Methods and compositions for treating an angiotensinogen- (AGT-) associated disorder

Abstract

The present disclosure relates to methods of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene, by administering to the subject a fixed dose of a single stranded oligonucleotide, and compositions thereof.

Description

[0001]Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO METHODS AND COMPOSITIONS FOR TREATING AN ANGIOTENSINOGEN- (AGT-) ASSOCIATED DISORDER RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 687,841, filed on August 28, 2024, the entire contents of which are incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on August 7, 2025, is named 121301_24120.xml and is 66,901 bytes in size. BACKGROUND The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the regulation of blood pressure. The RAAS cascade begins with the release of renin by the juxtaglomerular cells of the kidney into the circulation. Renin secretion is stimulated by several factors, including Na+ load in the distal tubule, β-sympathetic stimulation, or reduced renal perfusion. Active renin in the plasma cleaves angiotensinogen (produced by the liver) to angiotensin I, which is then converted by circulating and locally expressed angiotensin-converting enzyme (ACE) to angiotensin II. Most of the effects of angiotensin II on the RAAS are exerted by its binding to angiotensin II type 1 receptors (AT1R), leading to arterial vasoconstriction, tubular and glomerular effects, such as enhanced Na+ reabsorption or modulation of glomerular filtration rate. Dysregulation of the RAAS leading to, for example, excessive angiotensin II production or AT1R stimulation results in hypertension which can lead to, e.g., increased oxidative stress, promotion of inflammation, hypertrophy, and fibrosis in the heart, kidneys, and arteries, and result in, e.g., left ventricular fibrosis, arterial remodeling, and glomerulosclerosis. Therapies like RNA interference (RNAi) are in use for treating subjects having hypertension by inhibiting the expression of an angiotensinogen (AGT) gene. RNAi is an evolutionarily conserved mechanism in which endogenous (microRNA) or exogenous (siRNA, shRNA) short non-coding RNAs downregulate gene expression of mRNA transcripts in sequence-dependent manner. As a native pathway that leverages an efficient cellular catalytic mechanism, RNAi can be used to achieve robust, durable, and specific silencing of gene transcripts of interest, such as an AGT gene. Novel delivery solutions along with highly chemically modified siRNAs have improved potency, durability, and safety. In liver, infrequent delivery of metabolically stabilized siRNA conjugated to N- galactosamine (GalNAc) results in potent gene silencing that persists in humans with favorable safety and tolerability profiles. 1 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO However, in some circumstances, a subject may respond poorly to treatment with a dsRNA agent or receive too high a dose. In such instances, a compound which reverses the iRNA silencing activity of the dsRNA agent could be administered to at least partially reduce the RNAi activity of the dsRNA agent. In other instances, the long-lasting effect of dsRNA makes waiting for that effect to slowly diminish through natural clearance an unattractive option. Accordingly, there is a need in the art for compositions and methods that provide tailored control of RNAi pharmacology and, therefore, the therapeutic activity and / or side effects of siRNA- based therapeutics in vivo. SUMMARY The present disclosure provides methods and compositions for inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene. The methods comprise administering to the subject a fixed dose, e.g., about 25 mg to about 1,200 mg, of single stranded oligonucleotides (REVERSIRs), which reverse the RNAi silencing activity of a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene, to control and tailor RNAi pharmacology. In one aspect, the present disclosure provides a method of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- 2 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O- methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’- phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’- phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine- 3’-phosphate, and s is a phosphorothioate linkage, thereby inhibiting the RNAi inhibitory activity of the dsRNA agent, or a salt thereof, in the subject. In another aspect, the present disclosure provides a method of ameliorating in a subject in need thereof, a side effect of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O- methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’- phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’- phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine- 3’-phosphate, and s is a phosphorothioate linkage, thereby ameliorating the side effect of the dsRNA agent, or a salt thereof, in the subject. In another aspect, the present disclosure provides a method of treating a subject in need thereof, previously administered a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 3 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O- methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’- phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’- phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine- 3’-phosphate, and s is a phosphorothioate linkage, thereby treating the subject. In some embodiments, the fixed dose is administered to the subject at least once. In some embodiments, the fixed dose is split into three doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 8 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 8 hour intervals. In some embodiments, the subject is administered a fixed dose of about 25 mg to about 200 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg to about 400 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg to about 800 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg to about 1,200 mg. In some embodiments, the subject is administered a fixed dose of about 25 mg. In some embodiments, the subject is administered a fixed dose of about 75 mg. In some embodiments, the subject is administered a fixed dose of about 150 mg. In some embodiments, the subject is administered a fixed dose of about 300 mg. In some embodiments, the subject is administered a fixed dose of about 600 mg. In some embodiments, the subject is administered a fixed dose of about 1,200 mg. In some embodiments, the single stranded oligonucleotide is administered to the subject subcutaneously or intravenously. In some embodiments, the subcutaneous administration is subcutaneous injection. In some embodiments, the single stranded oligonucleotide comprises the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. 4 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the single stranded oligonucleotide consists of the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide is conjugated to at least one ligand. In some embodiments, the ligand is an N-acetylgalactosamine (GalNAc) derivative. In some embodiments, the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker. In some embodiments, the ligand is In some embodiments, the ligand is In some embodiments, the ligand is conjugated to a nucleoside comprising a deoxy sugar in the single stranded oligonucleotide. In some embodiments, the deoxy sugar is a 2’-deoxy ribose. In some embodiments, the ligand is conjugated to the 3’-terminus of the single stranded oligonucleotide. 5 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the single stranded oligonucleotide is in salt form. In some embodiments, the single stranded oligonucleotide is in sodium salt form. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence 5’-UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand comprises a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand consists of a nucleotide sequence 5’-UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand consists of a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine- 3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O- methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'- phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O- fluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine- 3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; 6 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O- methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'- phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O- fluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic 7 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the dsRNA agent is in salt form. In some embodiments, the dsRNA agent is in sodium salt form. In some embodiments, the salt form has the following structure (SEQ ID NOS: 1 and 2, respectively): In some embodiments, the single stranded oligonucleotide is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% complementary to the entire length of the antisense strand of the dsRNA agent, or a salt thereof. In some embodiments, the single stranded oligonucleotide is fully complementary to the antisense strand of the dsRNA agent, or a salt thereof. In some embodiments, the subject in need thereof is a human. In some embodiments, the subject in need thereof is suffering from hypotension. In some embodiments, the subject in need thereof is suffering from hyperkalemia In some embodiments, the subject in need thereof is suffering from renal dysfuntion. In some embodiments, one or more methods of the present disclosure further comprise administering to the subject an additional therapy or therapeutic agent selected from the group consisting of increased dietary fluid / salt, fludrocortisone / midodrine treatment, intravenous fluids, vasopressor medications, down-titration or interruption of concomitant antihypertensive medications, a low potassium diet, thiazide / loop diuretic medications, oral potassium binders, calcium, glucose, insulin, hemodialysis, and combinations thereof. In some embodiments, the single stranded oligonucleotide is administered in a pharmaceutical composition. 8 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the single stranded oligonucleotide is administered in an unbuffered solution. In some embodiments, the unbuffered solution is saline or water. In some embodiments, the single stranded oligonucleotide is administered in a buffer solution. In some embodiments, the buffer solution comprises acetate, citrate, prolamine, carbonate, phosphate, or any combination thereof. In some embodiments, the buffer solution is phosphate buffered saline (PBS). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts a schematic of a randomized, double-blind study design for evaluating the safety, tolerability, and pharmacokinetics of a single stranded oligonucleotide (REVERSIR), A- 762645, administered subcutaneously in healthy human adults. Figure 2 depicts a schematic of the single stranded oligonucleotide (SEQ ID NO: 100) (REVERSIR), A-762645. DETAILED DESCRIPTION The present disclosure provides methods and compositions for inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene. The methods comprise administering to the subject a fixed dose, e.g., about 25 mg to about 1,200 mg, of a single stranded oligonucleotide (REVERSIR), which reverses the RNAi silencing activity of a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene, to control and tailor RNAi pharmacology. The following detailed description discloses methods for inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene. The methods include administering to the subject a fixed dose, e.g., about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 9 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg), of a single stranded oligonucleotide (REVERSIR); as well as compositions comprising fixed doses of such a single stranded oligonucleotide (REVERSIR). I. Definitions In order that the present disclosure may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this disclosure. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to". The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise. For example, “sense strand or antisense strand” is understood as “sense strand or antisense strand or sense strand and antisense strand.” The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. The term “at least”, “no less than”, or “or more” prior to a number or series of numbers is understood to include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides in a nucleic acid molecule must be an integer. For example, “at least 19 nucleotides of a 21 nucleotide nucleic acid molecule” means that 19, 20, or 21 nucleotides have the indicated property. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. As used herein, “no more than” or “or less” is understood as the value adjacent to the phrase and logical lower values or integers, as logical from context, to zero. For example, a duplex with an overhang of “no more than 2 nucleotides” has a 2, 1, or 0 nucleotide overhang. When “no more than” is present before a series of numbers or a range, it is understood that “no more than” can modify each of the numbers in the series or range. As used herein, ranges include both the upper and lower limit. 