a modified oligonucleotide according to the following chemical notation (5’ to 3’): Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase,mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage.

[0154] In certain embodiments, the oligomeric agent is ION224 (represented in certain embodiments by Structure 1), e.g., ION224, and compositions containing ION224, includes any salt (e.g., pharmaceutically acceptable salt) of ION224, e.g., potassium, calcium, magnesium, and sodium salts (see, e.g., Structure 2), ester of ION224, or salts of such esters.

[0155] In certain embodiments, ION224 is represented by the following chemical notation (5’ to 3’): GalNAc3o Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1) or a salt thereof; wherein: A = an adenine nucleobase,mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodifiedDNA sugar moiety, s = a phosphorothioate internucleoside linkage, o = a phosphodiester internucleoside linkage; and GalNAc3=

[0156] In certain embodiments, compositions containing an oligomeric agent that contains a modified oligonucleotide targeting huan DGAT2 nucleic acid (e.g., a SEQ ID NO: 1 , SEQ ID NO: 2, ION224), are used in methods provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a cell or a subject having or at risk for MASLD, or for treating a subject having or at risk for MASLD. In certain embodiments, a composition containing the oligomeric agent is a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition consists of, or consists essentially of, the oligomeric agent, e.g., ION224, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of a sterile saline solution and the oligomeric agent, e.g., ION224. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of a buffered sterile saline solution and the oligomeric agent, e.g., ION224. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of sterile water and the oligomeric agent, e.g., ION224. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of the oligomeric agent, e.g., ION224, in phosphate buffered isotonic saline, pH 7.4 (e.g., 2mM to 10mM PBS).

[0157] In certain embodiments, a composition, e.g., pharmaceutical compositions, comprising the oligomeric agent, e.g., ION224, encompass any salt, e.g., any pharmaceutically acceptable salt, of the oligomeric agent, e.g., ION224, esters of the oligomeric agent, e.g., ION224, or salts of such esters. In certain embodiments,pharmaceutical compositions comprising an oligomeric agent, e.g., ION224, are capable of providing (directly or indirectly) the biologically active metabolite or residue thereof upon administration to a human subject. Accordingly, for example, the disclosure is also drawn to salts, e.g., pharmaceutically acceptable salts, of the oligomeric agent, e.g., ION224, prodrugs of the oligomeric agent, e.g., ION224, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts.

[0158] Under certain conditions, an oligomeric agent, e.g., ION224, acts as an acid in a composition. For example, although an oligomeric agent such as ION224 may be drawn or described in ionized form and / or protonated (free acid) form and / or in association with a cation (salt) form, solutions of the oligomeric agent, e.g., ION224, exist in equilibrium among such forms when in an aqueous composition. For example, a phosphate linkage of ION224 in aqueous solution exists in equilibrium among free acid, anion, and salt forms. Unless otherwise indicated, the term, “ION224,” is intended to include all such forms. Moreover, ION224 has several such linkages, each of which is in equilibrium. Thus, ION224 exists in solution in an ensemble of forms at multiple positions all at equilibrium. The term “ION224” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of ION224 followed by the term “or a salt thereof’ expressly includes all such forms that may be fully or partially protonated / de-protonated / in association with a cation. In certain instances, one or more specific cation is identified.

[0159] In certain embodiments, ION224 is in aqueous solution composition with sodium. In certain embodiments, ION224 is in aqueous solution composition with potassium. In certain embodiments, ION224 is in phosphate-buffered saline (PBS). In certain embodiments, ION224 is in water. In certain embodiments, the pH of the solution is adjusted with NaOH and / or HCI to achieve a desired pH (e.g., 7.4).

[0160] Certain pharmaceutical compositions are formulated based on a mode of delivery. Pharmaceutical compositions described herein can be administered in a number of different ways, e.g., depending on whether local or systemic treatment is desired and upon the area to be treated. Administration can be, for example, transdermal, epidermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion. In certain embodiments, a composition (e.g., pharmaceutical composition) containing an oligomeric agent, e.g., ION224, is administered by subcutaneous injection. In certain embodiments, a composition containing an oligomeric agent, e.g., ION224, is administered by a syringe.In certain embodiments a composition containing an oligomeric agent, e.g., ION224, is administered by a self contained auto- injector.B. Doses

[0161] Herein, certain specific doses or quantities are described. For clarity, a dose or quantity of an oligomeric agent, e.g., ION224, in milligrams indicates the mass of the free acid form of the oligomeric agent, e.g., ION224. As described above, in aqueous solution, a free acid is in equilibrium with anionic and salt forms. However, for simplicity of calculating dose or quantity, it is assumed that an oligomeric agent, e.g., ION224, exists as a solvent-free, sodium-acetate free, anhydrous, free acid. For example, where ION224 is in solution comprising sodium (e.g., saline), ION224 may be partially or fully deprotonated and in association with Na+ ions, including equilibrium over a combination of multiple different sites throughout the oligomeric compound. However, a mass of proton forms is nevertheless counted toward weight of the dose, and the mass of Na+ ions are not counted toward the weight of the dose. Thus, for example, a dose or quantity of 90 mg of ION224 equals the number of fully protonated molecules that weighs 90 mg.

[0162] In certain embodiments, provided herein are unit doses of oligomeric agent (e.g., a unit dose) that contains an modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) targeting DGAT2 nucleic acid, e.g., SEQ ID NO: 1 , SEQ ID NO: 2, ION224. In certain embodiments, the oligomeric agent is any such oligomeric agent described herein containing any such oligonucleotide described herein. Also provided are unit doses of a composition, e.g., pharmaceutical composition, containing such oligomeric agents. In certain embodiments, the composition contains ION224 in any or all forms, including any salt (e.g., pharmaceutically acceptable salt) of ION224, e.g., potassium, calcium, magnesium, and sodium salts (see, e.g., Structure 2), ester of ION224, or salts of such esters. In certain embodiments, the composition containing an oligomeric agent, e.g., ION224,

[0163] In certain embodiments, a composition, e.g., pharmaceutical composition, containing an oligomeric agent (e.g., a unit dose) that contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) having a nucleobase sequence targeting a DGAT2 nucleic acid, e.g., SEQ ID NO: 1 , SEQ ID NO: 2, ION224, contains an additional active agent. In certain embodiments, the composition contains a SGLT2 inhibitor. In certain embodiments, the SGLT2 inhibitor is Brenzavv (bexaglifloxin), Invokana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), Steglatro (ertugliflozin), or combination of any one or more such SGLT2 inhibitors. In certain embodiments, the composition contains a GLP1 agonist. In certain embodiments, the GLP1 agonist is Trulicity (dulaglutide), Bydureon bcise (exenatideextended release), Byetta (exenatide), Ozempic (semaglutide), Victoza or Saxenda (liraglutide), Adlyxin (lixisenatide), Rybelsus (semaglutide), or combination of any one or more such GLP1 agonists. In certain embodiments, the composition contains any other approved therapy for MASLD or MASH, e.g., rezdiffra (resmetirom).

[0164] In certain embodiments of a unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is effective to, when administered to a cell or subject, decrease the amount of DGAT2 RNA and / or DGAT2 protein in the cell or subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) by at least 70%, at least 75%, at least 80%, at least 85% or at least 90% compared to the amount or level of DGAT2 RNA and / or DGAT2 protein prior to any administration of the oligomeric agent (e.g., the baseline level or amount, or pre-administration level, of DGAT2 RNA and / or DGAT2 protein in the cell or subject).

[0165] In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is effective to treat, and / or ameliorate one or more symptoms of MASLD, such as hepatic steatosis, but does not significantly increase fibrosis in a subject having, or at risk for, MASLD, including, e.g, a subject having, or at risk for MASLD who has MASH. In certain embodiments, the quantity of oligomeric agent, e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, but does not significantly alter (e.g., increase) hepatic fibrosis in a subject having, or at risk for, MASH, including, e.g., a subject having, or at risk for MASLD who has MASH. In certain embodiments, the quantity of oligomeric agent, e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASLD, such as MASH resolution without worsening of fibrosis, improvement of MASH, without significantly altering (e.g., worsening) fibrosis levels in a subject having, or at risk for MASLD including, for example, a subject having, or at risk for, MASH. In certain embodiments, the quantity of oligomeric agent e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, but does not significantly alter (e.g., increase) fibrosis in a subject having, or at risk for MASH, including, e.g., a subject having, or at risk for MASH who has advanced fibrosis. In certain embodiments, the amount of oligomeric agent e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, such as reducing liver fat, lowering steatosis or improvement in glycemic control, but does not significantly worsen fibrosis and / or increase fibrotic score in a subject having, or at risk for MASH, including, for example, a subject having, or at risk for MASH who has advanced fibrosis. In certain embodiments, the quantity of oligomeric agent e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, e.g., improvement infibrosis score by one or more stage, but does not significantly worsen steatohepatitis in a subject having, or at risk for MASH, including, e.g., a subject having, or at risk for MASLD who has advanced fibrosis (e.g., stage 2, 3 or 4).

[0166] In certain embodiments, the quantity of oligomeric agent e.g., ION224, in the unit dose improves liver function, reduces liver fat, reduces steatosis, reduces liver fibrosis, reverses or attenuates MASH, and / or improves glycemic control in a subject having, or at risk for, MASLD (such as MASH). In certain embodiments the quantity of oligomeric agent e.g., ION224, in the unit dose improves liver function, reduces liver fat, reduces steatosis, reduces liver fibrosis, reverses or attenuates MASH, and / or improves glycemic control in a subject having, or at risk for, MASH. In certain embodiments, the quantity of oligomeric agent e.g., ION224, in the unit dose improves quality of life as assessed by patient reported outcomes of a subject having, or at risk for, MASLD. In certain embodiments, the quantity of oligomeric agent e.g., ION224, in the unit dose decreases the level liver triglycerides, liver fat and / or improves liver lipid profile of a subject having, or at risk for, MASH compared to the level prior to administration of the unit dose, or to the baseline level in a subject before any administration of the oligomeric agent, e.g., ION224.

[0167] In certain embodiments of the unit doses of a composition provided herein, the unit dose is administered as a loading dose. In certain embodiments, administration of one or more loading dose is effective in achieving a desired condition in a subject, for example, a desired initial concentration of oligomeric agent, e.g., ION224. In certain embodiments, administration of the loading dose(s) is / are effective in decreasing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) compared to the amount or level of DGAT2 RNA and / or DGAT2 protein prior to administration of the loading dose of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2). In certain embodiments, administration of the loading dose(s) is more effective to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) than administration of a maintenance dose is to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein). In certain embodiments, administration of a loading dose(s) is effective in decreasing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein)then administration of a maintenance dose is to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) in order to sustain the decreased amount or level of DGAT2 RNA and / or DGAT2 protein in the subject. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is greater than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is less than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is the same quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose.

[0168] In certain embodiments of the unit doses of a composition provided herein, the unit dose is administered as a maintenance dose. In certain embodiments, administration of the maintenance dose is effective in maintaining a desired condition in a subject that results from administration of the loading dose. In certain embodiments, administration of the maintenance dose is effective in maintaining an amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g, the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) that is less than the amount or level of DGAT2 RNA and / or DGAT2 protein priorto administration of the loading dose of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2). In certain embodiments, administration of the maintenance dose is effective in maintaining an amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) that is about the same as the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose, that is less than the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose, or that is more than the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose but less than the amount or level of DGAT2 RNA and / or DGAT2 protein prior to administration of the loading dose of the oligomeric agent (e.g., the baseline or preadministration level of DGAT2). In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose is greater than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in a unit does that is a maintenance dose is less than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose.

[0169] In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 75 mg to about 175 mg, about 80 mg to about 170 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 95 mg to about 155 mg, about 100 mg to about 150 mg, about 105 mg to about 145 mg, about 1 10 mg to about 140 mg, about 115 mg to about 135 mg, about 120 mg to about 130 mg, about 90 mg to about 120 mg, about 95 mg to about 120 mg, about 100 mg to about 120 mg, about 75 mg to about 115 mg, about 80 mg to about 1 10 mg, about 85 mg to about 105 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 125 mg, about 95 mg to about 120 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 1 15 mg to about 165 mg, about 120 mg to about160 mg, about 120 mg to about 150 mg, about 120 mg to about 135 mg, about 135 mg to about 160 mg, or about 95 mg to about 100 mg.

[0170] In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 75 mg to 175 mg, 80 mg to 170 mg, 85 mg to 165 mg, 90 mg to 160 mg, 95 mg to 155 mg, 100 mg to 150 mg, 105 mg to 145 mg, 1 10 mg to 140 mg, 1 15 mg to 135 mg, 120 mg to 130 mg, 90 mg to 120 mg, 95 mg to 120 mg, 100 mg to 120 mg, 75 mg to 1 15 mg, 80 mg to 110 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 90 mg, 90 mg to 95 mg, 95 mg to 125 mg, 95 mg to 120 mg, 85 mg to 165 mg, 90 mg to 160 mg, 115 mg to 165 mg, 120 mg to 160 mg, 120 mg to 150 mg, 120 mg to 135 mg, 135 mg to 160 mg, or 95 mg to 100 mg.

[0171] In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is at least about75 mg and less than 175 mg, at least about 75 mg and less than 170 mg, at least about75 mg and less than 165 mg, at least about 75 mg and less than 160 mg, at least about75 mg and less than 155 mg, at least about 75 mg and less than 150 mg, at least about75 mg and less than 145 mg, at least about 75 mg and less than 140 mg, at least about75 mg and less than 135 mg, at least about 75 mg and less than 130 mg, at least about75 mg and less than 125 mg, at least about 75 mg and less than 120 mg, at least about75 mg and less than 115 mg, at least about 75 mg and less than 1 10 mg, at least about75 mg and less than 105 mg, at least about 75 mg and less than 100 mg, at least about75 mg and less than 95 mg, at least about 20 mg and less than 90 mg, at least about 20 mg and less than 95 mg, at least about 80 mg and less than 95 mg, at least about 85 mg and less than 95 mg, at least about 85 mg and less than 90 mg, at least about 90 mg and less than 95 mg, at least about 90 mg and less than 100 mg, at least about 90 mg and less than 105 mg, at least about 90 mg and less than 1 10 mg, at least about 90 mg andless than 115 mg, at least about 90 mg and less than 120 mg, at least about 90 mg and less than 125 mg, at least about 90 mg and less than 130 mg, at least about 90 mg and less than 135 mg, at least about 90 mg and less than 140 mg, at least about 90 mg and less than 145 mg, at least about 90 mg and less than 150 mg, at least about 90 mg and less than 155 mg, or at least about 90 mg ar d less than 160 mg.

[0172] In certain embodiments c the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is about 85 mg, about 90 mg, about 95 mg, about 115 mg, about 120 mg, about 125 mg, about 150 mg, about 155 mg, about 160 mg, or about 165 mg.

