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The New England Journal of Medicine Jul 2023Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis.
METHODS
In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.
RESULTS
Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.
CONCLUSIONS
Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).
Topics: Humans; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Hypertension; Irbesartan; RNA Interference; Tetrazoles; Diet; Injections, Subcutaneous
PubMed: 37467498
DOI: 10.1056/NEJMoa2208391 -
Experimental Eye Research Sep 2019The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment... (Review)
Review
The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Body Fluids; Enzyme Inhibitors; Homeostasis; Humans; Neprilysin; Oligopeptides; RNA, Small Interfering; Receptor, Angiotensin, Type 2; Renin-Angiotensin System
PubMed: 31129252
DOI: 10.1016/j.exer.2019.05.020 -
Hypertension (Dallas, Tex. : 1979) Nov 2023Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients... (Review)
Review
Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LR, and the small-interfering RNA, zilebesiran. Conjugation to N-acetylgalactosamine enables targeted delivery to hepatocytes, where endosomal storage, slow leakage, and small-interfering RNA recycling (for zilebesiran) result in knockdown over several months. Indeed, zilebesiran has an impressive and durable effect on systolic BP, reduced by up to 20 mm Hg and sustained for 6 months after a single administration, likely due to its very effective knockdown of angiotensinogen, without causing acute kidney injury or hyperkalemia. By contrast, IONIS-AGT-LR caused less knockdown and marginal effects on BP. Future studies should evaluate any loss of efficacy relating to antidrug antibodies, safety issues associated with long-term angiotensinogen suppression, and broader benefits, especially in the context of common comorbidities such as type 2 diabetes and chronic kidney disease.
Topics: Humans; Angiotensinogen; Antihypertensive Agents; Diabetes Mellitus, Type 2; Hypertension; Blood Pressure; Renin-Angiotensin System; Angiotensin II; RNA, Small Interfering
PubMed: 37706295
DOI: 10.1161/HYPERTENSIONAHA.122.19430 -
Journal of the American Heart... Oct 2022
Small Interfering RNA Therapeutics in Hypertension: A Viewpoint on Vasopressor and Vasopressor-Sparing Strategies for Counteracting Blood Pressure Lowering by Angiotensinogen-Targeting Small Interfering RNA.
Topics: Animals; Humans; Rats; Angiotensinogen; Blood Pressure; RNA, Small Interfering; Hypertension; Rats, Inbred SHR; Vasoconstrictor Agents
PubMed: 36216481
DOI: 10.1161/JAHA.122.027694 -
Circulation Research Aug 2021[Figure: see text].
[Figure: see text].
Topics: Angiotensin II; Angiotensinogen; Animals; Heart Failure; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein; Sepsis
PubMed: 34238019
DOI: 10.1161/CIRCRESAHA.120.318075 -
JAMA Mar 2024Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an...
IMPORTANCE
Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis.
OBJECTIVE
To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.
DESIGN, SETTING, AND PARTICIPANTS
This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized.
INTERVENTIONS
Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.
MAIN OUTCOMES AND MEASURES
The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP.
RESULTS
Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients.
CONCLUSIONS AND RELEVANCE
In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04936035.
Topics: Adult; Humans; Female; Middle Aged; Male; Antihypertensive Agents; Blood Pressure; Angiotensinogen; RNA; RNA Interference; Double-Blind Method; Hypertension; Hypotension
PubMed: 38363577
DOI: 10.1001/jama.2024.0728 -
Hypertension (Dallas, Tex. : 1979) Jun 2019Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear....
Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (-68±4 mm Hg), followed by captopril+valsartan (-54±4 mm Hg), captopril (-23±2 mm Hg), siRNA (-14±2 mm Hg), and valsartan (-10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.
Topics: Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Gene Expression Regulation; Hypertension; Injections, Subcutaneous; Liver; Male; RNA; RNA, Small Interfering; Rats; Rats, Inbred SHR
PubMed: 31030610
DOI: 10.1161/HYPERTENSIONAHA.119.12703 -
The New England Journal of Medicine Jul 2023
Topics: Humans; Angiotensinogen; Blood Pressure; Hypertension
PubMed: 37467504
DOI: 10.1056/NEJMe2303534 -
Molecular and Cellular Endocrinology Jun 2021
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Chymases; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypertension; Kidney; Peptide Fragments; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance
PubMed: 33819521
DOI: 10.1016/j.mce.2021.111268 -
Current Opinion in Nephrology and... Mar 2020To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. (Review)
Review
PURPOSE OF REVIEW
To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases.
RECENT FINDINGS
Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease.
SUMMARY
Targeting angiotensinogen with RNA-based therapeutics is a promising new tool to treat hypertension and diseases beyond. Their long-lasting effects are particularly exciting, and if translated to a clinical application of at most a few administrations per year, may help to eliminate nonadherence.
Topics: Angiotensinogen; Animals; Humans; Hypertension; Oligonucleotides, Antisense; RNA, Small Interfering; Renin-Angiotensin System
PubMed: 31895165
DOI: 10.1097/MNH.0000000000000586