10 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In the event of a conflict between an indicated target site and the nucleotide sequence for a sense or antisense strand, the indicated sequence takes precedence. In the event of a conflict between a sequence and its indicated site on a transcript or other sequence, the nucleotide sequence recited in the specification takes precedence. As used herein, the term “nucleoside” refers to a glycosylamine comprising a nucleobase and a sugar. Nucleosides includes, but are not limited to, naturally occurring nucleosides, abasic nucleosides, modified nucleosides, and nucleosides having mimetic bases and / or sugar groups. As used herein, the term “nucleotide” refers to a glycosomine comprising a nucleobase and a sugar having a phosphate group covalently linked to the sugar. Nucleotides may be modified with any of a variety of substituents. As used herein, the term “nucleobase” refers to the base portion of a nucleoside or nucleotide. A nucleobase may comprise any atom or group of atoms capable of hydrogen bonding to a base of another nucleic acid. As used herein, the term “oligomeric compound” refers to a polymeric structure comprising two or more sub-structures and capable of hybridizing to a region of a nucleic acid molecule. In certain embodiments, oligomeric compounds are oligonucleosides. In certain embodiments, oligomeric compounds are oligonucleotides. In certain embodiments, oligomeric compounds are antisense compounds. In certain embodiments, oligomeric compounds are REVERSIR compounds. In certain embodiments, oligomeric compounds comprise conjugate groups. As used herein “oligonucleoside” refers to an oligonucleotide in which the internucleoside linkages do not contain a phosphorus atom. As used herein, the term “oligonucleotide” refers to an oligomeric compound comprising a plurality of linked nucleosides. In certain embodiment, one or more nucleotides of an oligonucleotide is modified. In certain embodiments, an oligonucleotide comprises ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). In certain embodiments, oligonucleotides are composed of naturally- and / or non-naturally-occurring nucleobases, sugars and covalent internucleoside linkages, and may further include non-nucleic acid conjugates. As used herein, the term “REVERSIR compound” or “REVERSIR” refers to a single- stranded oligomeric compound, such as a single stranded oligonucleotide, that is complementary to and capable of hybridizing (targeted to) with at least one strand of a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene. Without limitations, the REVERSIR compound may not only block unintended target pharmacodynamic (PD) effects, but also block any potential off-target activity that could occur with a dsRNA agent, or a salt thereof, e.g., a conjugated or unconjugated dsRNA agent, or a salt thereof. REVERSIRs bind to and are internalized into a cell through the asialoglycoprotein receptor (ASPGR) and irreversibly bind to the antisense strand of a dsRNA agent, or a salt thereof, in a functional RISC complex. The binding of the REVERSIR abrogates the mRNA target recognition and cleavage triggered by the hybridization of the dsRNA agent, or a salt thereof. 11 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO As used herein, the term “REVERSIR activity” refers to any decrease in intensity and / or duration of dsRNA activity attributable to hybridization of a REVERSIR compound to one of the strands of the dsRNA, or a salt thereof. The REVERSIR compounds disclosed herein are particularly effective in reducing theactivity of dsRNAs, or salts thereof, that inhibit the expression of an AGT gene. For example, theREVERSIR compounds disclosed herein can reduce within 24 hours to 7 days the activity of a dsRNA by at least about 20% or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 97%, or at least about 99% or up to and including a 100% decrease (i.e., absent level as compared to a reference sample), or any decrease between 20-100% or 50-100% as compared to a reference level. The reference level can be dsRNA activity in the absence of the REVERSIR compound. In some embodiments, the REVERSIR compounds described herein can reduce the activity of the dsRNA agent, or a salt thereof, by at least 5%, at least 10%, at least 15%, at least 20%, for example by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more and up to and including complete reduction or inhibition of dsRNA activity, within less than seven (e.g., within six days, five days, four days, three days, two days or one day) of administering or use of the REVERSIR compound. In some embodiments, the REVERSIR compounds can completely reduce the dsRNA activity within four days of administering or use of the REVERSIR compound. By complete reduction of dsRNA activity is meant a reduction of the dsRNA activity by at least 80% relative to a reference level. The terms “iRNA”, “RNAi agent,” “iRNA agent,” “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an AGT RNA transcript via an RNA-induced silencing complex (RISC) pathway. iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). The iRNA modulates, e.g., inhibits, the expression of an AGT mRNA sequence, e.g., in a cell, e.g., a cell within a subject, such as a mammalian subject. In certain embodiments, an “iRNA” for use in the compositions, uses, and methods of the disclosure is a double stranded RNA and is referred to herein as a “double stranded RNA agent,” “double stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA”, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to an AGT RNA. In some embodiments of the disclosure, a double stranded RNA (dsRNA) triggers the degradation of an AGT RNA, e.g., an mRNA, through a post- transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. The term “antisense strand” or "guide strand" refers to the strand of an iRNA, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence. 12 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO The term “sense strand” or "passenger strand" as used herein, refers to the strand of an iRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. As used herein the term “detecting dsRNA activity” or “measuring dsRNA activity” means that a test for detecting or measuring dsRNA activity is performed on a particular sample and compared to that of a control sample. Such detection and / or measuring can include values of zero. Thus, if a test for detection of dsRNA activity results in a finding of no dsRNA activity (dsRNA activity of zero), the step of “detecting dsRNA activity” has nevertheless been performed. As used herein the term “control sample” refers to a sample that has not been contacted with an oligomeric compound. As used herein “internucleoside linkage” refers to a covalent linkage between adjacent nucleosides. As used herein “naturally occurring internucleoside linkage” refers to a 3′ to 5′ phosphodiester linkage. As used herein, the term “target protein” refers to an Angiotensinogen (AGT) protein, the modulation of which is desired. As used herein, the term “target gene” refers to a gene encoding an AGT protein. As used herein, the term “target nucleic acid” refers to an AGT nucleic acid molecule the expression or activity of which is capable of being modulated by a conjugated or unconjugated dsRNA compound. Target nucleic acids include, but are not limited to, RNA (including, but not limited to pre-mRNA and mRNA or portions thereof) transcribed from DNA encoding an AGT protein, and also cDNA derived from such RNA, and miRNA. For example, the target nucleic acid can be an AGT gene, or an mRNA transcribed from the AGT gene. As used herein, the term “target siRNA” and “target dsRNA” refers to a compound that is targeted by a REVERSIR compound. For example, the target dsRNA agent is the dsRNA agent AD- 85481, also known as Zilebesiran (CAS Registry No.2380166-33-4). As used herein, the term “targeting” or “targeted to” refers to the association of antisense strand of a dsRNA to a particular target nucleic acid molecule or a particular region of nucleotides within a target nucleic acid molecule. As used herein, the term “nucleobase complementarity” refers to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair. 13 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO As used herein, the term “non-complementary nucleobase” refers to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization. As used herein, the term “complementary” refers to the capacity of an oligomeric compound to hybridize to another oligomeric compound or nucleic acid through nucleobase complementarity. In certain embodiments, an oligomeric compound and its target are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleobases that can bond with each other to allow stable association between the antisense compound and the target. One skilled in the art recognizes that the inclusion of mismatches is possible without eliminating the ability of the oligomeric compounds to remain in association. Therefore, described herein are oligomeric compounds that may comprise up to about 20% nucleotides that are mismatched (i.e., are not nucleobase complementary to the corresponding nucleotides of the target). Preferably the oligomeric compounds, contain no more than about 15%, more preferably not more than about 10%, most preferably not more than 5% or no mismatches. The remaining nucleotides are nucleobase complementary or otherwise do not disrupt hybridization (e.g., universal bases). One of ordinary skill in the art would recognize the compounds provided herein are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% complementary to a target nucleic acid. The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between between two oligonucletoides or polynucleotides, such as the antisense strand of a double stranded RNA agent and a REVERSIR, as will be understood from the context of their use. As used herein, “hybridization” means the pairing of complementary oligomeric compounds (e.g., an antisense strand of a dsRNA and its target nucleic acid or a REVERSIR to its target dsRNA). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleobases). For example, the natural base adenine is nucleobase complementary to the natural nucleobases thymidine and uracil which pair through the formation of hydrogen bonds. The natural base guanine is nucleobase complementary to the natural bases cytosine and 5-methyl cytosine. Hybridization can occur under varying circumstances. As used herein, the term “specifically hybridizes” refers to the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site. In certain embodiments, the antisense strand of an dsRNA specifically hybridizes to more than one target site. As used herein, the term “modulation” refers to a perturbation of function or activity when compared to the level of the function or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or 14 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO reduction) in gene expression. As further example, modulation of expression can include perturbing splice site selection of pre-mRNA processing. As used herein, the term “expression” refers to all the functions and steps by which a gene's coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to the products of transcription and translation. As used herein, “variant” refers to an alternative RNA transcript that can be produced from the same genomic region of DNA. Variants include, but are not limited to “pre-mRNA variants” which are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and exonic sequence. Variants also include, but are not limited to, those with alternate splice junctions, or alternate initiation and termination codons. As used herein, the term “2′-modified” or “2′-substituted” means a sugar comprising substituent at the 2′ position other than H or OH.2′-modified monomers, include, but are not limited to, BNA's and monomers (e.g., nucleosides and nucleotides) with 2′-substituents, such as allyl, amino, azido, thio, O-allyl, O—C1-C10 alkyl, —OCF3, O—(CH2)2-O—CH3, 2′-O(CH2)2SCH3, O—(CH2)2- O—N(Rm)(Rn), or O—CH2-C(═O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, oligomeric compounds comprise a 2′ modified monomer that does not have the formula 2′-O(CH2)nH, wherein n is one to six. In certain embodiments, oligomeric compounds comprise a 2′ modified monomer that does not have the formula 2′-OCH3. In certain embodiments, oligomeric compounds comprise a 2′ modified monomer that does not have the formula or, in the alternative, 2′-O(CH2)2OCH3. As used herein, the term “locked nucleic acid” or “LNA” or “locked nucleoside” or “locked nucleotide” refers to a nucleoside or nucleotide wherein the furanose portion of the nucleoside includes a bridge connecting two carbon atoms on the furanose ring, thereby forming a bicyclic ring system. Locked nucleic acids are also referred to as bicyclic nucleic acids (BNA). As used herein, unless otherwise indicated, the term “methyleneoxy LNA” alone refers to β- D-methyleneoxy LNA. As used herein, the term “MOE” refers to a 2′-O-methoxyethyl substituent. As used herein, the term “pharmaceutically acceptable salts” refers to salts of active compounds that retain the desired biological activity of the active compound and do not impart undesired toxicological effects thereto. A salt or a pharmaceutically acceptable salt of the single stranded oligonucleotide (REVERSIR) or the dsRNA agent of the disclosure, being used in the methods of the disclosure, includes any salt which is pharmaceutically acceptable, e.g., a sodium salt of the single stranded oligonucleotide or the dsRNA agent. In one embodiment, the pharmaceutically acceptable salt of the dsRNA of the disclosure being used in the methods of the disclosure has the following structure (SEQ ID NOS: 1 and 2, respectively): 15 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO As used herein, the term “cap structure” or “terminal cap moiety” refers to chemical modifications, which have been incorporated at either terminus of an antisense compound. The phrase “contacting a cell,” such as contacting a cell with a REVERSIR, as used herein, includes contacting a cell by any possible means. Contacting a cell includes contacting a cell in vitro or contacting a cell in vivo. The contacting may be done directly or indirectly. Thus, for example, the REVERSIR may be put into physical contact with the cell by the individual performing the method, or alternatively, the REVERSIR may be put into