[0173] In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 1 10 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, or 175 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 85 mg, 90 mg, 95 mg, 1 15 mg, 120 mg, 125 mg, 150 mg, 155 mg, 160 mg, or 165 mg.In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 100 mg to about 160 mg, about 110 mg to about 160 mg, about 120 mg to about 160 mg, about 90 mg to about 145 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 120 mg, about 100 mg to about 120 mg, about 85 mg to about 115 mg, about 90 mg to about 110 mg, about 85 mg to about 105 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 125 mg, about 95 mg to about 120 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 115 mg to about 165 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 135 mg, about 135 mg to about 160 mg, or about 95 mg to about 100 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg,about 160 mg, about or about 165 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 1 10 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 155 mg, 160 mg, or 165 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 90 mg to 160 mg.

[0174] In certain embodiments of the unit doses of a composition, the unit dose is in a single-dose container or the unit dose is in a multi-dose container. In certain embodiments, the container is a vial, tube or ampule. In certain embodiments, the unit dose is in a single dose container, such as, for example, a syringe, e.g., a pre-filled syringe, or cartridge. In certain embodiments, a unit dose is contained within a medical device, e.g., an autoinjector or pen injector. In certain embodiments, a multi-dose container contains 2- 12 unit doses, 2-1 1 unit doses, 2-10 unit doses, 2-9 unit doses, 2-8 unit doses, 2-7 unit doses, 2-6 unit doses, 2-5 unit doses, 2-4 unit doses, 2-3 unit doses, 12 unit doses, 11 unit doses, 10 unit doses, 9 unit doses, 8 unit doses, 7 unit doses, 6 unit doses, 5 unit doses, 4 unit doses, 3 unit doses, or 2 unit doses. In certain embodiments, an autoinjector or pen injector contains 1-12 unit doses, 1-11 unit doses, 1-10 unit doses, 1-9 unit doses, 1-8 unit doses, 1-7 unit doses, 1-6 unit doses, 1-5 unit doses, 1-4 unit doses, 1-3 unit doses, 1-2 unit doses, 12 unit doses, 11 unit doses, 10 unit doses, 9 unit doses, 8 unit doses, 7 unit doses, 6 unit doses, 5 unit doses, 4 unit doses, 3 unit doses, 2 unit doses or 1 unit dose.C. Kits

[0175] Also provided herein are kits containing any unit dose described herein of an oligomeric agent (or salt thereof), e.g., ION224, that contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 12-40 nucleosides) having a nucleobase sequence targeting a nucleobase sequence of a DGAT2 nucleic acid, e.g., SEQ ID NO: 1 or 2. Further provided herein are kits containing any unit dose described herein of a composition, e.g., pharmaceutical composition, comprising or consisting of, or consisting essentially of, an oligomeric agent, e.g., ION224, having a sequence targeting a nucleobase sequence of a DGAT2 nucleic acid, e.g., SEQ ID NO: 1 or 2. In certain embodiments, a kit contains the unit dose and instructions for use of the unit dose. In certain embodiments, a kit contains the unit dose, instructions for use of the unit dose, and means for administering the unit dose. In certain embodiments, the instructions are for use in reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD (such as MASH). In certain embodiments, the instructions are for use in reducing the amount of DGAT2 RNA and / or DGAT2 protein in asubject having or at risk for MASH. In certain embodiments, the instructions are for use in in treating, or ameliorating one or more symptoms of, MASLD in a subject having or at risk for MASLD (such as MASH). In certain embodiments, the instructions are for use in in treating, or ameliorating one or more symptoms of, MASLD in a subject having or at risk for MASH.VI. Methods

[0176] In certain embodiments, methods described herein include administering an oligomeric agent (e.g., a unit dose) that contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) having a nucleobase targeting a DGAT2 nucleic acid, e.g., ION224, SEQ ID NO: 1 or SEQ ID NO: 2, to a cell or subject. In certain embodiments, the oligomeric agent is any such oligomeric agent described herein and / or containing any such oligonucleotide described herein. In certain embodiments, a certain dose of the oligomeric agent is administered to the cell or subject.

[0177] In certain embodiments, provided herein are methods of administering an oligomeric agent, e.g., ION224, that contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) having a nucleobase sequence targeting a DGAT2 nucleic acid, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, which include administering a certain dose (e.g, a unit dose) of the oligomeric agent to a cell or subject. In certain embodiments, the oligomeric agent is ION224. In certain embodiments, the dose of the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, is a fixed dose. In certain embodiments, the dose of the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, is a weight-based dose. Also provided herein are methods for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a cell or subject, including methods for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a cell or a subject having or at risk for MASLD, or for treating, and / or ameliorating at least one symptom of MASLD in, a subject having or at risk for MASLD, that include administering a certain dose (e.g., a unit dose) of such an oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, to the subject. In certain embodiments, the dose of the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, is a fixed dose. In certain embodiments, the dose of the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, is a weightbased dose.

[0178] In certain embodiments, the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, is contained in a composition such as a pharmaceutical composition, e.g., a pharmaceutical formulation. In certain embodiments, the composition contains a pharmaceutically acceptable carrier or excipient. In certain embodiments, thepharmaceutical composition consists of an oligomeric agent, ION224, SEQ ID NO: 1 , SEQ ID NO: 2, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the oligomeric agent comprises or consists of a modified oligonucleotide according to the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein the modified oligonucleotide is conjugated to a GalNAc3moiety comprising a trishexylamino N-acetyl galactosamine conjugate moiety.

[0179] In certain embodiments, ION224 is represented by the following chemical notation (5’ to 3’):GalNAc3o Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds AdsGds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1); wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, o = a phosphodiester internucleoside linkage, and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety:

[0180] In certain embodiments, the methods include administering ION224 (represented in certain embodiments by Structure 1). ION224, and compositions containing ION224, includes any salt (e.g., pharmaceutically acceptable salt) of ION224, e.g., potassium, calcium, magnesium, and sodium salts (see, e.g., Structure 2), ester of ION224, or salts of such esters.

[0181] In certain embodiments, methods include use of an oligomeric agent, e.g, ION224, SEQ ID NO: 1 , SEQ ID NO: 2, administered in a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition consists of, or consists essentially of, the oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of a sterile saline solution and the oligomeric agent, e.g., ION224. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of sterile water and the oligomeric agent, e.g., ION224. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, the pharmaceutical composition comprises, consists of, or consists essentially of the oligomeric agent, e.g., ION224, in 2mM phosphate buffered isotonic saline, pH 7.4. As described herein, a dose or quantity of an oligomeric agent, e.g., ION224, in milligrams indicates the mass of the free acid form of the oligomeric agent, e.g., ION224. In aqueous solution, the free acid is in equilibrium with anionic and salt forms. However, for the purpose of calculating dose or quantity, it is assumed that the oligomeric agent, e.g., ION224, exists as a solvent-free, sodium-acetate free, anhydrous, free acid. For example, where an oligomeric agent, e.g., ION224, is in solution comprising sodium (e.g., saline), the oligomeric agent, e.g., ION224, may be partially or fully de-protonated and in association with Na+ ions. However, the mass of the protons is nevertheless countedtoward the weight of the dose, and the mass of the Na+ ions are not counted toward the weight of the dose.

[0182] In certain embodiments, methods comprise use of a dose (e.g., a unit dose) of an oligomeric agent provided herein, in a quantity of the oligomeric agent, e.g., ION224, effective to, when administered to a cell or subject, decrease the amount of DGAT2 RNA and / or DGAT2 protein in the cell or subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) by at least 70%, at least 75%, at least 80%, at least 85% or at least 90% compared to the amount or level of DGAT2 RNA and / or DGAT2 protein prior to any administration of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2 in the cell or subject).

[0183] In certain embodiments, methods comprise use of a dose (e.g., a unit dose) of the oligomeric agent, e.g., ION224, in a quantity effective to treat, and / or ameliorate one or more symptoms of MASLD, such as hepatic steatosis, but does not significantly increase fibrosis in a subject having, or at risk for, MASLD, including, e.g., a subject having, or at risk for MASLD who has MASH. In certain embodiments, methods comprise use of the quantity of oligomeric agent, e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, but does not significantly alter (e.g., increase) hepatic fibrosis in a subject having, or at risk for, MASH, including, e.g., a subject having, or at risk for MASLD who has MASH. In certain embodiments, methods comprise use of the quantity of oligomeric agent, e.g., ION224, in the unit dose effective in treating, and / or ameliorating one or more symptoms of, MASLD, such as MASH resolution without worsening of fibrosis, improvement of MASH, without significantly altering (e.g., worsening) fibrosis levels in a subject having, or at risk for MASLD including, for example, a subject having, or at risk for, MASH. In certain embodiments, methods comprise use of a quantity of oligomeric agent e.g., ION224, in the unit dose effective in treating, and / or ameliorating one or more symptoms of, MASH, but does not significantly alter (e.g., increase) fibrosis in a subject having, or at risk for MASH, including, e.g., a subject having, or at risk for MASH who has advanced fibrosis. In certain embodiments, methods comprise use of an amount of oligomeric agent e.g., ION224, in the unit dose is effective in treating, and / or ameliorating one or more symptoms of, MASH, such as reducing liver fat, lowering steatosis or improvement in glycemic control, but does not significantly worsen fibrosis and / or increase fibrotic score in a subject having, or at risk for MASH, including, for example, a subject having, or at risk for MASH who has advanced fibrosis. In certain embodiments, methods comprise use of a quantity of oligomeric agent e.g., ION224, in the unit dose effective in treating, and / or ameliorating one or more symptoms of, MASH, e.g., improvement in fibrosis score by one or morestage, but does not significantly worsen steatohepatitis in a subject having, or at risk for MASH, including, e.g., a subject having, or at risk for MASLD who has advanced fibrosis (e.g., stage 2, 3 or 4).

[0184] In certain embodiments, methods comprise use of the quantity of oligomeric agent e.g., ION224, in the unit dose improves liver function, reduces liver fat, reduces steatosis, reduces liver fibrosis, reverses or attenuates MASH, and / or improves glycemic control in a subject having, or at risk for, MASLD (such as MASH). In certain embodiments methods comprise use of the quantity of oligomeric agent e.g., ION224, in the unit dose improves liver function, reduces liver fat, reduces steatosis, reduces liver fibrosis, reverses or attenuates MASH, and / or improves glycemic control in a subject having, or at risk for, MASH. In certain embodiments, methods comprise use of the quantity of oligomeric agent e.g., ION224, in the unit dose improves quality of life as assessed by patient reported outcomes of a subject having, or at risk for, MASLD. In certain embodiments, methods comprise use of the quantity of oligomeric agent e.g., ION224, in the unit dose decreases the level liver triglycerides, liver fat and / or improves liver lipid profile of a subject having, or at risk for, MASH compared to the level priorto administration of the unit dose, or to the baseline level in a subject before any administration of the oligomeric agent, e.g., ION224.

[0185] In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the unit dose is administered as a loading dose. In certain embodiments, administration of one or more loading dose is effective in achieving a desired condition in a subject, for example, a desired initial concentration of oligomeric agent, e.g., ION224. In certain embodiments, administration of the loading dose(s) is / are effective in decreasing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) compared to the amount or level of DGAT2 RNA and / or DGAT2 protein priorto administration of the loading dose of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2). In certain embodiments, administration of the loading dose(s) is more effective to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) than administration of a maintenance dose is to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein). In certain embodiments, administration of a loading dose(s) is effective in decreasing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver,blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) then administration of a maintenance dose is to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) in order to sustain the decreased amount or level of DGAT2 RNA and / or DGAT2 protein in the subject. In certain embodiments, methods comprise use of the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is greater than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose. In certain embodiments, methods comprise use of the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is less than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose. In certain embodiments, methods comprise use of the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose is the same quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose.

[0186] In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the unit dose is administered as a maintenance dose. In certain embodiments, administration of the maintenance dose is effective in maintaining a desired condition in a subject that results from administration of the loading dose. In certain embodiments, administration of the maintenance dose is effective in maintaining an amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) that is less than the amount or level of DGAT2 RNA and / or DGAT2 protein prior to administration of the loading dose of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2). In certain embodiments, administration of the maintenance dose is effective in maintaining an amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) that is about the same as the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose, that is less than the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose, or that is more than the amount or level of DGAT2 RNA and / or DGAT2 protein after administration of the loading dose but less than the amount or level of DGAT2 RNA and / or DGAT2 protein prior to administration of the loading dose of the oligomeric agent (e.g., the baseline or pre-administration level of DGAT2). In certain embodiments, methods comprise use of the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a maintenance dose is greater than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose. In certain embodiments, methods compriseuse of the quantity of the oligomeric agent, e.g., ION224, in a unit does that is a maintenance dose is less than the quantity of the oligomeric agent, e.g., ION224, in a unit dose that is a loading dose.

[0187] In certain embodiments methods comprise use of unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 75 mg to about 175 mg, about 80 mg to about 170 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 95 mg to about 155 mg, about 100 mg to about 150 mg, about 105 mg to about 145 mg, about 1 10 mg to about 140 mg, about 115 mg to about 135 mg, about 120 mg to about 130 mg, about 90 mg to about 120 mg, about 95 mg to about 120 mg, about 100 mg to about 120 mg, about 75 mg to about 1 15 mg, about 80 mg to about 110 mg, about 85 mg to about 105 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 125 mg, about 95 mg to about 120 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 1 15 mg to about 165 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 135 mg, about 135 mg to about 160 mg, or about 95 mg to about 100 mg. In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 75 mg to 175 mg, 80 mg to 170 mg, 85 mg to 165 mg, 90 mg to 160 mg,95 mg to 155 mg, 100 mg to 150 mg, 105 mg to 145 mg, 1 10 mg to 140 mg, 115 mg to 135 mg, 120 mg to 130 mg, 90 mg to 120 mg, 95 mg to 120 mg, 100 mg to 120 mg, 75 mg to 115 mg, 80 mg to 1 10 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 90 mg, 90 mg to 95 mg, 95 mg to 125 mg, 95 mg to 120 mg, 85 mg to 165 mg, 90 mg to 160 mg, 1 15 mg to 165 mg, 120 mg to 160 mg, 120 mg to 150 mg, 120 mg to 135 mg, 135 mg to 160 mg, or 95 mg to 100 mg.