a situation that will permit or cause it to subsequently come into contact with the cell. Contacting a cell in vitro may be done, for example, by incubating the cell with the REVERSIR. Contacting a cell in vivo may be done, for example, by injecting the REVERSIR into or near the tissue where the cell is located, or by injecting the REVERSIR into another area, e.g., the bloodstream or the subcutaneous space, such that the agent will subsequently reach the tissue where the cell to be contacted is located. Combinations of in vitro and in vivo methods of contacting are also possible. For example, a cell may also be contacted in vitro with a REVERSIR and subsequently transplanted into a subject. In certain embodiments, contacting a cell with a REVERSIR includes “introducing” or “delivering the REVERSIR into the cell” by facilitating or effecting uptake or absorption into the cell. Absorption or uptake of a REVERSIR can occur through unaided diffusion or active cellular processes, or by auxiliary agents or devices. Introducing a REVERSIR compound into a cell may be in vitro or in vivo. For example, for in vivo introduction, REVERSIR can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such 16 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO as electroporation and lipofection. Further approaches are described herein below or are known in the art. "Therapeutically effective amount," as used herein, is intended to include the amount of a REVERSIR that, when administered to a subject, is sufficient for inhibiting in the subject the RNAi inhibitory activity of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; ameliorating in the subject a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating the subject previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene. In some embodiments, the "therapeutically effective amount" when referring to the amount of the dsRNA agent, also refers to the amount of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene, that when administered to a subject, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of disease). The "therapeutically effective amount" may vary depending on the REVERSIR and / or the dsRNA agent, or a salt thereof; how the REVERSIR and / or the dsRNA agent, or a salt thereof, is administered; the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. A "therapeutically-effective amount" also includes an amount of a REVERSIR that produces some desired effect at a reasonable benefit / risk ratio applicable to any treatment. The REVERSIR employed in the methods of the present disclosure may be administered in a sufficient amount to produce a reasonable benefit / risk ratio applicable to such treatment. As used herein, “administering” means providing an RNAi agent and / or REVERSIR to a subject such as a human, and includes, but is not limited to administering by a medical professional and self-administering. As used herein, the term “co-administering” means providing the RNAi agent and REVERSIR to a subject, such as a human subject. In certain embodiments, the RNAi agent and REVERSIR are administered together. In certain embodiments, the RNAi agent and REVERSIR are administered separately. In certain embodiments, the RNAi agent and REVERSIR are administered at the same time. In certain embodiments, the RNAi agent and REVERSIR are administered at different times. In certain embodiments, the RNAi agent and REVERSIR are administered through the same route of administration. In certain embodiments, the RNAi agent and REVERSIR are administered through different routes of administration. In certain embodiments, the RNAi agent and REVERSIR are contained in the same pharmaceutical formulation. In certain embodiments, the RNAi agent and REVERSIR are in separate formulations. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials (including salts), compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects 17 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Such carriers are known in the art. Pharmaceutically acceptable carriers include carriers for administration by injection. As used herein, the term "in vitro" refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within an organism (e.g. animal or a plant). As used herein, the term “ex vivo” refers to cells which are removed from a living organism and cultured outside the organism (e.g., in a test tube). As used herein, the term "in vivo" refers to events that occur within an organism (e.g. animal, plant, and / or microbe). As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, or a mouse), or a bird that expresses the universal target sequence, either endogenously or heterologously. In an embodiment, the subject is a human. In some embodiments, the subject is a female human. In other embodiments, the subject is a male human. In one embodiment, the subject is an adult subject. In another embodiment, the subject is a pediatric subject. In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities. As used herein, the term “parenteral administration,” refers to administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, or intramuscular administration. As used herein, the term “subcutaneous administration” refers to administration just below the skin. “Intravenous administration” means administration into a vein. As used herein, the term “dose” refers to a specified quantity of a pharmaceutical agent provided in a single administration. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single 18 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in an individual. As used herein, the term “dosage unit” refers to a form in which an RNAi agent and / or REVERSIR is provided. In certain embodiments, a dosage unit is a vial comprising lyophilized RNAi agent and / or REVERSIR. In certain embodiments, a dosage unit is a vial comprising reconstituted RNAi agent and / or REVERSIR. As used herein, the term “active pharmaceutical ingredient” refers to the substance in a pharmaceutical composition that provides a desired effect. As used herein, the term “side effects” refers to physiological responses attributable to a treatment other than desired effects. In certain embodiments, side effects include, without limitation, injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, and myopathies. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality. In some embodiments, the side effects inlcude one or more side effects associated with hypotension, hyperkalemia, and / or renal dysfuntion. In some embodiments, the side effects inlcude one or more side effects associated with hypotension. In some embodiments, the side effects inlcude one or more side effects associated with hyperkalemia. In some embodiments, the side effects inlcude one or more side effects associated with renal dysfuntion. The term “sample,” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs, or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the liver (e.g., whole liver or certain segments of liver or certain types of cells in the liver, such as, e.g., hepatocytes). In some embodiments, a “sample derived from a subject” refers to urine obtained from the subject. A “sample derived from a subject” can refer to blood or blood derived serum or plasma from the subject. II. Methods of the Disclosure The present disclosure provides methods of using the REVERSIR compounds of the disclosure for inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, 19 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene, and compositions thereof. Accordingly, in one aspect, the present disclosure provides a method of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). The method comprises administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3, 2, or 1 nucleotides and / or 3, 2, or 1 nucleotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O- methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’- phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’- phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine- 3’-phosphate, and s is a phosphorothioate linkage, thereby inhibiting the RNAi inhibitory activity of the dsRNA agent, or a salt thereof, in the subject. In another aspect, the present disclosure provides a method of ameliorating in a subject in need thereof, a side effect of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). The method comprises administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; 20 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3, 2, or 1 nucleotides and / or 3, 2, or 1 nucleotide modifications from the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA- 3’ of SEQ ID NO: 100, wherein a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’- phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'- O,4'-C-methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’- phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage, thereby ameliorating the side effect of the dsRNA agent, or a salt thereof, in the subject. In another aspect, the present disclosure provides a method of treating a subject in need thereof, previously administered a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). The method comprises administering to the subject a fixed dose of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3, 2, or 1 nucleotides and / or 3, 2, or 1 nucleotide modifications from the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA- 3’ of SEQ ID NO: 100, wherein a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’- phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'- O,4'-C-methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’- phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage, thereby treating the subject. For example, in certain instances it is desirable to inhibit the RNAi interference activity of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene, thereby restoring expression of AGT mRNA / protein. In particular, dsRNA agents, or salts thereof, have been used therapeutically and are long-acting. In certain instances, such long acting dsRNA agents, or salts 21 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO thereof, are desirable, for their convenience. In such instances, though, it can also be desirable to have a means to reverse the activity of the dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene. For example, a patient may respond poorly to treatment or receive too high a dose. In such an instance, a REVERSIR compound can be administered as, e.g., an antedote, to at least partially reduce the RNAi activity of the dsRNA agent, or a salt thereof. In certain embodiments, the long- lasting effect of the dsRNA agents, or salts thereof, makes waiting for that effect to slowly diminish through natural clearance an unattractive option. The dsRNA agents, or salts thereof, of the present disclosure are useful for inhibitting theexpression of an AGT gene. Such dsRNAs have therapeutic potential and their long half-lives make such dsRNAs particularly attractive, however, if a patient receives too high a dose, has surgery, or otherwise desires an increase in the expression of an AGT gene, a REVERSIR compound can be administered. Such REVERSIR compound will restore expression of an AGT gene more quickly than simply waiting for natural clearance of the dsRNA. This example is provided solely for illustrative purposes. The delivery of a fixed dose of the REVERSIR compound to a subject may be performed by contacting a cell of the subject with the REVERSIR compound, for example, in vitro or in vivo. For example, contacting a cell in vivo includes contacting a cell or group of cells within a subject, e.g., a human subject. Combinations of in vitro and in vivo methods of contacting a cell are also possible. Contacting a cell may be direct or indirect. Furthermore, contacting a cell may be accomplished via a targeting ligand, including any ligand described herein or known in the art. In some embodiments, the targeting ligand is a carbohydrate moiety, e.g., a GalNAc3 ligand, or any other ligand that directs the dsRNA agent and / or REVERSIR compound to a site of interest. In some embodiments, the fixed dose is administered to the subject at least once. In some embodiments, the fixed dose is split into three doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 8 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 8 hour intervals. In some embodiments, the subject is administered a fixed dose of about 25 mg to about 200 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg to about 400 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg to about 800 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg to about 1,200 mg. In some embodiments, the subject is administered a fixed dose of about 25 mg. In some embodiments, the subject is administered a fixed dose of about 50 mg. In some embodiments, the subject is administered a fixed dose of about 75 mg. In some embodiments, the subject is administered a fixed dose of about 100 mg. In some embodiments, the subject is administered a fixed 22 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO dose of about 150 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg. In some embodiments, the subject is administered a fixed dose of about 250 mg. In some embodiments, the subject is administered a fixed dose of about 300 mg. In some embodiments, the subject is administered a fixed dose of about 350 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg. In some embodiments, the subject is administered a fixed dose of about 450 mg. In some embodiments, the subject is administered a fixed dose of about 500 mg. In some embodiments, the subject is administered a fixed dose of about 550 mg. In some embodiments, the subject is administered a fixed dose of about 600 mg. In some embodiments, the subject is administered a fixed dose of about 650 mg. In some embodiments, the subject is administered a fixed dose of about 700 mg. In some embodiments, the subject is administered a fixed dose of about 750 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg. In some embodiments, the subject is administered a fixed dose of about 850 mg. In some embodiments, the subject is administered a fixed dose of about 900 mg. In some embodiments, the subject is administered a fixed dose of about 950 mg. In some embodiments, the subject is administered a fixed dose of about 1,000 mg. In some embodiments, the subject is administered a fixed dose of about 1,050 mg. In some embodiments, the subject is administered a fixed dose of about 1,100 mg. In some embodiments, the subject is administered a fixed dose of about 1,150 mg. In some embodiments, the subject is administered a fixed dose of about 1,200 mg. In some embodiments, the single stranded oligonucleotide is administered to the subject subcutaneously or intravenously. In some embodiments, the subcutaneous administration is subcutaneous injection. Inhibition of the RNAi interference activity of the dsRNA agent, or a salt thereof, may be manifested by a reduction of the amount of mRNA expressed by a first cell or group of cells as compared to a second cell or group of cells substantially identical to the first cell or group of cells. In other embodiments, inhibition of the RNAi interference activity of a dsRNA agent, or a salt thereof, may be assessed in terms of a reduction of a parameter that is functionally linked to the AGT mRNA expression, e.g., protein level in blood or serum from a subject. Expression may be determined in any cell by any assay known in the art. Inhibition of AGT protein may be manifested by a reduction in the level of the protein that is expressed by a cell or group of cells or in a subject sample (e.g., the level of protein in a blood sample derived from a subject). As explained above, for the assessment of mRNA suppression, the inhibition of protein expression levels in a treated cell or group of cells may similarly be expressed as a percentage of the level of protein in a control cell or group of cells, or the change in the level of protein in a subject sample, e.g., blood or serum derived therefrom. The level of AGT mRNA that is expressed by a cell or group of cells may be determined using any method known in the art for assessing mRNA expression. In one embodiment, the level of expression in a sample is determined by detecting a transcribed polynucleotide, or portion thereof, e.g., mRNA. RNA may be extracted from cells using RNA extraction techniques including, for 23 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasyTMRNA preparation kits (Qiagen®) or PAXgeneTM(PreAnalytixTM, Switzerland). Typical assay formats utilizing ribonucleic acid hybridization include nuclear run-on assays, RT-PCR, RNase protection assays, northern blotting, in situ hybridization, and microarray analysis. In some embodiments, the level of expression is determined using a nucleic acid probe. The term “probe”, as used herein, refers to any molecule that is capable of selectively binding to a specific transgene. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules. Isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or northern analyses, polymerase chain reaction (PCR) analyses and probe arrays. One method for the determination of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to transgene mRNA. In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix® gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in determining the level of transgene mRNA. An alternative method for determining the level of AGT expression in a sample involves the process of nucleic acid amplification or reverse transcriptase (to prepare cDNA) of for example mRNA in the sample, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Patent No.4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88:189-193), self sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio / Technology 6:1197), rolling circle replication (Lizardi et al., U.S. Patent No.5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such moleculesare present in very low numbers. In particular aspects of the disclosure , the level of expression isdetermined by quantitative fluorogenic RT-PCR (i.e., the TaqManTMSystem). The expression levels of mRNA may be monitored using a membrane blot (such as used in hybridization analysis such as northern, Southern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Patent Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference. The determination of transgene expression level may also comprise using nucleic acid probes in solution. 24 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the level of mRNA expression is assessed using branched DNA (bDNA) assays or real time PCR (qPCR). The use of these methods is described and exemplified in the Examples presented herein. The level of protein expression may be determined using any method known in the art for the measurement of protein levels. Such methods include, for example, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, fluid or gel precipitin reactions, absorption spectroscopy, a colorimetric assays, spectrophotometric assays, flow cytometry, immunodiffusion (single or double), immunoelectrophoresis, western blotting, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like. In another aspect, the present disclosure provides a method of treating a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of the single stranded oligonucleotide of the disclosure or the pharmaceutical composition of the disclosure, thereby treating the subject. In some embodiment, the subject in need thereof was previously administered a double stranded RNAi agent, or a salt thereof, that inhibits the expression of an AGT gene. The subject in need thereof may have been administered too high a dose of the dsRNA agent, or a salt thereof, and / or is experiencing off-target effects. The administration of the REVERSIR to the subject, thus, would act as an antidote to reverse the inhibition to the AGT gene by the dsRNA agent, or a salt thereof. The subject in need thereof, may have been administered too high a dose of the dsRNA agent, or a salt thereof, and is suffering from hypotension, hyperkalemia, and / or renal dysfunction. In some embodiments, the subject in need thereof is a human. In some embodiments, the subject in need thereof is suffering from hypotension. In some embodiments, the subject in need thereof is suffering from hyperkalemia. In some embodiments, the subject in need thereof is suffering from renal dysfuntion. In certain embodiments, the methods of the disclosure further comprise administering to the subject an additional therapy or therapeutic agent selected from the group consisting of increased dietary fluid / salt, fludrocortisone / midodrine treatment, intravenous fluids, vasopressor medications, down-titration or interruption of concomitant antihypertensive medications, a low potassium diet, thiazide / loop diuretic medications, oral potassium binders, calcium, glucose, insulin, and hemodialysis, or combinations thereof. In another aspect, the present disclosure provides a method of ameliorating in a subject a side effect of a dsRNA agent, or a salt thereof, which inhibits the expression of an AGT gene, such as an off-target effect and / or allergic reaction and / or immunostimulatory effect of administration of the dsRNA agent, or a salt thereof. The method includes, administering to the subject an effective amount of the single stranded oligonucleotide of the disclosure or the pharmaceutical composition of the disclosure, thereby ameliorating the side effect of the dsRNA agent, or a salt thereof, in the subject. 25 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO The in vivo methods of the disclosure may include administering to a subject a compositionby any means known in the art including, but not limited to oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal, and intrathecal), intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by intravenous infusion or injection. In certain embodiments, the compositions are administered by subcutaneous injection. In certain embodiments, the compositions are administered by intramuscular injection. In another aspect, the present disclsoure provides a method of treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, which inhibits the expression of anAGT gene. The method includes, administering to the subject an effective amount of the singlestranded oligonucleotide of the disclosure or the pharmaceutical composition of the disclosure ,thereby treating the subject. Efficacy of treatment can be assessed, for example by measuring in the subject the inhibition of the RNAi activity of the dsRNA agent, or a salt thereof (e.g., measuring the inhibition of AGT mRNA, AGT protein, and / or AGT activity). Such means for measuring the inhibition of RNAi activity may comprise a means for obtaining a sample from a subject, such as, e.g., a plasma sample. It is well within the ability of one skilled in the art to monitor efficacy of treatment by measuring any one of such parameters, or any combination of parameters. Comparisons of the later measurements with the initial measurements provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment by measuring such a parameter, or any combination of parameters. A treatment is evident when there is a statistically significant improvement in one or more parameters, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of inhibition of the RNAi activity of the dsRNA agent, or a salt thereof, and preferably at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Any compositions of the disclosure may be administered as a “free iRNA” or a “freeREVERSIR compound.” A free iRNA or free REVERSIR compound is administered in the absence of a pharmaceutical composition. The naked iRNA or naked REVERSIR compound may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution can be adjusted such that it is suitable for administering to a subject. Alternatively, a composition of the disclosure may be administered as a pharmaceuticalcomposition, such as a lipid formulation. 26 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO III. Delivery Methods of the Disclosure The delivery of a nucleic acid molecule, i.e.,a REVERSIR compound and / or a dsRNA agent, or a salt thereof, as described herein to a cell e.g., a cell within a subject, such as a human subject (e.g., a subject in need thereof) can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with the REVERSIR compound or the dsRNA agent, or a salt thereof, as described herein either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising the REVERSIR compound and / or the dsRNA agent, or a salt thereof, as described herein to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the REVERSIR compound and / or the dsRNA agent, or a salt thereof. These embodiments are discussed further below. In some embodiments, the single stranded oligonucleotide (REVERSIR) is administered to the subject subcutaneously or intravenously. In some embodiments, the subcutaneous administration is subcutaneous injection. One or more injections may be used to deliver the desired fixed dose of the single stranded oligonucleotide (REVERSIR), e.g., A-762645, for example, about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of the REVERSIR to the subject. In some embodiments, the fixed dose is administered to the subject at least once. In some embodiments, the fixed dose is split into three doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 8 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 8 hour intervals. In some embodiments, the subject is administered a fixed dose of about 25 mg to about 200 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg to about 400 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg to about 800 mg. In 27 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO some embodiments, the subject is administered a fixed dose of about 800 mg to about 1,200 mg. In some embodiments, the subject is administered a fixed dose of about 25 mg. In some embodiments, the subject is administered a fixed dose of about 50 mg. In some embodiments, the subject is administered a fixed dose of about 75 mg. In some embodiments, the subject is administered a fixed dose of about 100 mg. In some embodiments, the subject is administered a fixed dose of about 150 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg. In some embodiments, the subject is administered a fixed dose of about 250 mg. In some embodiments, the subject is administered a fixed dose of about 300 mg. In some embodiments, the subject is administered a fixed dose of about 350 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg. In some embodiments, the subject is administered a fixed dose of about 450 mg. In some embodiments, the subject is administered a fixed dose of about 500 mg. In some embodiments, the subject is administered a fixed dose of about 550 mg. In some embodiments, the subject is administered a fixed dose of about 600 mg. In some embodiments, the subject is administered a fixed dose of about 650 mg. In some embodiments, the subject is administered a fixed dose of about 700 mg. In some embodiments, the subject is administered a fixed dose of about 750 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg. In some embodiments, the subject is administered a fixed dose of about 850 mg. In some embodiments, the subject is administered a fixed dose of about 900 mg. In some embodiments, the subject is administered a fixed dose of about 950 mg. In some embodiments, the subject is administered a fixed dose of about 1,000 mg. In some embodiments, the subject is administered a fixed dose of about 1,050 mg. In some embodiments, the subject is administered a fixed dose of about 1,100 