[0188] In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is at least about 75 mg and less than 175 mg, at least about 75 mg and less than 170 mg, at least about 75 mg and less than 165 mg, at least about 75 mg and less than 160 mg, at least about 75 mg and less than 155 mg, at least about 75 mg and less than 150 mg, at least about 75 mg and less than 145 mg, at least about 75 mg and less than 140 mg, at least about 75 mg and less than 135 mg, at least about 75 mg and less than 130 mg, at least about 75 mg and less than 125 mg, at least about 75 mg and less than 120 mg, at least about 75 mg and less than 115 mg, at least about 75 mg and less than 1 10 mg, at least about 75 mg and less than 105 mg, at least about 75 mg and less than 100 mg, at least about 75 mg and less than 95 mg, at least about 20 mg and less than 90 mg, at least about 20 mg and less than 95 mg, at least about 80 mg and less than95 mg, at least about 85 mg and less than 95 mg, at least about 85 mg and less than 90 mg, at least about 90 mg and less than 95 mg, at least about 90 mg and less than 100 mg, at least about 90 mg and less than 105 mg, at least about 90 mg and less than 1 10 mg, at least about 90 mg and less than 1 15 mg, at least about 90 mg and less than 120 mg, at least about 90 mg and less than 125 mg, at least about 90 mg and less than 130 mg, at least about 90 mg and less than 135 mg, at least about 90 mg and less than 140 mg, at least about 90 mg and less than 145 mg, at least about 90 mg and less than 150 mg, at least about 90 mg and less than 155 mg, or at least about 90 mg and less than 160 mg.

[0189] In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is about 85 mg, about 90 mg, about 95 mg, about 1 15 mg, about120 mg, about 125 mg, about 150 mg, about 155 mg, about 160 mg, or about 165 mg. In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 1 10 mg, 1 15 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, or 175 mg. In certain embodiments of the unit doses of a composition provided herein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 85 mg, 90 mg, 95 mg, 1 15 mg, 120 mg, 125 mg, 150 mg, 155 mg, 160 mg, or 165 mg.

[0190] In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in a unit dose is within the range of about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 100 mg to about 160 mg, about 1 10 mg to about 160 mg, about 120 mg to about 160 mg, about 90 mg to about 145 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 120 mg, about 100 mg to about 120 mg, about 85 mg to about 1 15 mg, about 90 mg to about 1 10 mg, about 85 mg to about 105 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 125 mg, about 95 mg to about 120 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 115 mg to about 165 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 135 mg, about 135 mg to about 160 mg, or about 95 mg to about 100 mg. In certain embodiments of the unit doses of a composition providedherein, the quantity of the oligomeric agent, e.g., ION224, in the unit dose is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about or about 165 m. In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 155 mg, 160 mg, or 165 mg. In certain embodiments methods comprise use of the unit doses of a composition provided herein, wherein the quantity of the oligomeric agent, e.g., ION224, in the unit dose is 90 mg to 160 mg.Dosing Regimens

[0191] In certain embodiments, provided herein are methods (and compositions for use in the methods) of administering an oligomeric agent that contains a modified oligonucleotide (e.g., comprising a nucleobase sequence consisting of 16-30 nucleosides) having a nucleobase sequence targeting a DGAT2 nucleic acid, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, which include administering a quantity (e.g., dose, e.g., a unit dose) of the oligomeric agent, e.g., ION224, to a subject one time, at least two times, two or more times, or a plurality of times. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject more than once, e.g., at least two times or two or more times, and the administrations of the oligomeric agent are separated by a period of time in a dosing regimen. In certain embodiments, the doses of oligomeric agent, e.g., ION224, administered at separate times can be the same or different. In certain embodiments, the oligomeric agent is administered repeatedly for a certain period of time (e.g., treatment period or treatment duration). In certain embodiments, the oligomeric agent is administered repeatedly for an indeterminate period of time (e.g., no defined end time). In certain embodiments, the dose(s) (e.g., a unit dose) is / are any of the particular doses or amounts described herein. In certain embodiments, methods for (and compositions for use in the methods) of administering an oligomeric agent, e.g., ION224, provide a dosing regimen for reducing the level or amount of DGAT2 RNA and / or DGAT2 protein in a subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein). In certain embodiments, methods (and compositions for use in the methods) of administering an oligomeric agent, e.g., ION224, provide a dosing regimen for treating a subject having or at risk for MASLD, such as MASH. In certain embodiments, a subject has or is at risk for MASH.

[0192] In certain embodiments of the methods of administering an oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, to a subject, the subject has or is at risk for MASLD, such as MASH. In certain embodiments, the subject has or is at risk for advanced fibrosis. In certain embodiments, the subject is, or is at risk of being, susceptible to cirrhosis. In certain embodiments, the subject has liver dysfunction, diabetes, hypertension, hypertriglyceridemia, and / or fatty liver. In certain embodiments, the subject has or is at risk of having high body mass index or obesity.

[0193] In certain embodiments of methods of administering an oligomeric agent (e.g., a unit dose of an oligomeric agent) that contains a oligomeric agent e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered once every month. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered once every 4 weeks. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, is administered to a subject at an interval of once a month, an interval of once a quarter, or an interval of biannually. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, is administered to a subject at an interval of about once a week, an interval of about once every 2 weeks, an interval of about once every 3 weeks, an interval of about once every 4 weeks, an interval of about once every 5 weeks, or an interval of about once every 6 weeks. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 1 1 once every 12 weeks. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered once every 28 days. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered once every 84 days, once every 56 days, once every 30 days, once every 28 days, once every 20 days, or once every 14 days. In certain embodiments, the oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, or composition containing it, is administered at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times or more.

[0194] In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, administered according to any regimen described herein is within the range of about 75 mg to about 175 mg, about 80 mg to about 170 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 95 mg to about 155 mg, about 100 mg to about 150 mg, about 105 mg to about 145 mg, about 1 10 mg to about 140 mg, about 115 mg to about 135 mg, about 120 mg to about 130 mg, about 90 mg to about 120 mg, about 95 mg to about 120 mg, about 100 mg to about 120 mg, about 75 mg to about 115 mg, about80 mg to about 1 10 mg, about 85 mg to about 105 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 125 mg, about 95 mg to about 120 mg, about 85 mg to about 165 mg, about 90 mg to about 160 mg, about 1 15 mg to about 165 mg, about 120 mg to about 160 mg, about 120 mg to about 150 mg, about 120 mg to about 135 mg, about 135 mg to about 160 mg, or about 95 mg to about 100 mg. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, administered is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about or about 165 mg. In certain embodiments, the quantity of the oligomeric agent, e.g., ION224, administered is 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, or 165 mg. In any of the foregoing embodiments, the oligomeric agent, e.g., ION224, or composition containing it, can be administered by a syringe. In any of the foregoing embodiments, the oligomeric agent, e.g., ION224, or composition containing it, can be administered subcutaneously.

[0195] In certain embodiments of the methods of administering an oligomeric agent (e.g., a unit dose of an oligomeric agent) e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, the oligomeric agent, e.g, ION224, or composition containing it, is administered to a subject about once every 2 weeks for at least about 52 weeks, at least about 26 weeks, or at least about 13 weeks. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about once every 3 weeks for at least about 52 weeks, at least about 26 weeks, or at least about 13 weeks. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about once every 4 weeks for at least about 52 weeks, at least about 26 weeks, or at least about 13 weeks. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about once every 5 weeks for at least about 52 weeks, or at least about 26 weeks. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about every 6 weeks for at least about 52 weeks, at least about 26 weeks, or at least about 13 weeks. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about once every 4 weeks for an indeterminate period of time. In certain embodiments, administration of the oligomeric agent, e.g., ION224, is repeated monthly. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for at least about 3 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for at least about 6 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for at least about 9 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subjectonce a month for at least about 12 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for at least about 15 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for at least about 24 months. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject once a month for an indeterminate amount of time.

[0196] In certain embodiments of the methods of administering an oligomeric agent (e.g., a unit dose of an oligomeric agent) e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, the oligomeric agent, e.g., ION224, or composition containing it, is administered to a subject once about every 21 days, once about every 28 days, or once every 30 days. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject about every 21-28 days for at least about 90 days, at least about 120 days, at least about 180 days or at least about 365 days. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject every 28 days for at least about 90 days, at least about 120 days, at least about 180 days or at least about 365 days. In certain embodiments, the oligomeric agent, e.g., ION224, is administered to a subject every 28 days for an indeterminate period of time.

[0197] In certain embodiments, a method comprises administering to a subject about 90 mg of oligomeric agent, e.g., ION224, about once every 4 weeks. In certain embodiments, a method comprises administering to a subject 90 mg of oligomeric agent, e.g., ION224, once every 4 weeks. In certain embodiments a method comprises administering to a subject about 120 mg of oligomeric agent, e.g., ION224, about once every 4 weeks. In certain embodiments a method comprises administering to a subject 120 mg of oligomeric agent, e.g., ION224, once every 4 weeks. In certain embodiments a method comprises administering to a subject about 160 mg of oligomeric agent, e.g., ION224, subcutaneously about once every 4 weeks. In certain embodiments a method comprises administering to a subject 160 mg of oligomeric agent, e.g., ION224, subcutaneously once every 4 weeks. In certain embodiments a method comprises administering to a subject about 60 mg of oligomeric agent, e.g., ION224, subcutaneously about once every 4 weeks. In certain embodiments a method comprises administering to a subject 60 mg of oligomeric agent, e.g., ION224, subcutaneously once every 4 weeks.

[0198] In certain embodiments, methods comprise administering the oligomeric agent, e.g., ION224 (e.g., a unit dose of the oligomeric agent), for as long as required to decrease the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) to a desired level and / or to maintain a desired amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of thesubject, or the circulating level of DGAT2 RNA and / or DGAT2 protein). In certain embodiments, methods comprise administering the oligomeric agent, e.g., ION224 (e.g., a unit dose of the oligomeric agent), for as long as the subject needs treatment for, and / or amelioration of one or more symptoms of, MASLD, such as MASH.

[0199] In certain embodiments of the methods of administering an oligomeric agent, e.g., ION224 (e.g., a unit dose of the oligomeric agent), the method includes administration of first loading and subsequent maintenance doses of the oligomeric agent which are the same dose. In certain embodiments, the oligomeric agent (e.g., a unit dose), e.g., ION224, is administered one or more, at least two, two or more, or a plurality of times over a period of time (e.g., the treatment period). In certain embodiments, the quantity of oligomeric agent, e.g., ION224, administered each time is the same, i.e., the same dose is administered each time.

[0200] In certain embodiments, the quantity of oligomeric agent, e.g., ION224, at different time is not the same, i.e., different doses are administered at different times.For example, in certain embodiments, the quantity of oligomeric agent in the doses administered increases overtime or decreases overtime in the treatment period. In certain embodiments, a loading dose of the oligomeric agent, e.g., ION224, is administered at the start of treatment period and the dose reduces an amount or level of DGAT2 RNA and / or DGAT2 protein in the subject compared to the amount or level of DGAT2 RNA and / orDGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) prior to administration of the dose (e.g., a baseline or pre-administration amount or level of DGAT2 RNA and / or DGAT2 protein). The number of administrations of the oligomeric agent, e.g., ION224, during a period of time can vary depending on the desired outcome, for example, reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) or ameliorating one or more symptoms of MASLD in the subject. In certain embodiments, the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) decreases about 60%-90%, about 60%-89%, about 60%-85%, about 60%-80%, about 60%-75%, about 65%-90%, about 65%-89%, about 65%-85%, about 65%-80%, about 65%-75%, about 70%-90%, about 70%-89%, about 70%-85%, about 70%-80%, or about 70%-75% within about 2-3 weeks after administration of a dose compared to the amount or level of DGAT2 protein in the subject prior to any administration of the dose (e.g., the baseline amount or level). In certain embodiments, a dose of the oligomeric agent is administered to the subject one or more times during a treatmentperiod. In certain embodiments, a loading dose of oligomeric agent is administered once, or 2 times, 3 times, or 4 times, to achieve the desired reduced level of DGAT2 protein in the subject. In certain embodiments, subsequent maintenance dose(s) are regularly administered to maintain the effect. In certain embodiments, the same dose is administered each loading dose and each maintenance dose. In certain embodiments, different doses may be administered at different times in the loading treatment period, followed by same doses administered at same interval in the maintenance treatment period. In certain embodiments, the duration of the period of time (treatment period) is about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 24 months, about 2 years, about 3 years, about 4 years, or about 5 years or more. In certain embodiments, the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) decreases about 60%-90%, about 60%-89%, about 60%-85%, about 60%-80%, about 60%-75%, about 65%-90%, about 65%-89%, about 65%-85%, about 65%-80%, about 65%-75%, about 70%-90%, about 70%-89%, about 70%-85%, about 70%-80%, or about 70%-75% within about 2-3 weeks after administration of a first dose compared to the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject prior to administration of the first dose. In certain embodiments, the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) is maintained through the duration of the period of subsequently administered doses at about the same level as, or a lower level than, the level achieved about 2-3 weeks after the first administration of the dose of oligomeric agent. In certain embodiments, the oligomeric agent, e.g., ION224, or composition containing it, is administered parenterally. In certain embodiments, the oligomeric agent, e.g., ION224, is administered subcutaneously. In certain embodiments, a method comprises administering to a subject about 90 mg of ION224 subcutaneously about once every 4 weeks. In certain embodiments, a method comprises administering to a subject 90 mg of ION224 subcutaneously once every 4 weeks. In certain embodiments a method comprises administering to a subject about 120 mg of ION224 subcutaneously about once every 4 weeks. In certain embodiments a method comprises administering to a subject 120 mg of ION224 subcutaneously once every 4 weeks. In certain embodiments, a method comprises administering to a subject about 160 mg of ION224 subcutaneously about once every 4 weeks. In certain embodiments, a method comprises administering to a subject 160 mg of ION224 subcutaneously once every 4 weeks.

[0201] In certain embodiments of the methods (and compositions for use in the methods) of administering an oligomeric agent, e.g., a unit dose, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, a quantity of the oligomeric agent is administered as a loading dose and / or a maintenance dose. In certain embodiments, methods comprise administering one or more loading dose of the oligomeric agent, e.g., ION224, to a subject and subsequently administering one or more maintenance dose to the subject. In certain embodiments, the quantity of oligomeric agent in a loading dose and a maintenance dose is the same. In certain embodiments, the quantity of oligomeric agent in a loading dose and the quantity of oligomeric agent in a maintenance dose are different. In certain embodiments, the quantity of oligomeric agent in a loading dose is greater than the quantity of oligomeric agent in a maintenance dose. In certain embodiments, the quantity of oligomeric agent in a loading dose is less than the quantity of oligomeric agent in a maintenance dose. In certain embodiments, the quantity of oligomeric agent in each maintenance dose administered to a subject is the same. In certain embodiments, the quantity of oligomeric agent in two or more of the maintenance doses administered to a subject is not the same. In certain embodiments, the quantity of oligomeric agent in a maintenance dose administered to a subject two or more, or at least two, times differs and increases in one or more additional administrations given over time or decreases in one or more additional administrations given overtime.

[0202] In certain embodiments, methods comprise administering at least 1 loading dose, 2 loading doses, 3 loading doses, or4 loading doses of the oligomeric agent, e.g., ION224. In certain embodiments, methods comprise administering 1 , 2, or 3 loading doses of the oligomeric agent, e.g., ION224. In certain embodiments, methods comprise administering a loading dose of the oligomeric agent, e.g., ION224, about every day, every two days, every three days, every week, about every 2 weeks, or about every 3 weeks. In certain embodiments, methods comprise administering an initial loading dose of the oligomeric agent, e.g., ION224, and administering a second loading dose about 1 week after administering the initial loading dose. In certain embodiments, a first loading dose is the sole loading dose of the oligomeric agent.