mg. In some embodiments, the subject is administered a fixed dose of about 1,150 mg. In some embodiments, the subject is administered a fixed dose of about 1,200 mg. For delivery of nucleic acid molecules, e.g., REVERSIR and dsRNA agents, in general, any method of delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with thepresent disclosure (see e.g., Akhtar S. and Julian RL. (1992) Trends Cell. Biol. 2(5):139-144 andWO94 / 02595, which are incorporated herein by reference in their entireties). For in vivo delivery, factors to consider include, for example, biological stability of the delivered molecule, prevention of non-specific effects, and accumulation of the delivered molecule in the target tissue. IV. REVERSIR Compounds of the Disclosure The present disclosure provides single stranded oligonucleotide (REVERSIR) compounds, such as A-762645 shown in Figure 2 and Table 2, for use in methods of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD- 85481, also known as Zilebesiran); ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran); and / or treating a subject in need thereof, previously administered a 28 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). The methods comprise administering to the subject a fixed dose, e.g., about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg), of the REVERSIR compound (e.g., A-762645), which reverses the RNAi silencing activity of a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran), to control and tailor RNAi pharmacology. Generally, the REVERSIR compounds of the disclosure are single stranded oligonucleotides (oligomers) 16-30 nucleotides in length, e.g., 16-24, 18-22, or 18-20 nucleotides in length. The single stranded oligonucleotides comprise a nucleotide sequence substantially complementary to the antisense strand of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene. The nucleotide sequence of the oligonucleotides may be at least about 90%, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the entire nucleotide sequence of the antisense strand of the dsRNA agent (e.g. the dsRNA agent AD-85481, also known as Zilebesiran), or a salt thereof. In certain embodiments, the REVERSIR compounds are chemically modified oligomeric compounds, compared to naturally occurring oligomers, such as DNA or RNA. In some embodiments, the single stranded oligonucleotide comprises at least 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5’- CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123, wherein at least one nucleotide of the single stranded oligonucleotide comprises a nucleotide modification, thereby inhibiting the RNAi inhibitory activity of the dsRNA agent, or a salt thereof, in the subject. In some embodiments, the single stranded oligonucleotide comprises at least 14 contiguous nucleotides of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the single stranded oligonucleotide comprises at least 15 contiguous nucleotides of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the single stranded oligonucleotide comprises at least 16 contiguous nucleotides of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. 29 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the the single stranded oligonucleotide comprises at least 17 contiguous nucleotides of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the single stranded oligonucleotide comprises at least 18 contiguous nucleotides of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the single stranded oligonucleotide comprises the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the single stranded oligonucleotide consists of the nucleotide sequence 5’-CAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 123. In some embodiments, the REVERSIR compounds of the disclosure comprise a least one modified nucleotide, i.e., at least one modified monomer. In other embodiments, substantially all of the nucleotides of the oligonucleotide are modified nucleotides, e.g., not more than 5, 4, 3, 2, or 1 of the nucleotides are unmodified nucleotides, e.g., substantially all of the nucleotides comprise a nucleotide modification selected from the group consisting of a 2’-O-alkyl modification, a 2’-substituted alkoxy modification, a 2’-substituted alkyl modification, a 2’-halo modification, a deoxynucleotide modification, a D-Methyleneoxy (4′-CH2-O- 2′) locked nucleic acid (LNA) modification, a 2'-O-(2-Methoxyethyl) (MOE) modification, bridged nucleic acid (2′,4′-BNA), 2′-O-Ethyl (cEt), and a 2’-O-methyl modification. In still other embodiment, all of the nucleotides of the oligonucleotide are modified nucleotides, e.g., all of the nucleotides comprise a nucleotide modification selected from the group consisting of a 2’-O-alkyl modification, a 2’-substituted alkoxy modification, a 2’-substituted alkyl modification, a 2’-halo modification, a deoxynucleotide modification, a D-Methyleneoxy (4′-CH2-O- 2′) locked nucleic acid (LNA) modification, bridged nucleic acid (2′,4′-BNA), 2′-O-Ethyl (cEt), and a 2’-O-methyl modification. In some embodiments, the the single stranded oligonucleotide comprises at least five phosphorothioate internucleotide modifications. In some embodiments, the single stranded oligonucleotide comprises 6-14 phosphorothioate internucleotide modifications. In certain embodiments, the REVERSIR compounds of the disclosure comprise one or more β-D-Methyleneoxy (4′-CH2-O-2′) LNA modifications. In certain embodiments, the REVERSIR compounds of the disclosure comprise one or more α-D-Methyleneoxy (4′-CH2-O-2′) LNA modifications. In certain embodiments, the REVERSIR compounds of the disclosure comprise one or more (S)-cEt modifications. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O- methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’- 30 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’- phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine- 3’-phosphate, and s is a phosphorothioate linkage. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides of the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 15 contiguous nucleotides of the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 16 contiguous nucleotides of the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 17 contiguous nucleotides of the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 18 contiguous nucleotides of the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide consists of the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100. In some embodiments, the single stranded oligonucleotide comprises the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein the 3’-terminus of the single stranded oligonucleotide is conjugated to a ligand, wherein the ligand is In some embodiments, the single stranded oligonucleotide consists of the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100 31 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO wherein the 3’-terminus of the single stranded oligonucleotide is conjugated to a ligand, wherein the ligand is Additional REVERSIR compounds that may be used in the methods of the disclosure are described in International PCT Publication No. WO 2024 / 168010, the entire contents of which are incorporated herein by reference. V. Synthesis, Purification and Analysis of the REVERSIRs of the Disclosure Oligomerization of modified and unmodified nucleosides and nucleotides can be routinely performed according to literature procedures for DNA (Protocols for Oligonucleotides and Analogs, Ed. Agrawal (1993), Humana Press) and / or RNA (Scaringe, Methods (2001), 23, 206-217. Gait et al., Applications of Chemically synthesized RNA in RNA: Protein Interactions, Ed. Smith (1998), 1-36. Gallo et al., Tetrahedron (2001), 57, 5707-5713). The oligomeric compounds provided herein, i.e., REVERSIR compounds, can be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives. The disclosure is not limited by the method of antisense compound synthesis. Methods of purification and analysis of oligomeric compounds are known to those skilled in the art. Analysis methods include capillary electrophoresis (CE) and electrospray-mass spectroscopy. Such synthesis and analysis methods can be performed in multi-well plates. The method of the disclosure is not limited by the method of oligomer purification. The oligomeric compounds of the disclosure can be prepared using solution-phase or solid-phase organic synthesis, or enzymatically by methods known in the art. Organic synthesis offers the advantage that the oligomeric strands comprising non-natural or modified nucleotides can be easily prepared. Any other means for such synthesis known in the art can additionally or alternatively be employed. It is also known to use similar techniques to prepare other oligomeric compounds, such as those comprising phosphorothioates, phosphorodithioates and alkylated derivatives of intersugar 32 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WOlinkages. The double-stranded oligomeric compounds of the disclosure can be prepared using a two-step procedure. First, the individual strands of the double-stranded molecule are prepared separately. Then, the component strands are annealed. Regardless of the method of synthesis, the oligomeric compounds can be prepared in a solution (e.g., an aqueous and / or organic solution) that is appropriate for formulation. For example, the oligonmeric preparation can be precipitated and redissolved in pure double-distilled water, and lyophilized. The dried oligomeric compound can then be resuspended in a solution appropriate for the intended formulation process. Teachings regarding the synthesis of particular modified oligomeric compounds can be found in the following U.S. patents or pending patent applications: U.S. Pat. Nos.5,138,045 and 5,218,105, drawn to polyamine conjugated oligonucleotides; U.S. Pat. No.5,212,295, drawn to monomers for the preparation of oligonucleotides having chiral phosphorus linkages; U.S. Pat. Nos.5,378,825 and 5,541,307, drawn to oligonucleotides having modified backbones; U.S. Pat. No.5,386,023, drawn to backbone-modified oligonucleotides and the preparation thereof through reductive coupling; U.S. Pat. No.5,457,191, drawn to modified nucleobases based on the 3-deazapurine ring system and methods of synthesis thereof; U.S. Pat. No.5,459,255, drawn to modified nucleobases based on N-2 substituted purines; U.S. Pat. No.5,521,302, drawn to processes for preparing oligonucleotides having chiral phosphorus linkages; U.S. Pat. No.5,539,082, drawn to peptide nucleic acids; U.S. Pat. No. 5,554,746, drawn to oligonucleotides having beta-lactam backbones; U.S. Pat. No.5,571,902, drawn to methods and materials for the synthesis of oligonucleotides; U.S. Pat. No.5,578,718, drawn to nucleosides having alkylthio groups, wherein such groups can be used as linkers to other moieties attached at any of a variety of positions of the nucleoside; U.S. Pat. Nos.5,587,361 and 5,599,797, drawn to oligonucleotides having phosphorothioate linkages of high chiral purity; U.S. Pat. No. 5,506,351, drawn to processes for the preparation of 2'-O-alkyl guanosine and related compounds, including 2,6-diaminopurine compounds; U.S. Pat. No.5,587,469, drawn to oligonucleotides having N-2 substituted purines; U.S. Pat. No.5,587,470, drawn to oligonucleotides having 3-deazapurines; U.S. Pat. No.5,223,168, and U.S. Pat. No.5,608,046, both drawn to conjugated 4'-desmethyl nucleoside analogs; U.S. Pat. Nos.5,602,240, and 5,610,289, drawn to backbone-modified oligonucleotide analogs; and U.S. Pat. Nos.6,262,241, and 5,459,255, drawn to, inter alia, methods of synthesizing 2'-fluoro-oligonucleotides. VI. dsRNA Agents of the Disclosure The present disclosure provides REVERSIRs for use in methods of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran); ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran); and / or treating a subject in need thereof, previously 33 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). Suitable dsRNA agents, or salts thereof, for use in the methods of the disclosure include the dsRNA agent AD-85481, also known as Zilebesiran. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence 5’-UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand comprises a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand consists of a nucleotide sequence 5’-UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand consists of a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine- 3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O- methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'- phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O- fluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer. In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of 34 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine- 3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic In some embodiments, the dsRNA agent, or a salt thereof, comprises a sense strand and anantisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O- methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'- phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O- fluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic 35 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Further, a pharmaceutically acceptable salt form of the dsRNA of the disclosure being used inthe methods of the disclosure includes any salt that is pharmaceutically acceptable, e.g., a sodium saltof the dsRNA agent. In one embodiment, the pharmaceutically acceptable salt of the dsRNA of thedisclosure being used in the methods of the disclosure has the following structure (SEQ ID NOS: 1and 2, respectively): Additional dsRNA agents that may be used in the methods of the disclosure are described inInternational PCT Publication Nos WO 2015 / 179724 and WO 2019 / 222166, the entire contents of each of which are incorporated herein by reference. 36 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO VII. Pharmaceutical Compositions of the Disclosure The present disclosure also includes pharmaceutical compositions and formulations whichinclude the single stranded oligonucleotides (REVERSIRs), e.g., A-762645, for use in the methods of the disclosure. In one embodiment, provided herein are pharmaceutical compositions containing a single stranded oligonucleotide, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the single stranded oligonucleotide , e.g., A- 762645, are useful for methods of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran); ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran); and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene (e.g. the dsRNA agent AD-85481, also known as Zilebesiran). Such pharmaceutical compositions are formulated based on the mode of delivery. The pharmaceutical compositions comprising single stranded oligonucleotides of thedisclosure, e.g., A-762645, may be, for example, solutions with or without a buffer, or compositionscontaining pharmaceutically acceptable carriers. Such compositions include, for example, aqueous or crystalline compositions, liposomal formulations, micellar formulations, emulsions, and gene therapy vectors. In the methods of the disclosure, the single stranded oligonucleotide, e.g., A-762645, may be administered in a solution. A free single stranded oligonucleotide, e.g., A-762645, may be administered in an unbuffered solution, e.g., in saline or in water. Alternatively, the free single stranded oligonucleotide, e.g., A-762645, may also be administered in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution containing the single stranded oligonucleotide can be adjusted such that it is suitable for administering to a subject. In some embodiments, the buffer solution further comprises an agent for controlling the osmolarity of the solution, such that the osmolarity is kept at a desired value, e.g., at the physiologic values of the human plasma. Solutes which can be added to the buffer solution to control the osmolarity include, but are not limited to, proteins, peptides, amino acids, non-metabolized polymers, vitamins, ions, sugars, metabolites, organic acids, lipids, or salts. In some embodiments, the agent for controlling the osmolarity of the solution is a salt. In certain embodiments, the agent for controlling the osmolarity of the solution is sodium chloride or potassium chloride. In some embodiments, the pharmaceutical compositions of the disclosure are pyrogen free ornon-pyrogenic. The pharmaceutical compositions of the present disclosure can be administered in a numberof ways depending upon whether local or systemic treatment is desired and upon the area to be 37 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO treated. Administration can be topical (e.g., by a transdermal patch), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal, e.g., via an implanted device; or intracranial, e.g., by intraparenchymal, intrathecal or intraventricular, administration. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by subcutaneous (SC), intramuscular (IM), or intravenous (IV) delivery. Thepharmaceutical compositions of the disclosure may be administered in dosages sufficient forinhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene; ameliorating in a subject in need thereof, a side effect of a dsRNA agent, or a salt thereof, that inhibits the expression of an AGT gene; and / or treating a subject in need thereof, previously administered a dsRNA agent, or a salt thereof, that inhibits the expression of an angiotensinogen AGT gene. In some embodiments, a fixed dose of of about 25 mg to about 1,200 mg (e.g., about 25 to about 200 mg; about 200 mg to about 400 mg; about 400 mg to about 800 mg; about 800 mg to about 1,200 mg; about 25 mg to about 150 mg; about 150 mg to about 300 mg; about 300 mg to about 450 mg; about 450 mg to about 600 mg; about 600 mg to about 750 mg; about 750 mg to about 900 mg; about 900 mg to about 1,050 mg; about 1,050 mg to about 1,200 mg; about 25 mg to about 100 mg; about 100 mg to about 200 mg; about 200 mg to about 300 mg; about 300 mg to about 400 mg; about 400 mg to about 500 mg; about 500 mg to about 600 mg; about 600 mg to about 700 mg; about 700 mg to about 800 mg; about 800 mg to about 900 mg; about 900 mg to about 1,000 mg; about 1,000 mg to about 1,100 mg; about 1,100 mg to about 1,200 mg; about 25 mg; 50 mg; 75 mg; 100 mg; 150 mg; 200 mg; 250 mg; 300 mg; 350 mg; 400 mg; 450 mg; 500 mg; 550 mg; 600 mg; 650 mg; 700 mg; 750 mg; 800 mg; 850 mg; 900 mg; 950 mg; 1,000 mg; 1,050 mg; 1,100 mg; 1,150 mg; or 1,200 mg) of the single stranded oligonucleotides, e.g., A-762645, is administered to the subject. In some embodiments, a single dose of the pharmaceutical compositions can be long lasting. In other embodiments, a repeat-dose regimen may be administered. In some embodiments, the fixed dose is administered to the subject at least once. In some embodiments, the fixed dose is split into three doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 24 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 12 hour intervals. In some embodiments, the fixed dose is split into three doses and administered to the subject at 8 hour intervals. In some embodiments, the fixed dose is split into two doses and administered to the subject at 8 hour intervals. In some embodiments, the subject is administered a fixed dose of about 25 mg to about 200 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg to about 400 mg. 38 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO In some embodiments, the subject is administered a fixed dose of about 400 mg to about 800 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg to about 1,200 mg. In some embodiments, the subject is administered a fixed dose of about 25 mg. In some embodiments, the subject is administered a fixed dose of about 50 mg. In some embodiments, the subject is administered a fixed dose of about 75 mg. In some embodiments, the subject is administered a fixed dose of about 100 mg. In some embodiments, the subject is administered a fixed dose of about 150 mg. In some embodiments, the subject is administered a fixed dose of about 200 mg. In some embodiments, the subject is administered a fixed dose of about 250 mg. In some embodiments, the subject is administered a fixed dose of about 300 mg. In some embodiments, the subject is administered a fixed dose of about 350 mg. In some embodiments, the subject is administered a fixed dose of about 400 mg. In some embodiments, the subject is administered a fixed dose of about 450 mg. In some embodiments, the subject is administered a fixed dose of about 500 mg. In some embodiments, the subject is administered a fixed dose of about 550 mg. In some embodiments, the subject is administered a fixed dose of about 600 mg. In some embodiments, the subject is administered a fixed dose of about 650 mg. In some embodiments, the subject is administered a fixed dose of about 700 mg. In some embodiments, the subject is administered a fixed dose of about 750 mg. In some embodiments, the subject is administered a fixed dose of about 800 mg. In some embodiments, the subject is administered a fixed dose of about 850 mg. In some embodiments, the subject is administered a fixed dose of about 900 mg. In some embodiments, the subject is administered a fixed dose of about 950 mg. In some embodiments, the subject is administered a fixed dose of about 1,000 mg. In some embodiments, the subject is administered a fixed dose of about 1,050 mg. In some embodiments, the subject is administered a fixed dose of about 1,100 mg. In some embodiments, the subject is administered a fixed dose of about 1,150 mg. In some embodiments, the subject is administered a fixed dose of about 1,200 mg. In some embodiments, the single stranded oligonucleotide, e.g., A-762645, is administered to the subject subcutaneously or intravenously. In some embodiments, the subcutaneous administration is subcutaneous injection. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to mutations present in the subject, previous treatments, the general health or age of the subject, and other diseases present. Moreover, treatment of a subject with a prophylactically or therapeutically effective amount, as appropriate, of a composition can include a single treatment or a series of treatments. The single stranded oligonucleotide can be delivered in a manner to target a particular tissue. Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids. 39 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO The pharmaceutical formulations of the present disclosure, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers. VIII. Kits of the Disclosure In certain aspects, the present disclosure also provides kits for performing any of the methodsof the disclosure. In one aspect, the present disclosure provides a kit for performing one or more ofthe methods desribed herein, comprising a) the single stranded oligonucleotide of the disclosure, e.g., A-762645; b) instructions for use; and c) optionally, means for administering the single stranded oligonucleotide, e.g., A-762645, to the subject in need thereof (e.g., an injection device, such as a pre- filled syringe). In another aspect, the present disclosure provides a kit for performing one or more of themethods desribed herein, comprising a) the dsRNA agent, or a salt thereof, (e.g. the dsRNA agent AD-85481, also known as Zilebesiran) and the single stranded oligonucleotide of the disclosure, e.g., A-762645; b) instructions for use; and c) optionally, means for administering the dsRNA agent, or a salt thereof, and / or the single stranded oligonucleotide to the subject in need thereof (e.g., an injection device, such as a pre-filled syringe). The instructions for use comprise, for example, instructions for administering a prophylactically or therapeutically effective amount of the single stranded oligonucleotide or a pharmaceutical formulation of the single stranded oligonucleotide. The single stranded oligonucleotide or pharmaceutical composition may be in a vial or a pre-filled syringe. The kits may optionally further comprise means for measuring the inhibition of the RNAi activity of the dsRNA agent, or a salt thereof (e.g., means for measuring the inhibition of AGT mRNA, AGT protein, and / or AGT activity). Such means for measuring the inhibition of RNAi activity may comprise a means forobtaining a sample from a subject, such as, e.g., a plasma sample. The kits of the disclosure mayoptionally further comprise means for determining the therapeutically effective or prophylactically effective amount. In certain embodiments the individual components of the pharmaceutical formulation may be provided in one container, e.g., a vial or a pre-filled syringe. Alternatively, it may be desirable to provide the components of the pharmaceutical formulation separately in two or more containers, e.g., one container for the single stranded oligonucleotide and / or dsRNA agent, or a salt thereof, preparation, and at least another for a carrier compound. The kit may be packaged in a number of different configurations such as one or more containers in a single box. The different components can be combined, e.g., according to instructions provided with the kit. The components can be combined 40 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO according to a method described herein, e.g., to prepare and administer a pharmaceutical composition. The kit can also include a delivery device. This disclosure is further illustrated by the following examples which should not be construedas limiting. The entire contents of all references, patents and published patent applications cited throughout this application, as well as the informal Sequence Listing and Figures, are hereby incorporated herein by reference. EXAMPLES Table 1. Abbreviations of nucleotide monomers used in nucleic acid sequence representation. It will be understood that these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'- phosphodiester bonds; and it is understood that when the nucleotide contains a 2’-fluoro modification, then the fluoro replaces the hydroxy at that position in the parent nucleotide (i.e., it is a 2’-deoxy-2’-fluoronucleotide). It is to be further understood that the nucleotide abbreviations in the table omit the3’-phosphate (i.e., they are 3’-OH) when placed at the 3’-terminal position of an oligonucleotide. 41 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 42 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 43 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Example 1. Phase 1 Clinical Trial of REVERSIR A randomized, double-blind (DB), placebo-controlled, single ascending dose (SAD) Phase 1 study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of subcutaneous (SC) administration of a single stranded oligonucleotide (REVERSIR), A-762645, to adult healthy volunteers. A schematic of the study design is depicted in Figure 1. 