[0203] In certain embodiments, methods comprise administering at least 1 maintenance dose, at least 2 maintenance doses, at least 3 maintenance doses, at least 4 maintenance doses, at least 5 maintenance doses, at least 6 maintenance doses of the oligomeric agent, at least 9 maintenance doses, at least 12 maintenance doses, at least 18 maintenance doses of the oligomeric agent, at least 24 maintenance doses, at least 36 maintenance doses, or at least 60 maintenance doses or more of the oligomeric agent e.g., ION224. In certain embodiments, methods comprise administering 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 18, 24, 36, or 60 maintenance doses of the oligomeric agent, e.g., ION224.In certain embodiments, methods comprise administering a maintenance dose of the oligomeric agent, e.g., ION224, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, or about once every 8 weeks. In certain embodiments, methods comprise administering a first maintenance dose of the oligomeric agent, e.g., ION224, and administering a second maintenance dose about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks after administering the first maintenance dose.

[0204] In certain embodiments, one or more maintenance doses of oligomeric agent, e.g., ION224, are administered to the subject during a period of time (e.g., a maintenance period) after administration of one or more loading doses. In certain embodiments, the period of time during which one or more loading doses is / are administered and the period of time during which one or more maintenance doses is / are administered overlap. In certain embodiments, the period of time during which one or more loading doses is / are administered and the period of time during which one or more maintenance doses is / are administered do not overlap. In certain embodiments, a maintenance dose is administered after the only or last loading dose is administered. The number of maintenance doses administered can vary depending on the desired outcome, for example, reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) or ameliorating one or more symptoms of MASLD in the subject. In certain embodiments, about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 or more maintenance doses are administered during the period of time. In certain embodiments, the duration of the period of time is about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 24 months, about 2 years, about 3 years, about 4 years, or about 5 years or more. In certain embodiments, the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, orthe circulating level of DGAT2 RNA and / or DGAT2 protein) decreases about 60%-90%, about 60%-89%, about 60%-85%, about 60%-80%, about 60%-75%, about 65%-90%, about 65%-89%, about 65%-85%, about 65%-80%, about 65%-75%, about 70%-90%, about 70%-89%, about 70%-85%, about 70%-80%, or about 70%-75% within about 2-3 weeks after administration of a loading dose compared to the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject prior to administration of the loading dose. In certain embodiments, the amount or level of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2RNA and / or DGAT2 protein) is maintained through the duration of the period of subsequently administered maintenance doses (e.g., the maintenance period) at about the same level as, or a lower level than, the level achieved about 2 weeks after administration of the loading dose(s). In certain embodiments, a method comprises administering to a subject a loading dose of about 90 mg of oligomeric agent, e.g., ION224, followed by one or more maintenance doses of about 90 mg each of oligomeric agent, e.g., ION224, about once every 4 weeks. In certain embodiments a method comprises administering to a subject a loading dose of about 120 mg of oligomeric agent, e.g., ION224, followed by one or more maintenance doses of about 120 mg each of oligomeric agent, e.g., ION224, about once every 4 weeks. In certain embodiments, a method comprises administering to a subject a loading dose of about 160 mg of oligomeric agent, e.g., ION224, followed by one or more maintenance doses of about 160 mg each of oligomeric agent, e.g., ION224, about once every 4 weeks.

[0205] In certain embodiments, methods comprise administering a loading dose of the oligomeric agent, e.g., ION224, once about every 2 weeks, and subsequently administering a maintenance dose of the oligomeric agent, e.g., ION224, once about every 4 weeks. In certain embodiments, methods comprise administering a loading dose once about every 4 weeks, and subsequently administering a maintenance dose once about every 4 weeks.

[0206] In certain embodiments, methods comprise administering a first maintenance dose or doses of the oligomeric agent, e.g., ION224, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks, after administering the last loading dose of the oligomeric agent, e.g., ION224.

[0207] In certain embodiments, methods comprise administering a loading dose of about 75 mg to about 175 mg of the oligomeric agent, e.g., ION224, in the same month as administering a maintenance dose of about 75 mg to about 175 mg of the oligomeric agent, e.g., ION224. In certain embodiments, the loading dose is about 75 mg, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 85 mg, 95 mg, 115 mg, 125 mg, 155 mg, 165 mg, or 170 mg of the oligomeric agent, e.g., ION224. In certain embodiments, the maintenance dose is about about 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 85 mg, 95 mg, 1 15 mg, 125 mg, 155 mg, 165 mg, or 170 mg of the oligomeric agent, e.g., ION224. In certain embodiments, the loading dose is about 90 mg of the oligomeric agent, e.g., ION224. In certain embodiments, a maintenance dose is about 90 mg of the oligomeric agent, e.g., ION224. In certain embodiments, a loading dose is about 120 mg of the oligomeric agent, e.g., ION224. In certain embodiments, a maintenance dose is about 120 mg of the oligomericagent, e.g., ION224. In certain embodiments, the loading dose is administered once in the first week and the maintenance dose is administered for as long as the subject needs treatment.

[0208] In certain embodiments of the methods (and compositions for use in the methods) of administering an oligomeric agent, e.g., ION224, SEQ ID NO: 1 , SEQ ID NO: 2, the oligomeric agent is administered to a subject more than once (e.g., two or more times or at least two times) over a certain time period or duration of treatment (e.g., treatment period). In certain embodiments, the quantity of the oligomeric agent in each dose administered over the time period and / or the frequency of administration of the oligomeric agent over time, or for a certain time period, may be adjusted or changed depending on certain factors. For example, in certain embodiments, the quantity of the oligomeric agent, e.g., ION224, in each dose administered over time (or the frequency of administration of oligomeric agent) may be increased or decreased, for example, in response to a clinical or laboratory parameter, in order to reduce, mitigate, alleviate or prevent undesired side effects or adverse effects, or based on a subject’s status. In certain embodiments of the methods (and compositions for use in the methods) of administering an oligomeric agent, e.g., ION224, the quantity, or dose, of the oligomeric agent administered to the subject at each administration is increased over time or for a certain time period. In certain embodiments of the methods (and compositions for use in the methods) of administering an oligomeric agent, e.g., ION224, the quantity of the oligomeric agent administered to the subject at each administration is decreased over time or for a certain time period.

[0209] In certain embodiments of the methods, a method includes administering a first quantity of an oligomeric agent, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2, to a subject one or more (e.g., two or more, at least two, or a plurality of) times for a first period of time followed by administering a second quantity of the oligomeric agent one or more times (e.g., two or more, at least two, or a plurality of unit doses) for a second period of time, wherein the second quantity is smaller than the first quantity (i.e., the second unit dose quantity is a lower dose than that of the first quantity). In certain embodiments, the first period of time and the second period of time do not overlap. In certain embodiments, a method comprises administering to a subject about 90 mg of the oligomeric agent, e.g., ION224, once every 4 weeks for a first period of time followed by administering to the subject about 120 mg mg of the oligomeric agent, e.g., ION224, once every 4 weeks for a second period of time. In certain embodiments, a method comprises administering to a subject about 120 mg of the oligomeric agent, e.g., ION224, once every 4 weeks for a first period of time followed by administering to the subject about 90 mg mg of the oligomeric agent, e.g., ION224, once every 4 weeks for a second period of time. Incertain embodiments, the first period of time and the second period of time do not overlap. In a certain embodiments, the first period of time is about 9 to about 13 weeks and the second period of time is about 9 to about 13 weeks, or the first period of time is about 21 to about 25 weeks and the second period of time is about 26 to about 52 weeks or an indeterminate period of time.VII. Therapy

[0210] In certain embodiments, methods and compositions are provided for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, such as MASH, MASH with fibrosis, MASH with advanced fibrosis or MASH with cirrhosis. Also provided herein are methods and compositions for treating, one or more symptoms of MASLD in a subject having or at risk for MASLD, such as MASH; as well as methods and compositions for ameliorating one or more symptoms of MASLD in a subject having or at risk for MASLD, such as MASH. In certain provided methods, the method includes administration of an oligomeric agent comprising a modified oligonucleotide having a nucleobase sequence targeting a DGAT2 nucleic acid, e.g., ION224., SEQ ID NO: 1 , SEQ ID NO: 2. In certain embodiments, the oligomeric agent comprises a cell-targeting ligand, that interacts with a receptor on the surface of a liver cell. In certain embodiments, the cell-targeting moiety contains a carbohydrate, e.g., N- acetyl galactosamine (GalNAc). In certain embodiments the method includes administering to a cell, tissue, or subject a unit dose of ION224; and in certain embodiments the composition comprises, consists essentially of or consists of a unit dose of ION224. In certain embodiments, the method includes administering a pharmaceutically acceptable carrier or excipient and the oligomeric agent, e.g., ION224. In certain embodiments, the composition comprises or consists of a pharmaceutically acceptable carrier or excipient and the oligomeric agent, e.g., ION224.

[0211] In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating, and / or ameliorating one or more symptoms of MASLD in, a subject having or at risk for MASLD, the MASLD is MASH. In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject has a hepatosteatosis. In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject has or is at risk for MASH. In certain embodiments of the methods andcompositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject has a increased liver fat. In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject has advanced fibrosis. In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject has diabetes. In certain embodiments of the methods and compositions for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions for treating a subject having or at risk for MASLD, the subject is overweight or has obesity.

[0212] In certain embodiments of the methods and compositions provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions provided herein for treating a subject having or at risk for MASLD, the amount of DGAT2 RNA and / or DGAT2 protein in a subject to whom (or in a cell to which) an oligomeric agent (or salt thereof), e.g., ION224 as described herein is administered is reduced. In certain embodiments, the amount of DGAT2 RNA and / or DGAT2 protein in the subject (e.g., the amount of DGAT2 protein in the liver, blood, serum or plasma of the subject, or the circulating level of DGAT2 RNA and / or DGAT2 protein) is decreased by at least 70%, at least 75%, at least 80%, at least 85% or at least 90% compared to the amount or level of DGAT2 RNA and / or DGAT2 protein prior to any administration of an oligomeric agent or ION224, or a composition containing it. In certain embodiments, the amount of oligomeric agent (or salt thereof), e.g., ION224 administered to the subject in the method is about 75 to about 175 mg, or about 80 to about 165 mg, or about 85 mg to about 155 mg, or about 90 to about 150 mg, or about 90 mg, or about 120 mg, or about 120 mg, or about 150 mg. In certain embodiments of the methods and compositions provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions provided herein for treating a subject having or at risk for MASLD, the oligomeric agent is ION224, or the composition contains ION224, or the method includes administering ION224 or a composition containing ION224. In certain embodiments, the composition consists of ION224 and a pharmaceutically acceptable carrier.

[0213] In certain embodiments of the methods and compositions provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods and compositions provided herein for treating asubject having or at risk for MASLD, the subject is, or is at risk of having increased liver fat or hepatis steatosis. In certain embodiments, the subject has insulin resistance, liver dysfunction, high liver enzymes (including, e.g., AST, ALT), hypertriglyceridemia, hypercholesterolemia, fatty liver, and / or liver disease. In certain embodiments, the subject has or is at risk of having hepatosteatosis, chronic liver disease, or cirrhosis. In certain embodiments, the subject has high body mass index, obesity, and / or hypertension. In certain embodiments, is not being treated concurrently with an anti-hypertensive treatment, and / or is not being treated concurrently with an SGLT2 inhibitor or GLP1 agonist. In certain embodiments, the subject is maintaining a healthy diet for MASLD. In certain embodiments, the subject is being treated with a dose and / or dosing regimen of an SGLT2 inhibitor or GLP1 agonist and / or a dose and / or dosing regimen of rezdiffra (resmetirom). In certain embodiments of the methods for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods for treating a subject having or at risk for MASLD, that include administration of an oligomeric agent, e.g., ION224 as described herein, the method is effective in treating, or ameliorating one or more symptoms of, MASLD, e.g., MASH, without causing worsening of fibrosis, or at risk for MASLD (such as MASH), or does not significantly alter (e.g., increase) hepatosteatosis levels in a subject having, or at risk for MASLD (such as MASH), or does not significantly increase fibrosis levels in a subject having, or at risk for MASLD (such as MASH).

[0214] In certain embodiments of the methods and compositions for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for, MASLD, or the methods and compositions for treating a subject having, or at risk for, MASLD, in which the method includes administration of (or the composition contains, consists essentially of, or consists of) an oligomeric agent (or salt thereof), e.g., ION224 as described herein, administration of the oligomeric agent, e.g., ION224 improves liver function, reduces fatty liver, reduces hepatosteatosis, reduces liver fibrosis, reverses or attenuates MASH, and / or increases glycemic control in the subject. In certain embodiments, administration of the oligomeric agent, e.g., ION224 improves MASH resolution without worsening fibrosis, improves fibrosis score without worsening hepatosteatosis, reduces liver fat, and / or improves quality of life as assessed by patient reported outcomes of a subject having, or at risk for, MASLD. In certain embodiments, administration of the oligomeric agent, e.g., ION224 improves MASH or resolves MASH of the subject. In certain embodiments, the level of liver enzymes, e.g., AST and / or ALT of a subject to whom the oligomeric agent, e.g., ION224, or a composition containing the oligomeric agent, e.g., ION224, is administered decreases compared to the baseline level prior to any administration of the oligomeric agent, e.g., ION224.

[0215] In certain embodiments of the methods provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods provided herein for treating, and / or ameliorating one or more symptoms of MASLD in, a subject having or at risk for MASLD, the method includes administering an oligomeric agent (or salt thereof), e.g., ION224 as described herein and no other active agent for the treatment of MASLD is administered to the subject for the duration of the oligomeric agent treatment period. In certain embodiments of the methods provided herein for reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD, or the methods provided herein for treating, and / or ameliorating one or more symptoms of MASLD in, a subject having or at risk for MASLD, the method includes administering an oligomeric agent (or salt thereof), e.g., ION224 as described herein and administering an additional active agent. In certain embodiments, the method includes administering an oligomeric agent, e.g., ION224 as described herein and administering a SGLT2 inhibitor for MASLD, e.g., MASH. In certain embodiments, the SGLT2 inhibitor is one or more of Brenzavv (bexaglifloxin), Invokana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), Steglatro (ertugliflozin). In certain embodiments, the method includes administering the oligomeric agent, e.g., ION224 to the subject as described herein and administering a GLP1 agonist for treatment of MASLD, e.g, MASH. In certain embodiments, the GLP1 agonist is one or more of Trulicity (dulaglutide) , Bydureon bcise (exenatide extended release), Byetta (exenatide), Ozempic (semaglutide), Victoza, Saxenda (liraglutide), Adlyxin (lixisenatide), Rybelsus (semaglutide). In certain embodiments, the method includes administering an oligomeric agent or ION224 as described herein and administering rezdiffra (resmetirom).