44 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Diagnosis and Main Eligibility Criteria This study includes adult healthy volunteers. Study Drug, Dose, and Mode of Administration A-762645 is an SC administered single-stranded N-acetylgalactosamine (GalNAc)-conjugated oligonucleotide designed to specifically reverse the pharmacodynamic (PD) effects of Zilebesiran (AD-85481). A schematic depiction of A-762645 is presented in Figure 2. Placebo (sodium chloride 0.9% w / v for SC administration) is administered at the same volume as A-762645 within each cohort. Study drug is administered as a single SC dose. The chemical modifications are defined as follows: a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O- methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C-methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'- C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage. The 3’end of the the single stranded oligonucleotide is covalently linked to an N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol (also referred to as Hyp-(GalNAc- alkyl)3 or L96) ligand, the structure of which is shown in Table 1. Table 3. Unmodified and Modified Nucleotide Sequences of Zilebesiran (AD-85481) The chemical modifications are defined as follows: a, c, g, and u are 2'-O-methyladenosine-3'- phosphate, 2'-O-methylcytidine-3'-phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O- methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O-fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'- phosphate, respectively; dT is a deoxy-thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer. The 3’end of the sense strand is covalently linked to an N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol (also referred to as Hyp-(GalNAc- alkyl)3 or L96) ligand, the structure of which is shown in Table 1. 45 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Duration of Treatment and Study Participation The duration of treatment with A-762645 is up to 3 months. The estimated total time on study for each healthy volunteer is up to 4 months, including up to 30 days of screening and up to 3 months of treatment. Statistical Methods The planned enrollment for this study is up to 78 healthy volunteers. The populations (analysis sets) are defined as follows: Safety Analysis Set: All healthy volunteers who received any amount of study drug. All by- treatment analyses based on the Safety Analysis Set are grouped according to the treatment actually received. Pharmacokinetics (PK) Analysis Set: All healthy volunteers who received at least 1 full dose of A-762645 and have at least 1 evaluable postdose PK assessment. All by treatment analyses based on the PK Analysis Set are grouped according to the treatment actually received. Pharmacodynamics (PD) Analysis Set: All healthy volunteers who received at least 1 full dose of study drug and have at least 1 postdose assessment of serum angiotensinogen (AGT). All by- treatment analyses based on the PD Analysis Set are grouped according to the treatment actually received. Safety data is analyzed using the Safety Analysis Set. The PK and PD Analysis Sets are used to conduct PK and PD analyses, respectively. Objectives And Endpoints Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AGT=angiotensinogen; AUC=area under the concentration-time curve; Cmax=maximum plasma concentration; ECG=electrocardiogram; fe=fraction excreted in urine; PK=pharmacokinetic; tmax=time to maximum plasma concentration. 46 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO Summary of Study Design Healthy volunteers are enrolled in 1 of 5 planned SAD cohorts. Up to 2 optional cohorts are added to better understand the safety and tolerability of a single dose of A-762645. The first 2 cohorts include 5 healthy volunteers and subsequent cohorts include 8 healthy volunteers (Figure 1). Sentinel pair dosing is performed at the initiation of the first 2 dose cohorts. The 2 sentinel healthy volunteers in each cohort is monitored for adverse events (AEs) for at least 7 days prior to study drug administration to the remaining 3 healthy volunteers in the respective dose cohort. The Safety Review Committee (SRC) determines when to continue dosing within the cohort based on available safety and tolerability data. Subsequent cohorts, including up to 2 optional cohorts, enroll 8 healthy volunteers randomized 3:1 (A-762645:placebo). Up to 4 additional healthy volunteers, randomized 3:1 (A-762645:placebo), are enrolled in each cohort if it is deemed necessary by the SRC. The decision to proceed to dosing the next cohort and the actual dose to be administered is determined by the SRC based on at least 7 days of postdose safety and tolerability data. Healthy volunteer eligibility is determined during screening (between Days -30 and -1). Eligible healthy volunteers are admitted to the clinical study site on Day -1 or earlier, if allowed per local regulation and / or site policy, to confirm eligibility and conduct predose assessments. On Day 1, healthy volunteers receive a single SC dose of study drug (A-762645 or placebo). Healthy volunteers who are dosed remain inpatient in the study site until discharge on Day 3. During the 3-month DB period, healthy volunteers return to the clinical study site on an outpatient basis for safety, tolerability, and laboratory assessments through Month 3. Each cohort is unblinded when all healthy volunteers in an individual cohort have completed the Month 3 visit or withdrawn from the study. Study Drug Dosing and Progression The starting dose of A-762645 for healthy volunteers in Cohort 1 is 25 mg. Based on nonclinical pharmacology studies, this starting dose is expected to be safe and well tolerated. The maximum dose administered does not exceed 1200 mg. For each dose progression / escalation, the decision to proceed to dosing the next cohort and the actual dose administered is determined by the SRC based on review of at least 7 days of postdose safety and tolerability data (i.e.,, AEs) and available PK data from at least 4 of 5 healthy volunteers (for Cohorts 1 and 2) or 6 of 8 healthy volunteers (for all other cohorts) and cumulative safety data (e.g., if a safety signal is observed, then upon SRC recommendation, a de-escalation cohort is initiated). The following are the dose levels: ^Cohort 1: 25 mg^ Cohort 2: 75 mg^ Cohort 3: 150 mg^ Cohort 4: 300 mg47 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO ^Cohort 5: 600 mg^ Optional cohort(s): ≤1200 mgSentinel pair dosing is performed at the initiation of the first 2 dose cohorts. The 2 sentinel healthy volunteers in each cohort are monitored for AEs for at least 7 days prior to study drug administration to the remaining 3 healthy volunteers in the respective dose cohort. The SRC determines when to continue dosing within the cohort based on available safety and tolerability data. In the first 2 cohorts, 2 sentinel healthy volunteers are randomized 1:1 (A-762645:placebo) and the 3 remaining healthy volunteers are randomized 2:1 (A-762645:placebo). Subsequent cohorts, including up to 2 optional cohorts, enroll 8 healthy volunteers randomized 3:1 (A-762645:placebo). Up to 4 additional healthy volunteers, randomized 3:1 (A-762645:placebo), are enrolled in each cohort if it is deemed necessary by the SRC, for a total of up to 78 healthy volunteers. The exact doses to be administered may be modified (higher or lower) from planned doses based on emerging safety and PK data from preceding cohorts. Dose progression / escalation proceeds accordingly such that optional dosing regimens are explored and that dosing regimens are adjusted in line with evolving safety and tolerability data. Dose progressions do not exceed 2-fold increments from the previous dose (except Cohort 2) and do not exceed the planned maximum dose of 1200 mg. Inclusion Criteria Healthy volunteers are eligible to be included in the study if all the following criteria apply: Age and Sex 1. Male or female age 18 to 65 years, inclusive, at the time of initial informed consent.Healthy Volunteer Characteristics 2. Body mass index ≥18 kg / m2 and ≤28 kg / m2.3. 12-lead ECG within normal limits or with no clinically significant abnormalities in theopinion of the Investigator. Fridericia-corrected QT interval should be <450 msec in males or <470 msec in females. Informed Consent 4. Healthy volunteer is able to understand and is willing and able to comply with the studyrequirements and to provide written informed consent. Exclusion Criteria Healthy volunteers are excluded from the study if any of the following criteria apply: Laboratory Assessments 1. Has any of the following laboratory parameter assessments at screening:a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit ofnormal (ULN). b. Total bilirubin >ULN. Healthy volunteers with elevated total bilirubin that is secondary todocumented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. 48 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO c. International normalized ratio (INR) >1.1.2. Has known human immunodeficiency virus infection; or known current or chronic hepatitis Cvirus or hepatitis B virus infection.3. Has an estimated glomerular filtration rate (eGFR) of <90 mL / min / 1.73m2 at screening(calculation is based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).4. History of albuminuria (defined as urine albumin:creatinine ratio >30 mg / g or >30 mg / day) orlaboratory results consistent with this diagnosis upon screening.5. Any clinical safety laboratory result considered clinically significant and unacceptable by theInvestigator. Prior / Concomitant Therapy6. Received an investigational agent within the last 30 days or 5 half-lives, whichever is longer,before the dose of study drug, or are in follow-up of another clinical study before study enrollment. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational.7. Currently taking, taken within 6 months before randomization, or anticipated to receive anRNAi therapeutic or antisense oligonucleotide other than A-762645 (approved or investigational) during the study.8. Used prescription drugs within 14 days or 5 half-lives (whichever is longer) prior toscreening, with the following exceptions: a. Hormone replacement therapy (e.g., estrogen, thyroid)b. Oral contraceptives, injectable progesterone, and subdermal implantsc. Proton pump inhibitorsd. Histamine H2-receptor antagonistse. Nonsteroidal anti-inflammatory drugs (NSAIDs)9. Used over-the-counter medication, excluding routine vitamins, proton pump inhibitors,histamine H2-receptor antagonists, and NSAIDs, within 7 days or 5 half-lives, whichever is longer, prior to dosing, unless determined by the Investigator to be not clinically relevant.10. Previously treated with at least 1 dose of Zilebesiran in another clinical study.Medical Conditions11. Clinically relevant history or presence of respiratory, gastrointestinal, renal, cardiovascular,hepatic, hematological, lymphatic, neurological, psychiatric, musculoskeletal, genitourinary, immunological, and other inflammatory diseases, or dermatological (including eczema and dermatitis) or connective tissue diseases or disorders.12. History of multiple drug allergies or history of allergic reaction to any component of orexcipient in the study drug. 49 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 13. Has other medical conditions or comorbidities which, in the opinion of the Investigator,would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the healthy volunteer. 14. Clinically significant illness, in the opinion of the Investigator, within 7 days prior torandomization. 15. History of intolerance to SC injection(s).Contraception, Pregnancy, and Breastfeeding 16. Is not willing to comply with the contraceptive requirements during the study period.17. Female healthy volunteer is pregnant, planning a pregnancy, or breastfeeding.Alcohol Use 18. Unwilling or unable to limit alcohol consumption throughout the course of the study. Alcoholintake of >2 units / day is excluded during the study (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]). 19. History or clinical evidence of drug / chemical or alcohol use disorder, within the last12 months before screening, in the opinion of the Investigator. 20. Positive test result for alcohol and / or drugs of abuse during screening.Other 21. Healthy volunteer is not randomized to a cohort because the cohort is closed and there are noother options for the healthy volunteer to be randomized in the study. Pharmacodynamic Analysis Serum AGT is summarized over time for all healthy volunteers in the PD Analysis Set. Pharmacokinetic Analysis Pharmacokinetic analyses is conducted using the PK Analysis Set. PK parameters are summarized by descriptive statistics for each A-762645 dose level. Pharmacokinetic parameters include but are not be limited to: maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), fraction excreted in urine (fe), elimination half-life (t½β), area under the concentration-time curve (AUC), apparent clearance, and apparent volume of distribution. Other parameters may be calculated, if deemed necessary. Anti-drug Antibody Analyses The frequency and percentage of healthy volunteers with confirmed positive ADA assay at any time during study and at each scheduled visit is summarized. The titer results for healthy volunteers with confirmed positive ADA results is summarized. Safety Analyses 50 ME1\56018359.v1 Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO The primary endpoint is the frequency and percentage of healthy volunteers with treatment- emergent AEs (hereafter referred to simply as AEs). Safety assessments also include vital signs, ECGs, clinical laboratory assessments, and physical exams. Extent of exposure is summarized by dose level and overall. Prior and concomitant medications are coded using the World Health Organization Drug Dictionary. Results are tabulated by Anatomical Therapeutic Chemical Classification System and Preferred Term (PT). Adverse events are classified according to the Medical Dictionary for Regulatory Activities System Organ Class (SOC) and PT by dose level and overall. AEs, SAEs, study-drug related AEs, and AEs leading to death are summarized by SOC and PT for each dose level and overall. Descriptive statistics are provided for clinical laboratory parameters, ECG, and vital signs summarizing the observed values and changes from baseline over time. Laboratory shift tables from baseline grade (or category) to worst post-baseline grade (or category) are presented for laboratory parameters that are graded or categorized. Other safety summaries are presented as appropriate. EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims. 51 ME1\56018359.v1