[0216] In certain embodiments of the methods and compositions for administering an oligomeric agent or ION224 provided herein, or the methods and compositions for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for, MASLD, or the methods and compositions for treating a subject having, or at risk for, MASLD, the method includes administering (or the composition contains, consists essentially of, or consists of) a quantity (or a dose, fixed dose, a unit dose) of the oligomeric agent (or salt thereof), e.g., ION224 within the range of about 75 mg to about 175 mg. In certain embodiments, the amount of oligomeric agent, e.g., ION224, is about 75 mg, or is about 80 mg, or is or is about 85 mg, or is or is about 90 mg, or is or is about 95 mg, or is or is about 100 mg, or is or is about 105 mg, or is or is about 110 mg, or is or is about 115 mg, or is or is about 120 mg, or is or is about 125 mg, or is or is about 130 mg, or is or is about 135 mg, or is or is about 140 mg, or is or is about 145 mg, or is or is about 150 mg, or is or is about 155 mg, or is or is about 160 mg, or is or is about 165 mg, or is or is about 170 mg, or is or is about 175 mg. In certainembodiments, the quantity of oligomeric agent (or salt thereof), e.g., ION224 is in a pharmaceutical composition. In certain embodiments, the pharmaceutical composition contains a pharmaceutically acceptable carrier or excipient. In certain embodiments, a composition contains, or consists of a pharmaceutically acceptable carrier and, about 90 mg or about 120 mg of the oligomeric agent, e.g., ION224. In certain embodiments, the quantity of oligomeric agent (or salt thereof), e.g., ION224 is in a unit dose form. In certain embodiments, the unit dose contains, or consists of a pharmaceutically acceptable carrier and, 75-175 mg, or 85-165 mg, or 90-160 mg, or 90-120 mg, or 120-160 mg of the oligomeric agent, e.g., ION224, or 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg, or 155 mg, or 160 mg, or 165 mg of the oligomeric agent, e.g., ION224. In certain embodiments, the unit dose is formulated for parenteral administration, e.g., subcutaneous administration, to a subject, such as a subject having or at risk for MASLD, such as MASH. In certain embodiments, a composition contains an oligomeric agent (or salt thereof), e.g., ION224 and another active agent. In certain embodiments, the method includes administering an oligomeric agent, e.g., ION224 as described herein and administering a SGLT2 inhibitor for MASLD, e.g., MASH. In certain embodiments, the SGLT2 inhibitor is one or more of Brenzaw (bexaglifloxin), Invokana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), Steglatro (ertugliflozin). In certain embodiments, the method includes administering the oligomeric agent, e.g., ION224 to the subject as described herein and administering a GLP1 agonist for treatment of MASLD, e.g., MASH. In certain embodiments, the GLP1 agonist is one or more of Trulicity (dulaglutide), Bydureon bcise (exenatide extended release), Byetta (exenatide), Ozempic (semaglutide), Victoza, Saxenda (liraglutide), Adlyxin (lixisenatide), Rybelsus (semaglutide). In certain embodiments, the method includes administering an oligomeric agent or ION224 as described herein and administering rezdiffra (resmetirom). In certain embodiments of the methods and compositions, the amount of the oligomeric agent (or salt thereof), e.g., ION224 administered in the method, or contained in the composition, is effective in treating, or ameliorating one or more symptoms of, MASLD, e.g., MASH, but does not significantly increase fibrosis or steatosis in the liver in a subject having, or at risk for MASLD (such as MASH), or does not significantly increase liver fat levels in a subject having, or at risk for MASLD (such as MASH), or but does not significantly alter liver enzyme homeostasis or increase fibrosis or steatosis levels in the liver in a subject having, or at risk for MASLD (such as MASH).

[0217] In certain embodiments of the methods for administering an oligomeric agent (or salt thereof), e.g., ION224 provided herein, or the methods for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for,MASLD, or the methods for treating a subject having, or at risk for, MASLD, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 times or more. In certain embodiments, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered once every 84 days, once every 56 days, once every 30 days, once every 28 days, or once every 21 days. In certain embodiments, the oligomeric agent, e.g., ION224, or composition containing it, is administered once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks. In certain embodiments, the oligomeric agent (or salt thereof), e.g., ION224 is administered over a period of about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 39 weeks, about 52 weeks, or more. In certain embodiments, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered about once every 4 weeks for at least about 13 weeks, at least about 17 weeks, at least about 21 weeks, at least about 25 weeks, at least about 26 weeks, at least about 27 weeks, at least about 29 weeks, at least about 33 weeks, at least about 37 weeks, at least about 41 weeks, at least about 45 weeks, at least about 49 weeks, at least about 52 weeks, or at least about 53 weeks. In certain embodiments, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered by a syringe. In certain embodiments, the oligomeric agent (or salt thereof) or ION224, or composition containing it, is administered subcutaneously.

[0218] In certain embodiments of the methods for administering an oligomeric agent (or salt thereof), e.g., ION224 provided herein, or the methods for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for, MASLD, or the methods for treating a subject having, or at risk for, MASLD, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered, concurrently with at least one other active agent. In certain embodiments, the at least one other active agent treats MASLD, e.g., MASH, or a symptom thereof. In certain embodiments, the oligomeric agent, e.g., ION224, is administered concurrently with the at least one other active agent to produce a combinational effect. In certain embodiments, the oligomeric agent, e.g., ION224, is administered concurrently with the at least one other active agent to produce a synergistic effect. Concurrent administration of an oligomeric agent, e.g., ION224, and at least one other active agent means the oligomeric agent, e.g., ION224, is administered and at least one other active agent is also administered to the subject. In certain embodiments, at least a period of time during the total treatment timeperiod (duration) comprises concurrent administration. In certain embodiments, concurrent administration of at least one other active agent spans the total treatment time period of the oligomeric agent, e.g., ION224. In certain embodiments, concurrent administration with at least one other active agent comprises at least one other active agent that is the same throughout concurrent administration. In certain embodiments, concurrent administration with at least one other active agent comprises at least one other active agent that change over concurrent administration.

[0219] In certain embodiments of concurrent administration, the oligomeric agent, e.g., ION224, and the at least one other active agent are administered simultaneously (i.e., within the same 24-hour period). In certain embodiments, the oligomeric agent, e.g., ION224, and the at least one other active agent may be contained together in a single formulation or composition, or may be separate compositions. In certain embodiments of concurrent administration, the oligomeric agent, e.g., ION224, and the at least one other active agent are administered sequentially (i.e., a first administration followed by a second administration). In certain embodiments administration is minutes apart. In some embodiments, administration is hours apart. In some embodiments administration is 1 , 2, 3, 4, or 5 hours apart. In some embodiments, administration is half a day or a day apart.

[0220] In certain embodiments, an active agent that may be administered concurrently with the oligomeric agent, e.g., ION224, is an SGLT2 inhibitor (SGLT2i, e.g., Brenzaw (bexaglifloxin), Invokana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), Steglatro (ertugliflozin)), a GLP1 agonist (e.g. Trulicity (dulaglutide), Bydureon bcise (exenatide extended release), Byetta (exenatide), Ozempic (semaglutide), Victoza, Saxenda (liraglutide), Adlyxin (lixisenatide), Rybelsus (semaglutide)), or rezdiffra (resmetirom), or combination of any of the agents.

[0221] In certain embodiments of the methods for administering an oligomeric agent (or salt thereof), e.g., ION224 provided herein, or the methods for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for, MASLD, or the methods for treating a subject having, or at risk for, MASLD, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, is administered, concurrently with rezdiffra (resmetirom). In certain embodiments, the oligomeric agent, e.g., ION224, and the rezdiffra (resmetirom) are administered simultaneously (i.e., within the same 24-hour period). In certain embodiments, the oligomeric agent, e.g., ION224, and the rezdiffra (resmetirom) are administered sequentially (i.e., more than 24 hours apart). In certain embodiments, the oligomeric agent, e.g., ION224, and the rezdiffra (resmetirom) or are administered in a single composition containing both molecules. Incertain embodiments, the oligomeric agent, e.g., ION224, and the rezdiffra (resmetirom) are administered in separate compositions.

[0222] In certain embodiments of the methods for administering an oligomeric agent (or salt thereof), e.g., ION224 provided herein, or the methods for reducing the amount or level of DGAT2 RNA and / or DGAT2 protein in a subject having, or at risk for, MASLD, or the methods for treating a subject having, or at risk for, MASLD, the oligomeric agent (or salt thereof), e.g., ION224, or composition containing it, are suitable for any patient population having or at risk for MASLD (e.g., MASH). In certain embodiments, such methods are particularly suitable for subjects having a mutation in PNPLA3. Rong et al. (Cell Metabolism 2024) demonstrated that inhibition of DGAT2 suppressed SREBP1 , resulting in reduction of PNPLA3 expression. Rong suggested that inhibitors of DGAT2 may be beneficial to those who carry a PNPLA3 mutation, e.g., mutation I148M, is associated with high prevalence of MASH, liver fibrosis and complications thereof. Thus, the compositions and methods are suitable for subjects having mutations in PNPLA3, e.g., PNPLA3 I148M. In certain embodiments, a subject is identified as having one or more mutation in PNPLA3. In certain embodiments a subject is heterozygous for a mutation in PNPLA3. In certain embodiments a subject is homozygous for a mutation in PNPLA3. In certain embodiments a PNPLA3 mutation is the rs738409 148M risk allele. In certain embodiments, a subject is identified as having one or more mutation including the rs738409 148M risk allele of PNPLA3. In certain embodiments a subject is heterozygous for the rs738409 148M risk allele in PNPLA3. In certain embodiments a subject is homozygous for the rs738409 148M risk allele in PNPLA3.Nonlimiting Disclosure and Incorporation by Reference

[0223] All documents, or portions of documents, cited in this application, including, but not limited to, literature publications, patent publications, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated-by- reference for the portions of the document discussed herein, as well as in their entirety.

[0224] While certain compounds, compositions, and methods have been described herein with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, ENSEMBL identifiers, and the like recited in the present application is incorporated herein by reference in its entirety.

[0225] The sequence listing accompanying this filing identifies each nucleic acid sequence as either “RNA” or “DNA” as required; however, one of skill in the art will readily appreciate that designation of “RNA” or “DNA” to describe modifiedoligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2’-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (i.e., 2’-OH in place of one 2’-H of DNA) or as an RNA having a modified base (i.e., thymine (5-methyl uracil) in place of an uracil of RNA); and certain nucleic acid compounds described herein comprise one or more nucleosides comprising modified sugar moieties having 2’-substituent(s) that are neither OH nor H. One of skill in the art will readily appreciate that labeling such nucleic acid compounds “RNA” or “DNA” does not alter or limit the description of such nucleic acid compounds.

[0226] Herein, the description of compounds as having “the nucleobase sequence of’ a SEQ ID NO. describes only the nucleobase sequence. Accordingly, absent additional description, such description of compounds by reference to a nucleobase sequence of a SEQ ID NO. does not limit sugar or internucleoside linkage modifications or presence or absence of additional substituents such as a conjugate group. Further, absent additional description, the nucleobases of a compound “having the nucleobase sequence of’ a SEQ ID NO. include such compounds having modified forms of the identified nucleobases as described herein.

[0227] Herein, the description of compounds by chemical notation (subscripts and / or superscripts to indicate chemical modifications) without reference to a specific Compound No. include only each noted modification, but may include additional substituents, such as a conjugate group, unless otherwise indicated. For example, the chemical notation of “AesTkomCezGdsCd” indicates a compound wherein the first nucleoside, which comprises a 2’-MOE sugar moiety (indicated by the “e” subscript) and an unmodified adenine nucleobase, is linked to the second nucleoside via a phosphorothioate linkage (indicated by the “s” subscript); the second nucleoside, which comprises a cEt sugar moiety (indicated by the “k” subscript) and an unmodified thymine nucleobase, is linked to the third nucleoside via a phosphodiester linkage (indicated by the “o” subscript); the third nucleoside, which comprises a 2 -MOE sugar moiety and a 5-methyl modified cytosine nucleobase (indicated by the “m” superscript), is linked to the fourth nucleoside via a mesyl phosphoramidate linkage (indicated by the “z” subscript); the fourth nucleoside, which comprises a 2’-p-D-deoxyribosyl sugar moiety (indicated by the “d” subscript) and an unmodified guanine nucleobase, is linked to the fifth nucleoside with a phosphorothioate linkage; and the fifth nucleoside comprises a 2’-p-D-deoxyribosyl sugar moiety and an unmodified cytosine nucleobase; and the compound may include additional substituents, such as a conjugate group.

[0228] Herein, where a specific compound (e.g., with reference to a Compound No.) is described by chemical notation, each nucleobase, sugar, and internucleosidelinkage of such specific compound is modified only as indicated. Accordingly, in the context of a description of a specific compound having a particular Compound No., “AesTeomCesGdsCd” indicates a compound wherein the first nucleoside, which comprises a 2’-MOE sugar moiety (indicated by the “e” subscript) and an unmodified adenine nucleobase, is linked to the second nucleoside via a phosphorothioate linkage (indicated by the “s” subscript); the second nucleoside and an unmodified thymine nucleobase, is linked to the third nucleoside via a phosphodiester linkage (indicated by the “o” subscript); the third nucleoside, which comprises a 2’-MOE sugar moiety and a 5-methyl modified cytosine nucleobase (indicated by the “m” superscript); the fourth nucleoside, which comprises a 2’-p-D-deoxyribosyl sugar moiety (indicated by the “d” subscript) and an unmodified guanine nucleobase, is linked to the fifth nucleoside with a phosphorothioate linkage; and the fifth nucleoside comprises a 2’-|3-D-deoxyribosyl sugar moiety and an unmodified cytosine nucleobase; and the compound does not include additional substituents. Herein, sugar, internucleoside linkage, and nucleobase modifications may be indicated within a nucleotide or nucleobase sequence (e.g., by superscript or subscript, as shown above) or may be indicated in text accompanying a sequence (e.g., in separate text that appears within or above or below a table of compounds).

[0229] Where a specific compound is described herein by way of a drawn chemical structure, each nucleobase, sugar, and internucleoside linkage of such a specific compound includes only the modifications indicated in the drawn chemical structure. One of skill will appreciate, however, that drawn compounds may exist in equilibrium between tautomeric forms and / or as salts in equilibrium with protonated or ionic forms. Drawn structures are intended to capture all such forms of such compounds.

[0230] While effort has been made to accurately describe compounds in the accompanying sequence listing, should there be any discrepancies between a description in this specification and in the accompanying sequence listing, the description in the specification and not in the sequence listing is the accurate description.

[0231] The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the1H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to:2H or3H in place of1H,13C or14C in place of12C,15N in place of14N,17O or18O in place of16O, and33S,34S,35S, or36S in place of32S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopicsubstitutions may make the compound suitable for research or diagnostic purposes such as imaging.EXAMPLES

[0232] 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.ION224

[0233] ION224 (previously known as ION769357) is an oligomeric compound comprising a chimeric, modified antisense oligonucleotide (ASO) targeted to DGAT2 pre- mRNA. The ASO is covalently conjugated to a conjugate group comprising a triantennary GalNAc, a high-affinity ligand for the hepatocyte-specific ASGPR, to form an ASO-GalNAc conjugate. This GalNAc conjugate approach results in enhanced ASO delivery to hepatocytes vs. non-parenchymal cells, thus achieving effective liver concentrations of the drug at lower doses. This increases ASO potency by approximately 10-fold in mice (Prakash et al. 2014) and 30-fold in humans (Crooke et al. 2018) compared to unconjugated ASOs. The ASO portion of ION224 is fully complementary to base-pair positions 26,377 - 26,396 bp within the second intronic region of human DGAT2 pre-mRNA (NC_000011.10) and binds to the RNA by Watson-Crick base pairing. The hybridization (binding) of ION224 to the cognate RNA results in DGAT2 pre-mRNA cleavage by the ribonuclease H1 (RNase H1 , a nonspecific endonuclease that catalyzes the cleavage of RNA via hydrolytic mechanism), thus preventing production of the DGAT2 protein. Antisense-mediated reduction of target mRNA levels is predictable and dose-dependent. Maximal inhibition of greater than 90% of control levels is typically achievable in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010). Furthermore, reduction in the target mRNA levels using this approach correlates directly with a subsequent reduction in target protein levels.

[0234] ION224 is a white to yellow solid. The pH of a 5% (w / v) aqueous solution of ION224 is 7.4. In accordance with USP definitions, ION224 is freely soluble in water and aqueous sodium acetate buffer (pH 3). ION224 injection was provided as a sterile solution with 0.8-mL deliverable volume in stoppered and sealed glass vials. The drug product formulation contained 100 mg / mL ION224 in 10 mM phosphate buffer and 2.5 mg / mL sodium chloride. The target pH is 7.4. The drug product is clear and colorless to yellow. The molecular formula of the ION224 sodium salt is: C296 H437 N77 Na2oOi56 P20 Si3Na2o In certain embodiments, the following chemical notation represents ION224:

[0235] GalNAc3o Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1), wherein A = an adenine, mC = a 5’-methyl cytosine G = a guanine, T = a thymine, e = a 2’-0-methoxyethyl modified nucleoside, d = a 2’-deoxynucleoside, and s = a phosphorothioate internucleoside linkage, and o = phosphodiester linkage. ION224 sodium salt is represented by the following chemical structure:(SEQ ID NO: 1).

[0236] The anion of ION224 may be represented by the following chemical structure:(SEQ ID NO: 1).Example 1: Effect oflON224 in Healthy Volunteers

[0237] A double blind, randomized, placebo-controlled phase 1 study of ION224 was conducted with healthy volunteers assessing safety and tolerability of ION224 in 4 single-ascending dose cohorts (40, 80, 120, and 160 mg). Following a screening period, eligible healthy participants were randomized to treatment (33 subjects treated with ION224 or placebo in a 3:1 randomization ratio) and received a single, subcutaneous (SC) dose of ION224 (or placebo) at day 1 , then followed. Subjects were evaluated for safety on Days 1 , 2, 4, 8, 15, 22, 29, 43, 57 and 85 after being dosed, and PK assessments followed almost the same schedule. The primary objective was to assess safety, tolerability, and pharmacokinetics (PK) of subcutaneously administered ION224. Duringthe first 24 hours after dosing, subjects were monitored by Holter to enable data acquisition for QT-PK analysis.

[0238] Following SC administration, ION224 was absorbed rapidly into the systemic circulation with a median Tmax of 2.00 to 3.00 hours. After reaching Cmax, plasma ION224 concentrations declined in a multi-phasic fashion, with an initial, relatively rapid disposition phase that dominated the plasma clearance, followed by a slower apparent elimination phase with a half-life of approximately 2 weeks. Mean peak (Cmax) and total exposure (AUC) were dose-dependent over the studied dose-range. Low renal clearance was observed for the first 24 hours post-dose suggesting that the initial plasma clearance is likely due to rapid tissue uptake and not excretion. Metabolism evaluation indicated the intact ION224 ASO to be the most abundant oligonucleotide (100%) in human plasma. No ION224 metabolites (1 , 2 or 3 GalNAc sugar deletions and unconjugated ION224) and no shortmer metabolites were detected in plasma.

[0239] Holter monitoring did not disclose any clinically significant changes in ECG parameters. ION224 demonstrated no clinically significant effects on QTc and had no clinically relevant effects on studied ECG parameters (HR, PR, QRS intervals, and QTcF). The concentration-QTc analysis demonstrated a flat slope for the relationship between ION224 plasma concentration and placebo-adjusted QTcF variation.

[0240] ION224 was well tolerated at all dose levels tested in the Phase 1 study. Overall, there were no differences between the treatment groups in clinical chemistry and no changes in hematology, coagulation, urinalysis, ECGs, or vital signs. No significant platelet count decrease was identified. Two subjects withdrew from the study unrelated to treatment and were replaced. There were 3 mild and 1 moderate TEAEs, all events resolved. No SAE was reported. One (1) subject in ION224 160-mg cohort had elevated platelet count on study Day 1 pre-dose, and platelet counts increased post-dose, remaining above lower limit of normal (LLN) through Day 29; however, the subject remained asymptomatic and no AE was reported. Two (2) subjects presented with ALT elevations > ULN pre-dose, and these mild elevations in ALT fluctuated during the study, with values remaining < 2 x ULN and both subjects were asymptomatic throughout the study. No other laboratory test displayed any abnormality, and no AE was reported.Example 2: Effects of ION224 in Subjects with Confirmed Non-Alcoholic Steatohepatitis

[0241] An adaptive, two part, double-blind, randomized, placebo-controlled phase 2 study of monthly subcutaneous administration of ION224 was conducted with subjects having confirmed non-alcoholic steatohepatitis to assess the safety, tolerability and efficacy of ION224. 160 subjects were enrolled in the study to receive ION224 orplacebo. In part 1 , approximately subjects were randomized 1 :1 :1 to one of 3 dose cohorts 60 mg, 90 mg, or 120 mg), then within each dose cohort, randomized 3:1 to receive ION224 or placebo. For part 2, subjects were randomized 1 :1 to one of 2 selected dose cohorts (90 mg or 120 mg), then in a 2:1 ratio to receive either ION224 or placebo within each cohort. See FIG 1.

[0242] Main criteria for subject inclusion were: (i) biopsy-proven MASH; (ii) NAS score of > 4; (iii) F1-3 (Part 1) and F2-3 (Part 2); (iv) MRI-PDFF>10%; (v) ALT / AST< 200 U / L; (vi) TBL< 1.3 mg / dL; (vii) HbA1c <9.5% and (viii) on stable doses of current drug(s) affecting lipid metabolism.

[0243] ION224 and matching placebo vials were provided to study sites. All doses were administered by SC injection by a qualified professional blinded to the identity of the drug. Vials contain 0.8 mL of 100 mg / mL ION224 or matching placebo. Vials were for single use only. SC injection volumes were 0.6, 0.9, and 1 .2 mL for Cohorts A, B, and C, respectively, with the 0.9 and 1 .2 mL dose (or any dose with a volume greater than 0.8 mL) given as 2 non-contiguous injections with half of the total volume. Criteria for selection of the 2 doses in Part 2 to further enroll subjects were: safety and tolerability of the doses, as well as efficacy as measured primarily by relative difference in percentage reduction of liver fat fraction assessed by MRI-PDFF (reduction in liver steatosis), and secondarily by the magnitude of plasma ALT / AST reduction. Subjects were requested to maintain his / her diet and exercise routine throughout the study. During the screening period subjects submitted to an MRI-PDFF to assess liver fat content. MRIs were conducted using standardized procedures and settings and evaluated by an independent central reader. Baseline transient elastography were performed by fibroscan analysis to assess liver tissue attenuation and stiffness using standard methodology. Additionally, ALT / AST and total bilirubin (TBL) were collected at least 2 weeks apart. If a historical liver biopsy (within 6 months of screening) was not available, liver biopsy was performed during the screening period after the qualifying MRI-PDFF to confirm eligibility.

[0244] The primary objective of the study was to assess the effects of multiple ION224 doses when administered subcutaneously (SC) for 49 weeks on non-alcoholic steatohepatitis (NASH) histologic improvement, i.e., the proportion of subjects achieving at least a 2-point reduction in NAFLD Activity Score (NAS) at the end of treatment, with at least 1 -point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis. Additional objectives included assessment of the effects of multiple SC doses of ION224 on the proportion of subjects achieving NASH resolution, as defined by a score of 0 for ballooning and a score of 0 or 1 for inflammation by the NAS, and without worsening of fibrosis, as assessed through liver biopsy; identification of the proportion of subjects achieving reduction of at least 1 stage in the fibrosis score, andwithout worsening of steatohepatitis by the NAS, assessed through liver biopsy; changes in liver steatosis by magnetic resonance imaging-derived proton density fat fraction (MRI- PDFF); liver biochemistry tests, including transaminases and plasma lipid profile; as well as additional changes in NASH histologic features at the end of treatment, including, e.g., transient elastography parameters, indices of glycemic control, including HbA1c, body weight and BMI; and to assess the safety and tolerability of ION224.

[0245] Table 1 depicts demographics and baseline MASH characteristics of subjects in the study, consistent with adults with confirmed MASH. Table 2 depicts baseline cardiovascular risk characteristics of subjects, consistent with adults with confirmed MASH.TABLE 1 :Demographics and Baseline MASH Characteristics of SubjectsTABLE 2: Baseline Cardiovascular Risk Characteristics

[0246] All subjects returned to the study site at the pre-specified time points in the schedule of procedures for imaging, safety and laboratory assessments. These included samples for PK analysis, chemistry, blood coagulation, hematology, urinalysis, adverse event reporting and concomitant medication usage. Additional blood tests including lipids and exploratory biomarkers were collected. The pharmacodynamic effect of multiple SC doses of ION224 for 49 weeks was assessed by: the proportion of subjects achieving at the end of treatment at least 2-point reduction in NAFLD activity score (NAS) with at least 1 -point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis. Results were compared with those from subjects dosed with placebo.

[0247] Further pharmacodynamic effects following multiple ION224 doses when administered SC were assessed by: change from baseline in hepatic fat content measurement as evaluated by MRI-PDFF and calculated by an independent, blinded-to- treatment, central reader; the proportion of subjects achieving, at the end of treatment, NASH resolution, as defined by a score of 0 for ballooning and a score of 0 or 1 for inflammation by the NAS, and without worsening of fibrosis, assessed through liver biopsy; the proportion of subjects achieving at the end of treatment, reduction of at least 1 stage in the fibrosis score, and without worsening of steatohepatitis by the NAS, assessed through liver biopsy; the proportion of subjects achieving, at the end of treatment, a combination of NASH resolution and a 1 stage improvement in fibrosis; the proportion of subjects with ALT and AST < 1 .5 ULN at the end of treatment; the absolute and percent changes from baseline in liver-related laboratory tests, including ALT, AST, bilirubin, and gamma-glutamyl transferase; and the absolute and percent changes from baseline inplasma fasting lipid profile (such as TG, total cholesterol, low-density lipoproteincholesterol [LDL-c], and high-density lipoprotein-cholesterol [HDL-c]). Additional exploratory endpoints included measurements of absolute and percent changes over time in potential biomarkers of DGAT2 activity reduction and NASH improvement following multiple SC ION224 doses; potential exposure-response analysis using relevant exposure parameters and biomarkers and / or clinical outcomes, as appropriate; changes over time from baseline in hepatic transient elastography parameters: controlled attenuation and tissue stiffness; changes over time from baseline in indices of glycemic control including HbA1c; and changes over time from baseline in body weight and body mass index.

[0248] Pharmacokinetics following multiple SC doses were evaluated by changes over time in selected plasma post-treatment concentrations of ION224 (as a total full-length ASO, including fully conjugated, partially conjugated, and unconjugated ION224) and metabolites. PK parameters included maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve (AUC), and plasma half-life (ty2). Results are presented in Example 3 below.

[0249] Following study completion and data analysis, ION224 was found to demonstrate a higher proportion of subjects achieving the primary endpoint of MASH resolution without worsening of fibrosis. There was approximately twenty percent (20%) improvement in fibrosis as compared to placebo. See FIG2A-C. The proportion of participants (PPS) achieving a combination of MASH resolution and at least 1 stage improvement in fibrosis at the end of treatment was 17.9% for the 90 mg group (N = 39) and 14.7% for the 120 mg group (N = 34) vs 6.3% for the pooled placebo group (N = 32). The differences compared to placebo were not statistically significant.

[0250] In addition, treatment with ION224 achieved MASH resolution without worsening of steatohepatitis (NAS) in patients with F2 and F3 Fibrosis. See FIG 3A-B. The improved effects from ION224 treatment were observed in measures of both a reduction in ballooning as well as a reduction in inflammation after treatment. See FIG 3C. The improvements in liver steatosis seen in ION224 treated patients were dose dependent and consistent increases in improvement demonstrated over time. See FIG 3D-E. In those subjects who had higher baseline ALT / AST levels at the outset of the study, treatment with higher dose of ION224 (120 mg) demonstrated reductions in ALT / AST, and there was a significant correlation between improvement in steatosis and enzyme reductions. See FIG 3F. Furthermore, a higher proportion of subjects treated with ION224 achieved greater than fifty percent (50%) relative reduction in liver fat and significant lowering of steatosis.

[0251] Patients in all treatment groups demonstrated good glycemic control at baseline, with HbA1 c values ranging from 6.5%-6.9%. While glycemic control worsenedover the course of the study in the placebo group (mean absolute change from baseline of +0.3% for HbA1c), a dose-responsive improvement in HbA1c values was observed in the ION224 treatment groups, with a placebo-adjusted reduction (LSM difference) of - 0.1%, -0.3%, and -0.4% at 60mg, 90 mg and 120 mg dosing groups, respectively.

[0252] The enhanced liver fibrosis score (ELF) scores showed a significant reduction in the absolute change from baseline of the 120 mg ION224 treated group at Day 386 with a difference in LSM of -0-41 (p = 0.013), these changes were correlated with reductions in ALT and liver steatosis by MRI-PDFF.