Claims

Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO We claim:

1. A method of inhibiting in a subject in need thereof, the RNAi inhibitory activity of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C- methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage, thereby inhibiting the RNAi inhibitory activity of the dsRNA agent, or a salt thereof, in the subject.

2. A method of ameliorating in a subject in need thereof, a side effect of a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C- methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage, thereby ameliorating the side effect of the dsRNA agent, or a salt thereof, in the subject.

3. A method of treating a subject in need thereof, previously administered a double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, that inhibits the expression of an angiotensinogen (AGT) gene, the method comprising administering to the subject a fixed dose of about 25 mg to about 1,200 mg of a single stranded oligonucleotide, wherein the single stranded oligonucleotide comprises a modified nucleotide sequence comprising at least 14 contiguous nucleotides differing by no more than 3 nucleotides and / or 52 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO nucelotide modifications from the modified nucleotide sequence 5’- csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO: 100, wherein a is 2'-O-methyladenosine-3’-phosphate, c is 2'-O-methylcytidine-3’-phosphate, g is 2'-O-methylguanosine-3’-phosphate, u is 2'-O-methyluridine-3’-phosphate, (Aln) is 2'-O,4'-C- methylene adenosine-3’-phosphate, (m5Cln) is 2'-O,4'-C-methylene 5-methylcytidine-3’-phosphate, dA is 2’-deoxyadenosine-3’-phosphate, and s is a phosphorothioate linkage, thereby treating the subject.

4. The method of any one of claims 1-3, wherein the fixed dose is administered to the subject at least once.

5. The method of any one of claims 1-3, wherein the fixed dose is split into three doses and administered to the subject at 24 hour intervals.

6. The method of any one of claims 1-3, wherein the fixed dose is split into two doses and administered to the subject at 24 hour intervals.

7. The method of any one of claims 1-3, wherein the fixed dose is split into three doses and administered to the subject at 12 hour intervals.

8. The method of any one of claims 1-3, wherein the fixed dose is split into two doses and administered to the subject at 12 hour intervals.

9. The method of any one of claims 1-3, wherein the fixed dose is split into three doses and administered to the subject at 8 hour intervals.

10. The method of any one of claims 1-3, wherein the fixed dose is split into two doses and administered to the subject at 8 hour intervals.

11. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 25 mg to about 200 mg.

12. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 200 mg to about 400 mg.

13. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 400 mg to about 800 mg. 53 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 14. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 800 mg to about 1,200 mg.

15. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 25 mg.

16. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 75 mg.

17. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 150 mg.

18. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 300 mg.

19. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 600 mg.

20. The method of any one of claims 1-10, wherein the subject is administered a fixed dose of about 1,200 mg.

21. The method of any one of claims 1-20, wherein the single stranded oligonucleotide is administered to the subject subcutaneously or intravenously.

22. The method of claim 21, wherein the subcutaneous administration is subcutaneous injection.

23. The method of any one of claims 1-22, wherein the single stranded oligonucleotide comprises the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO:

100.

24. The method of any one of claims 1-23, wherein the single stranded oligonucleotide consists of the modified nucleotide sequence 5’-csasuscscs(Aln)csasasusgs(Aln)gs(Aln)gsusas(m5Cln)dA-3’ of SEQ ID NO:

100.

25. The method of any one of claims 1-24, wherein the single stranded oligonucleotide is conjugated to at least one ligand. 54 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 26. The method of claim 25, wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

27. The method of claim 25, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

28. The method of claim 25, wherein the ligand is29. The method of claim 25, wherein the ligand is30. The method of any one of claims 25-29, wherein the ligand is conjugated to a nucleoside comprising a deoxy sugar in the single stranded oligonucleotide. 55 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 31. The method of claim 30, wherein the deoxy sugar is a 2’-deoxy ribose.

32. The method of any one of claims 25-31, wherein the ligand is conjugated to the 3’-terminus of the single stranded oligonucleotide.

33. The method of any one of claims 1-32, wherein the dsRNA agent, or a salt thereof, comprisesa sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence 5’- UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand comprises a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10.

34. The method of any one of claims 1-33, wherein the dsRNA agent, or a salt thereof, comprisesa sense strand and an antisense strand forming a double stranded region, wherein the antisense strand consists of a nucleotide sequence 5’- UGUACUCUCAUUGUGGAUGACGA-3’ of SEQ ID NO: 9, and the sense strand consists of a nucleotide sequence 5’-GUCAUCCACAAUGAGAGUACA-3’ of SEQ ID NO: 10.

35. The method of any one of claims 1-32, wherein the dsRNA agent, or a salt thereof, comprisesa sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'- phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer.

36. The method of any one of claims 1-32 and 35, wherein the dsRNA agent, or a salt thereof,comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'- phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- 56 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer.

37. The method of any one of claims 1-32 and 35-36, wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the modified nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand comprises the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'- phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematicwherein X is O.

38. The method of any one of claims 1-32 and 35-37, wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand consists of the modified nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO: 11, and the sense strand consists of the modified nucleotide sequence 5’-gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO: 12, wherein a, c, g, and u are 2'-O-methyladenosine-3'-phosphate, 2'-O-methylcytidine-3'- phosphate, 2'-O-methylguanosine-3'-phosphate, and 2'-O-methyluridine-3'-phosphate, respectively; Af, Cf, Gf, and Uf are 2'-O-fluoroadenosine-3'-phosphate, 2'-O-fluorocytidine-3'-phosphate, 2'-O- fluoroguanosine-3'-phosphate, and 2'-O-fluorouridine-3'-phosphate, respectively; dT is a deoxy- 57 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO thymine; s is a phosphorothioate linkage; and (Tgn) is thymidine-glycol nucleic acid (GNA) S-isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematicwherein X is O.

39. The method of any one of claims 33-38, wherein the single stranded oligonucleotide is at least about 90% complementary to the entire length of the antisense strand of the dsRNA agent, or a salt thereof.

40. The method of any one of claims 33-39, wherein the single stranded oligonucleotide is fully complementary to the antisense strand of the dsRNA agent, or a salt thereof.

41. The method of any one of claims 1-40, wherein the subject in need thereof is a human.

42. The method of claim 41, wherein the subject in need thereof is suffering from hypotension.

43. The method of claim 41, wherein the subject in need thereof is suffering from hyperkalemia.

44. The method of claim 41, wherein the subject in need thereof is suffering from renal dysfuntion.

45. The method of any one of claims 1-44, further comprising administering to the subject an additional therapy or therapeutic agent selected from the group consisting of increased dietary fluid / salt, fludrocortisone / midodrine treatment, intravenous fluids, vasopressor medications, down-titration or interruption of concomitant antihypertensive medications, a low potassium diet, thiazide / loop diuretic medications, oral potassium binders, calcium, glucose, insulin, hemodialysis, and combinations thereof. 58 ME1\56018359.v1Attorney Docket No.: 121301-24120 Alnyam Docket No.: ALN-532-WO Roche Docket No.: P39560-WO 46. The method of any one of claims 1-45, wherein the single stranded oligonucleotide is administered in a pharmaceutical composition.

47. The method of claim 46, wherein the single stranded oligonucleotide is administered in an unbuffered solution.

48. The method of claim 47, wherein the unbuffered solution is saline or water.

49. The method of claim 46, wherein the single stranded oligonucleotide is administered in a buffer solution.

50. The method of claim 49, wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, phosphate, or any combination thereof.

51. The method of claim 49, wherein the buffer solution is phosphate buffered saline (PBS). 59 ME1\56018359.v1

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