[0253] ION224 was well tolerated throughout the study, with a favorable safety profile (consistent with results from the Phase 1 study), as no safety concerns related to liver, kidney or platelets were raised, the ALT / AST profiles did not worsen over time, and no Gl side effects were identified. A lower rate of early termination of study participants for ION224 treated subjects as compared to those receiving placebo, with the majority of early terminations not associated with adverse events. See Table 3. Furthermore, overall, in subjects treated with ION224 HbA1c was improved and no hypertriglyceridemia, worsening lipids or body weight changes were evidenced.TABLE 3:ION224CS2 Subject Disposition

[0254] Thus, results from the Phase 2 study provide strong data supporting potential for histological benefit of ION224 treatment of liver disease, including MASLDand MASH, as supported by i. significant effects on NAS improvement, leading to MASH resolution without worsening fibrosis; ii. lowering steatosis translating to fibrosis improvement; iii. dose dependent, consistently increased and improved effects on hepatic steatosis over treatment time. ION224 is safe and tolerable and provides convenience of injections about once every four weeks. Further, the unique targeting of DGAT2 provides a unique mechanism amenable to combination with several other therapies. Additionally ION224 has the potential for use in targeted populations of MASH patients due to the established link between DGAT2 inhibition and PNPLA3 suppression (Rong et al 2024, Cell Metabolism), proving a unique precision medicine approach to target MASH patients with PNPLA3 risk alleles.Example 3: Effects of ION224 in Subjects with Confirmed Non-Alcoholic Steatohepatitis, secondary pharmacokinetic endpoints

[0255] Pharmacokinetics following multiple SC doses of patients enrolled in the study described in Example 2 were evaluated by changes over time in selected plasma post-treatment concentrations of ION224 (as a total full-length ASO, including fully conjugated, partially conjugated, and unconjugated ION224) and metabolites. PK parameters included maximum observed plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration-time curve (AUC). Results are presented in Table 4 below.TABLE 4:Summary of Plasma ION224 Pharmacokinetic Parameters by Treatment After a Single DoseCV - coefficient of variation; N = number of subjects.

Claims

WHAT IS CLAIMED IS:

1. A method of treating metabolic dysfunction associated steatotic liver disease (MASLD) in a subject in need thereof comprising administering to the subject about 75 mg to about 175 mg of a DGAT2 oligomeric compound; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

2. Use of about 75 mg to about 175 mg of an oligomeric compound or a salt thereof in the manufacture of a medicament for treating MASLD in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

3. Use of about 75 mg to about 175 mg of an oligomeric compound or a salt thereof for treating MASLD in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCdsTeo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

4. A method for reducing DGAT2 RNA and / or DGAT2 protein in a subject, comprising administering 75 mg to 175 mg of an oligomeric compound or salt thereof to a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3- conjugated modified oligonucleotide, wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’): Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

5. Use of 75 mg to 175 mg of an oligomeric compound or a salt thereof for reducing DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASLD; wherein the oligomeric compound is a GalNAc3-conjugated modified oligonucleotide,wherein the modified oligonucleotide is represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof; wherein: A - an adenine nucleobase, mC — a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

6. The method or use of any one of claims 1-5, wherein the oligomeric compound is represented by the following chemical notation (5’ to 3’):GalNAc3o Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 1); wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

7. The method or use of any one of claims 1-6, wherein the oligomeric compound is represented by the following Structure 1 :(SEQ ID NO: 1) or a salt thereof.

8. The method or use of any one of claims 1-7, wherein the oligomeric compound is a sodium salt or a potassium salt.

9. The method or use of any one of claims 1-8, wherein the oligomeric compound is a sodium salt represented by the following Structure 2:(SEQ ID NO: 1).

10. The method or use of any one of claims 1 -9, wherein the amount of DGAT2 protein in the liver of the subject is reduced compared to the baseline amount of DGAT2 protein in the subject prior to any administration of the oligomeric compound or salt thereof.1 1 . The method or use of any one of claims 10, wherein the amount of DGAT2 RNA and / or DGAT2 protein is decreased by at least 70%, at least 75%, at least 80% at least 85% or at least 90% compared to the baseline amount of DGAT2 RNA and / or DGAT2 protein in the subject prior to any administration of the oligomeric compound or salt thereof.

12. The method or use of any one of claims 1-1 1 , wherein the subject has or is at risk for metabolic dysfunction associated steatohepatitis (MASH), liver fibrosis, advanced liver fibrosis, or cirrhosis.

13. The method or use of claim 12, wherein the subject has one or more of: MASH without cirrhosis, MASH with advanced liver fibrosis, liver stiffness, liver fibrosis, and cirrhosis.

14. The method or use of claim 12, wherein the subject has one or more of: diabetes, high body mass index, obesity, high HbA1C, dyslipidemia, high cholesterol, high triglycerides, hypertension and inflammation.

15. The method or use of any one of claims 1-14, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of the oligomeric compound or salt thereof within the range of about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 165 mg, about 75 mg to about 160 mg, about 75 mg to about 155 mg, about 75 mg to about 150 mg, about 75 about 75 mg to about 145 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg, about 75 mg to about 1 15 mg, about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 80 mg to about 95 mg, about 85 mg to about 95 mg, about 90 mg to about 95 mg, about 80 mg to about 125 mg, about 85 mg to about 175 mg, about 85 mg to about 170 mg, about 85 mg to about 165 mg, about 85 mg to about 160 mg, about 85 mg to about 155 mg, about 85 mg to about 150 mg, about 85 to about 145 mg, about 85 mg to about 140 mg, about 85 mg to about 130 mg, about 85 mg to about 125 mg, about 85 mg to about 120 mg, about 85 mg to about 1 15 mg, about 85 mg to about 110 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 95 mg, about 85 mg to about 125 mg, about 90 mg to about 125 mg, about 95 mg to about 125 mg, about 100 mg to about 125 mg, about 1 15 mg to about 125 mg, about 1 15 mg to about 120 mg, about 120 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 1 15 mg, about 95 mg to about 1 10 mg, about 95 mg to about 105 mg, about 95 mg to about 100 mg, about 100 mg to about 120 mg, about 100 mg to about 1 15 mg, about 100 mg to about 110 mg, about 100 mg to about 105 mg, about 105 mg to about 120 mg, about 105 mg to about 115 mg, about 105 mg to about 1 10 mg, about 110 mg to about 120 mg, about 1 10 mg to about 1 15 mg, about 115 mg to about 120 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 105 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 85 mg to about 120 mg, about 90 mg to about 95 mg, about 85 mg to about 105 mg, about 85 mg to 100 mg, 85 mg to about 95 mg, about 85 mg to about 1 15 mg, about 85 mg to about 90 mg, about 85 mg to about 95 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 165 mg, about 90 mg to about 160 mg, about 90 mg to about 155 mg, about 90 mg to about 150 mg, about 90 to about 145 mg .about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 1 15 mg, about 120 mg to about 175 mg, about 125 mg to about 175 mg, about 130 mg to about 175 mg, about140 mg to about 165 mg, about 150 mg to about 165 mg, about 150 mg to about 160 mg, or about 160 mg to about 165 mg.

16. The method or use of any one of claims 1-14, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of at least about 50 mg and less than about 150 mg, at least about 75 mg and less than about 150 mg, at least about 75 mg and less than about 140 mg, at least about 75 mg and less than about 130 mg, at least about 75 mg and less than about 125 mg, at least about 75 mg and less than about 120 mg, at least about 75 mg and less than about 1 15 mg, at least about 75 mg and less than about 1 10 mg, at least about 75 mg and less than about 100 mg, at least about 75 mg and less than about 95 mg, at least about 80 mg and less than about 95 mg, at least about 85 mg and less than about 95 mg, at least about 90 mg and less than about 95 mg, at least about 80 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 90 mg and less than about 125 mg, at least about 95 mg and less than about 125 mg, at least about 100 mg and less than about 125 mg, at least about 1 15 mg and less than about 125 mg, at least about 1 15 mg and less than about 120 mg, at least about 120 mg and less than about 125 mg, at least about 90 mg and less than about 120 mg, at least about 95 mg and less than about 1 15 mg, at least about 95 mg and less than about 110 mg, at least about 95 mg and less than about 105 mg, at least about 95 mg and less than about 100 mg, at least about 100 mg and less than about 120 mg, at least about 100 mg and less than about 115 mg, at least about 100 mg and less than about 110 mg, at least about 100 mg and less than about 105 mg, at least about 105 mg and less than about 120 mg, at least about 105 mg and less than about 1 15 mg, at least about 105 mg and less than about 1 10 mg, at least about 1 10 mg and less than about 120 mg, at least about 110 mg and less than about 1 15 mg, at least about 1 15 mg and less than about 120 mg, at least about 80 mg and less than about 120 mg, at least about 80 mg and less than about 110 mg, at least about 80 mg and less than about 105 mg, at least about 80 mg and less than about 100 mg, at least about 80 mg and less than about 95 mg, at least about 80 mg and less than about 90 mg, at least about 85 mg and less than about 90 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 120 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 105 mg, at least about 85 mg and less than 100 mg, at least about 85 mg and less than about 95 mg, at least about 85 mg and less than about 1 15 mg, at least about 85 mg and less than about 90 mg, or at least about 85 mg and less than about 95 mg of the oligomeric compound or salt thereof.

17. The method or use of claim 16, wherein administering or use of the oligomeric compound or salt thereof comprises administering or use of a fixed dose of 75 mg to 150 mg, 75 mg to 140 mg, 75 mg to 130 mg, 75 mg to 125 mg, 75 mg to 120 mg, 75 mg to 115 mg, 75 mg to 110 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85 mg, 75 mg to 80 mg, 80 mg to 85 mg, 80 mg to 125 mg, 85 mg to 125 mg, 90 mg to 125 mg, 95 mg to 125 mg, 100 mg to 125 mg, 105 mg to 125 mg, 110 mg to 125 mg, 115 mg to 125 mg, 120 mg to 125 mg, 115 mg to 120 mg, 90 mg to 120 mg, 95 mg to 115 mg, 95 mg to 110 mg, 95 mg to 105 mg, 95 mg to 100 mg, 100 mg to 120 mg, 100 mg to 115 mg, 100 mg to 110 mg, 100 mg to 105 mg, 105 mg to 120 mg, 105 mg to 115 mg, 105 mg to 110 mg, 110 mg to 120 mg, 110 mg to 115 mg, 115 mg to 120 mg, 80 mg to 120 mg, 80 mg to 110 mg, 80 mg to 105 mg, 80 mg to 100 mg, 80 mg to 95 mg, 80 mg to 90 mg, 85 mg to 90 mg, 90 mg to 95 mg, 85 mg to 120 mg, 90 mg to 95 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 115 mg, 85 mg to 90 mg, or 85 mg to 95 mg of the oligomeric compound or salt thereof.

18. The method or use of claim 15, wherein the administering or use comprises administering or use of a fixed dose of the oligomeric compound or salt thereof within the range of about 80 mg to about 130 mg, about 85 mg to about 130 mg, about 90 mg to about 130 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, or about 85 mg to about 95 mg.

19. The method or use of claim 16, wherein administering or use comprises administering or use of a fixed dose of about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof.

20. The method or use of claim 17, wherein the administering or use comprises administering or use of a fixed dose of 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or salt thereof.21 . The method or use of claim 19, comprising administering or use of a fixed dose of about 85 mg of the oligomeric compound or salt thereof.

22. The method or use of claim 19, comprising administering or use of a fixed dose of about 90 mg of the oligomeric compound or salt thereof.

23. The method or use of claim 19, comprising administering or use of a fixed dose of about 95 mg of the oligomeric compound or salt thereof.

24. The method or use of claim 19, comprising administering or use of a fixed dose of about 100 mg of the oligomeric compound or salt thereof.

25. The method or use of claim 19, comprising administering or use of a fixed dose of about 115 mg of the oligomeric compound or salt thereof.

26. The method or use of claim 19, comprising administering or use of a fixed dose of about 120 mg of the oligomeric compound or salt thereof.

27. The method or use of claim 19, comprising administering or use of a fixed dose of about 125 mg of the oligomeric compound or salt thereof.

28. The method or use of claim 20, comprising administering or use of a fixed dose of 80 mg to 125 mg of the oligomeric compound or salt thereof.

29. The method or use of claim 20, comprising administering or use of a unit dose of 85 mg of the oligomeric compound or salt thereof.

30. The method or use of claim 20, comprising administering or use of a fixed dose of 90 mg of the oligomeric compound or salt thereof.31 . The method or use of claim 20, comprising administering or use of a fixed dose of 95 mg of the oligomeric compound or salt thereof.

32. The method or use of claim 20, comprising administering or use of a fixed dose of 100 mg of the oligomeric compound or salt thereof.

33. The method or use of claim 20, comprising administering or use of a fixed dose of 110 mg of the oligomeric compound or salt thereof.

34. The method or use of claim 20, comprising administering or use of a fixed dose of 115 mg of the oligomeric compound or salt thereof.

35. The method or use of claim 20, comprising administering or use of a fixed dose of 120 mg of the oligomeric compound or salt thereof.

36. The method or use of claim 20, comprising administering or use of a fixed dose of 125 mg of the oligomeric compound or salt thereof.

37. The method or use of any one of claims 1-36, wherein the oligomeric compound or salt thereof is ION224 or a salt thereof.

38. The method of any one of claims 1-37, wherein the oligomeric compound or salt thereof is administered once about every 4 weeks or once about every 28 days.

39. The method of any one of claims 1-37, wherein the oligomeric compound or salt thereof is administered at an interval of about once a month, about once every two months, or about once every three months.

40. The method of any one of claims 1-37, wherein the oligomeric compound or salt thereof is administered about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, or about once every 10 weeks.41 . The method or use of any one of claims 1-40, wherein administering or use comprises administering or use of a fixed dose of 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 10 mg, 1 15 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or salt thereof once every 3 weeks, once every 4 weeks, once every 5 weeks or once every 6 weeks.

42. The method or use of any one of claims 1 -40, wherein administering or use comprises administering or use of a fixed dose of about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof once about every 3 weeks, once about every 4 weeks, once about every 5 weeks or once about every 6 weeks, wherein the oligomeric compound is formulated for parenteral administration.

43. The method or use of claim 42, wherein administering or use comprises administering or use of a fixed dose of 90 mg or about 90 mg, or 120 mg or about 120 mg of the oligomeric compound or salt thereof once every 28 days or about every 28 days, oronce every 4 weeks or about every 4 weeks, or once a month or about once a month, wherein the oligomeric compound is formulated for subcutaneous administration.

44. The method or use of claim 42, wherein administering or use comprises administering or use of a fixed dose of about 90 mg or about 120 mg of the oligomeric compound or salt thereof once about every 28 days or once about every 4 weeks, or once about every month, wherein the oligomeric compound is formulated for subcutaneous administration.

45. The method or use of any one of claims 1-44, wherein the oligomeric compound or salt thereof comprises administering or use of a loading dose.

46. The method or use of claim 45, wherein the administering or use comprises one or more maintenance doses of the oligomeric compound or salt thereof.

47. The method or use of claim 46, wherein the loading dose comprises a greater amount of the oligomeric compound or salt thereof than a maintenance dose.

48. The method or use of claim 46, wherein the loading dose and the maintenance dose comprises the same amount of the oligomeric compound or salt thereof.

49. The method or use of any one of claims 1 -48, wherein the administration or use of the oligomeric compound or salt thereof is effective to decrease the amount of DGAT2 RNA and / or DGAT2 protein in the subject by at least 70%, at least 75%, at least 80%, or at least 85% compared to the baseline amount of DGAT2 RNA and / or DGAT2 protein in the subject prior to any administration or use of the oligomeric compound or salt thereof.

50. The method or use of any one of claims 1-49, wherein the oligomeric compound or salt thereof is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

51. The method or use of claim 50, wherein the pharmaceutical composition comprises water, saline, or phosphate buffered isotonic saline, pH 7.4.

52. The method or use of any one of claims 1-51 , wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered parenterally.

53. The method or use of claim 52, wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered subcutaneously or intravenously.

54. The method or use of claim 53, wherein the oligomeric compound or salt thereof, or pharmaceutical composition is administered by a syringe, optionally by an autoinjector device.

55. The method or use of any one of claims 1-54, wherein such method or use is effective to treat MASH and / or ameliorate one or more symptoms of MASH, but does not significantly increase fibrosis and / or worsen steatohepatitis in a subject having, or at risk for, MASH.

56. The method or use of claim 55, wherein such method or use improves hepatocellular ballooning or lobular inflammation, reduces at least one stage in the fibrosis score, reduces liver steatosis, reverses or attenuates MASH histologic features, improves liver biochemistry tests, improves plasma lipid profile, improves indices of glycemic control, improves HbA1c, improves BMI, and / or improves quality of life in the subject having, or at risk for, MASH.

57. A method of treating MASH in a subject, comprising administering a fixed dose of 80 mg to 130 mg of an oligomeric compound or a salt thereof to a subject; wherein administering the oligomeric compound results in amelioration of one or more symptoms and / or lack of progression of MASH, without worsening of fibrosis; wherein the oligomeric compound is represented by the following structure:(SEQ ID NO: 1), wherein the oligomeric compound is formulated with a pharmaceutically acceptable carrier or excipient selected from sterile water or sterile saline or phosphate buffered saline, formulated for parenteral administration.

58. The method of claim 57, wherein the fixed dose is formulated for subcutaneous administration and contained in a single use vial, pre-filled syringe or an autoinjector device.

59. The method of claim 57, wherein administering the oligomeric compound or salt thereof comprises administering or use of a loading dose.

60. The method or use of claim 59, wherein the administering or use comprises one or more maintenance doses of the oligomeric compound or salt thereof once about every 28 days or once about every 4 weeks, or once about every month.

61. A unit dose comprising 75 mg to 150 mg of an oligomeric compound comprising a GalNAc-conjugated modified oligonucleotide represented by the following chemical notation (5’ to 3’):Tes Geo mCeo mCeo Aeo Tds Tds Tds Ads Ads Tds Gds Ads Gds mCds Teo Teo mCes Aes mCe (SEQ ID NO: 2), or a salt thereof;wherein: A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’-MOE sugar moiety, d = an unmodified DNA sugar moiety, s = a phosphorothioate internucleoside linkage, and o = a phosphodiester internucleoside linkage; and wherein GalNAc3is a trishexylamino N-acetyl galactosamine conjugate moiety.

62. A unit dose comprising 75 mg to 150 mg of an oligomeric compound represented by the following Structure 1 :(SEQ ID NO: 1) or a salt thereof.

63. A unit dose comprising 75 mg to 150 mg an oligomeric compound represented by the following sodium salt Structure 2:(SEQ ID NO: 1).

64. The unit dose of any one of claims 61-63, comprising an amount of the oligomeric compound or salt thereof within the range of about 75 mg to about 175 mg, about 75 mg to about 170 mg, about 75 mg to about 165 mg, about 75 mg to about 160 mg, about 75 mg to about 155 mg, about 75 mg to about 150 mg, about 75 about 75 mg to about 145 mg to about 140 mg, about 75 mg to about 130 mg, about 75 mg to about 125 mg, about 75 mg to about 120 mg, about 75 mg to about 115 mg, about 75 mg to about 110 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 80 mg to about 95 mg, about 85 mg to about 95 mg, about 90 mg to about 95 mg, about 80 mg to about 125 mg, about 85 mg to about 175 mg, about 85 mg to about 170 mg, about 85 mg to about 165 mg, about 85 mg to about 160 mg, about 85 mg to about 155 mg, about 85 mg to about 150 mg, about 85 to about 145 mg, about 85 mg to about 140 mg, about 85 mg to about 130 mg, about 85 mg to about 125 mg, about 85 mg to about 120 mg, about 85 mg to about 115 mg, about 85 mg to about 110 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 95 mg, about 85 mg to about 125 mg, about 90 mg to about 125 mg, about 95 mg to about 125 mg, about 100 mg to about 125 mg, about 115 mg to about 125 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 90 mg to about 120 mg, about 95 mg to about 115 mg, about 95 mg to about 110 mg, about 95 mg to about 105 mg, about 95 mg to about 100 mg, about 100mg to about 120 mg, about 100 mg to about 1 15 mg, about 100 mg to about 110 mg, about 100 mg to about 105 mg, about 105 mg to about 120 mg, about 105 mg to about 115 mg, about 105 mg to about 1 10 mg, about 110 mg to about 120 mg, about 1 10 mg to about 1 15 mg, about 115 mg to about 120 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 105 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 85 mg to about 120 mg, about 90 mg to about 95 mg, about 85 mg to about 105 mg, about 85 mg to 100 mg, 85 mg to about 95 mg, about 85 mg to about 1 15 mg, about 85 mg to about 90 mg, about 85 mg to about 95 mg, about 90 mg to about 175 mg, about 90 mg to about 170 mg, about 90 mg to about 165 mg, about 90 mg to about 160 mg, about 90 mg to about 155 mg, about 90 mg to about 150 mg, about 90 to about 145 mg .about 90 mg to about 140 mg, about 90 mg to about 130 mg, about 90 mg to about 125 mg, about 90 mg to about 120 mg, about 90 mg to about 1 15 mg, about 120 mg to about 175 mg, about 125 mg to about 175 mg, about 130 mg to about 175 mg, about 140 mg to about 165 mg, about 150 mg to about 165 mg, about 150 mg to about 160 mg, or about 160 mg to about 165 mg.

65. The unit dose of any one of claims 61-63, comprising an amount of the oligomeric compound or salt thereof of at least about 50 mg and less than about 150 mg, at least about 75 mg and less than about 150 mg, at least about 75 mg and less than about 140 mg, at least about 75 mg and less than about 130 mg, at least about 75 mg and less than about 125 mg, at least about 75 mg and less than about 120 mg, at least about 75 mg and less than about 1 15 mg, at least about 75 mg and less than about 110 mg, at least about 75 mg and less than about 100 mg, at least about 75 mg and less than about 95 mg, at least about 80 mg and less than about 95 mg, at least about 85 mg and less than about 95 mg, at least about 90 mg and less than about 95 mg, at least about 80 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 85 mg and less than about 125 mg, at least about 90 mg and less than about 125 mg, at least about 95 mg and less than about 125 mg, at least about 100 mg and less than about 125 mg, at least about 115 mg and less than about 125 mg, at least about 115 mg and less than about 120 mg, at least about 120 mg and less than about 125 mg, at least about 90 mg and less than about 120 mg, at least about 95 mg and less than about 1 15 mg, at least about 95 mg and less than about 1 10 mg, at least about 95 mg and less than about 105 mg, at least about 95 mg and less than about 100 mg, at least about 100 mg and less than about 120 mg, at least about 100 mg and less than about 1 15 mg, at least about 100 mg and less than about 1 10 mg, at least about 100 mg and less than about 105 mg, at least about 105 mg and less than about 120 mg, at least about 105 mg and less than about1 15 mg, at least about 105 mg and less than about 1 10 mg, at least about 110 mg and less than about 120 mg, at least about 110 mg and less than about 1 15 mg, at least about 1 15 mg and less than about 120 mg, at least about 80 mg and less than about 120 mg, at least about 80 mg and less than about 1 10 mg, at least about 80 mg and less than about 105 mg, at least about 80 mg and less than about 100 mg, at least about 80 mg and less than about 95 mg, at least about 80 mg and less than about 90 mg, at least about 85 mg and less than about 90 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 120 mg, at least about 90 mg and less than about 95 mg, at least about 85 mg and less than about 105 mg, at least about 85 mg and less than 100 mg, at least about 85 mg and less than about 95 mg, at least about 85 mg and less than about 115 mg, at least about 85 mg and less than about 90 mg, or at least about 85 mg and less than about 95 mg.

66. The unit dose of claim 65, comprising a fixed dose of 75 mg to 150 mg, 75 mg to 140 mg, 75 mg to 130 mg, 75 mg to 125 mg, 75 mg to 120 mg, 75 mg to 115 mg, 75 mg to 1 10 mg, 75 mg to 100 mg, 75 mg to 95 mg, 75 mg to 90 mg, 75 mg to 85 mg, 75 mg to 80 mg, 80 mg to 85 mg, 80 mg to 125 mg, 85 mg to 125 mg, 90 mg to 125 mg, 95 mg to 125 mg, 100 mg to 125 mg, 105 mg to 125 mg, 1 10 mg to 125 mg, 1 15 mg to 125 mg, 120 mg to 125 mg, 1 15 mg to 120 mg, 90 mg to 120 mg, 95 mg to 115 mg, 95 mg to1 10 mg, 95 mg to 105 mg, 95 mg to 100 mg, 100 mg to 120 mg, 100 mg to 1 15 mg, 100 mg to 110 mg, 100 mg to 105 mg, 105 mg to 120 mg, 105 mg to 115 mg, 105 mg to 1 10 mg, 110 mg to 120 mg, 1 10 mg to 1 15 mg, 1 15 mg to 120 mg, 80 mg to 120 mg, 80 mg to 1 10 mg, 80 mg to 105 mg, 80 mg to 100 mg, 80 mg to 95 mg, 80 mg to 90 mg, 85 mg to 90 mg, 90 mg to 95 mg, 85 mg to 120 mg, 90 mg to 95 mg, 85 mg to 105 mg, 85 mg to 100 mg, 85 mg to 95 mg, 85 mg to 115 mg, 85 mg to 90 mg, or 85 mg to 95 mg of the oligomeric compound or salt thereof.

67. The unit dose of claim 65, comprising a fixed dose of the oligomeric compound or salt thereof within the range of about 80 mg to about 130 mg, about 85 mg to about 130 mg, about 90 mg to about 130 mg, about 110 mg to about 130 mg, about 1 15 mg to about 125 mg, about 80 mg to about 125 mg, about 80 mg to about 120 mg, about 80 mg to about 110 mg, about 80 mg to about 100 mg, or about 85 mg to about 95 mg.

68. The unit dose of claim 66, comprising about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 1 15 mg, about 120 mg, about 125 mg, or about 130 mg of the oligomeric compound or salt thereof.

69. The unit dose of claim 67, comprising a fixed dose of 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 115 mg, 120 mg, 125 mg, or 130 mg of the oligomeric compound or salt thereof.

70. The unit dose of claim 69, comprising about 85 mg of the oligomeric compound or salt thereof.

71. The unit dose of claim 69, comprising about 90 mg of the oligomeric compound or salt thereof.

72. The unit dose of claim 69, comprising about 95 mg of the oligomeric compound or salt thereof.

73. The unit dose of claim 69, comprising about 100 mg of the oligomeric compound or salt thereof.

74. The unit dose of claim 69, comprising about 115 mg of the oligomeric compound or salt thereof.

75. The unit dose of claim 69, comprising about 120 mg of the oligomeric compound or salt thereof.

76. The unit dose of claim 69, comprising about 125 mg of the oligomeric compound or salt thereof.

77. The unit dose of claim 70, comprising a fixed dose of 80 mg to 125 mg of the oligomeric compound or salt thereof.

78. The unit dose of claim 70, comprising a unit dose of 85 mg of the oligomeric compound or salt thereof.

79. The unit dose of claim 70, comprising a unit dose of 90 mg of the oligomeric compound or salt thereof.

80. The unit dose of claim 70, comprising a unit dose of 95 mg of the oligomeric compound or salt thereof.

81. The unit dose of claim 70, comprising a unit dose of 100 mg of the oligomeric compound or salt thereof.

82. The unit dose of claim 70, comprising a unit dose of 110 mg of the oligomeric compound or salt thereof.

83. The unit dose of claim 70, comprising a unit dose of 115 mg of the oligomeric compound or salt thereof.

84. The unit dose of claim 70, comprising a unit dose of 120 mg of the oligomeric compound or salt thereof.

85. The unit dose of claim 70, comprising a unit dose of 125 mg of the oligomeric compound or salt thereof.

86. The unit dose of any one of claims 61-85, wherein the unit dose wherein the oligomeric compound or salt thereof is ION224 or a salt thereof.

87. The unit dose of any one of claims 61-86, further comprising a pharmaceutically acceptable carrier, adjuvant or excipient.

88. The unit dose of claims 87, consisting of the oligomeric compound or salt thereof and a pharmaceutically acceptable carrier or excipient.

89. The unit dose of claim 88, wherein the pharmaceutically acceptable carrier or excipient is sterile water or sterile saline or phosphate buffered saline.

90. The unit dose of claim 89, consisting of the oligomeric compound or salt thereof and sterile water or sterile saline or phosphate buffered saline.

91. The unit dose of any one of claims 61-90, formulated for parenteral administration.

92. The unit dose of claim 91 , formulated for subcutaneous, intramuscular, or intravenous administration.

93. The unit dose of claim 91 , formulated for subcutaneous administration.

94. The unit dose of any one of claims 61-93, contained in a single-dose vial.

95. The unit dose of any one of claims 61-93, provided in multi-dose vials.

96. The unit dose of any one of claims 61-93, contained in a prefilled syringe.

97. The unit dose of any one of claims 61-93, contained in a single-dose prefilled syringe.

98. The unit dose of any one of claims 61-93, contained in an autoinjector device.

99. A kit, comprising:(a) the unit dose of any one of claims 61-98, and(b) instructions for use, and, optionally,(c) means for administering the unit dose.

100. The kit of claim 99, wherein the instructions are for use in reducing the amount of DGAT2 RNA and / or DGAT2 protein in a subject having or at risk for MASH.

101. A unit dose comprising 85 mg to 125 mg of an oligomeric compound represented by the following sodium salt:(SEQ ID NO: 1), and a pharmaceutically acceptable carrier or excipient selected from sterile water or sterile saline or phosphate buffered saline, formulated for parenteral administration.

102. The unit dose of claim 101 , formulated for subcutaneous administration and contained in a single use vial, pre-filled syringe or an autoinjector device.

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