Entering a New Era of Antihypertensive Therapy

Commentary on: Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391 Commentary on: Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391 About 130 million US adults have hypertension,1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Hypertension. 2018; 71: e13-e115https://doi.org/10.1161/HYP.0000000000000065Crossref PubMed Scopus (2986) Google Scholar yet fewer than half have controlled blood pressure (BP), which has worsened in recent years.2Muntner P. Hardy S.T. Fine L.J. et al.Trends in blood pressure control among US adults with hypertension, 1999-2000 to 2017-2018.JAMA. 2020; 324: 1190-1200https://doi.org/10.1001/jama.2020.14545Crossref PubMed Scopus (466) Google Scholar For quite some time, hypertension seemed to be considered a "solved" problem that was ignored by the world of pharmacologic research and development. The last time a new class of antihypertensive medication was approved by the US Food and Drug Administration (FDA) was direct renin inhibitors in 2007, which have not panned out to be particularly effective or well tolerated over existing therapies.3Harel Z. Gilbert C. Wald R. et al.The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis.BMJ. 2012; 344: e42https://doi.org/10.1136/bmj.e42Crossref PubMed Scopus (113) Google Scholar,4Wang G.M. Li L.J. Tang W.L. Wright J.M. Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension.Cochrane Database Syst Rev. 2020; 10: CD012569https://doi.org/10.1002/14651858.CD012569.pub2Crossref PubMed Scopus (2) Google Scholar Prior to that, the first angiotensin receptor blocker was approved in 1995. Inadequate BP control is a major cause of disability, morbidity, and mortality and is driven by many factors, including clinician inertia and insufficient response to multiple antihypertensive classes, particularly in chronic kidney disease (CKD).5An J. Kurella Tamura M. Odden M.C. et al.Prevalence of apparent treatment-resistant hypertension in chronic kidney disease in two large US health care systems.Clin J Am Soc Nephrol. 2022; 17: 1457-1466https://doi.org/10.2215/CJN.04110422Crossref PubMed Scopus (8) Google Scholar Furthermore, many patients with hypertension struggle with polypharmacy, resulting in a litany of adverse medication effects, financial toxicity, and poor adherence. While drug companies have tried to improve upon existing drug classes by creating longer-acting agents with fewer adverse effects and that are available in fixed-dose combinations, none have had a palpable impact on BP control and prescribing patterns at the population level. Innovations are direly needed to address the numerous barriers to controlling BP. In a turn of the tides, multiple new antihypertensive therapies are currently undergoing investigation. Several of these therapies introduce innovative therapeutic approaches, address novel targets (Fig 1), and show promising early results. The most groundbreaking of these is zilebesiran. Zilebesiran is a first-in-class small interfering RNA that binds to the hepatic asialoglycoprotein receptor, resulting in a reduction in angiotensinogen messenger RNA and thus a decrease in hepatic production of angiotensinogen.6Uijl E. Mirabito Colafella K.M. Sun Y. et al.Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen.Hypertension. 2019; 73: 1249-1257https://doi.org/10.1161/HYPERTENSIONAHA.119.12703Crossref PubMed Scopus (64) Google Scholar,7Desai A.S. Webb D.J. Taubel J. et al.Zilebesiran, an RNA interference therapeutic agent for hypertension.N Engl J Med. 2023; 389: 228-238https://doi.org/10.1056/NEJMoa2208391Crossref PubMed Scopus (44) Google Scholar Consequently, synthesis of both angiotensin I and II are suppressed, resulting in BP reduction. In the recently published phase 1 trial of zilebesiran,7Desai A.S. Webb D.J. Taubel J. et al.Zilebesiran, an RNA interference therapeutic agent for hypertension.N Engl J Med. 2023; 389: 228-238https://doi.org/10.1056/NEJMoa2208391Crossref PubMed Scopus (44) Google Scholar Desai et al performed a 3-step study to evaluate the safety and pharmacodynamics of this exceptionally long-acting medication (ie, lasting for several months with a single, subcutaneously administered dose) in 107 hypertensive participants aged 18-65 years in the United Kingdom. Individuals with an estimated glomerular filtration rate <60 mL/min/1.73 m2, diabetes, or cardiovascular disease were excluded. In the first step of the trial, participants were randomly assigned to varying doses of zilebesiran versus placebo. In the second step of the trial, participants were randomly assigned to the highest dose of zilebesiran (800 mg) vs placebo and were monitored on sequentially administered low- then high-sodium diets. In the third step, all participants received the highest dose of zilebesiran (no placebo), and any participants with systolic BPs ≥120 mm Hg 6 weeks after administration were initiated on a once-daily angiotensin receptor blocker (irbesartan). Although the primary focus of the study was to determine the safety of the medication and the duration and magnitude of angiotensinogen reduction, participants also underwent repeated 24-hour ambulatory BP monitoring to evaluate changes in systolic and diastolic BP as exploratory end points. The study demonstrated that adverse events were overall similar in the zilebesiran and placebo groups over a minimum of 12 weeks of follow-up.7Desai A.S. Webb D.J. Taubel J. et al.Zilebesiran, an RNA interference therapeutic agent for hypertension.N Engl J Med. 2023; 389: 228-238https://doi.org/10.1056/NEJMoa2208391Crossref PubMed Scopus (44) Google Scholar Injection-site reactions were the only notable treatment-related adverse event, which occurred among 5 (6%) participants in the zilebesiran group and no participants in the placebo group. Notably, there were no reported episodes of hypotension, hyperkalemia, or acute kidney injury and no change in creatinine with zilebesiran. Low titers of antibodies against the drug were detected in 2 (2%) participants. The highest dose of zilebesiran reduced angiotensinogen levels rapidly by >90%, lasting for at least 24 weeks. In exploratory analyses, participants who received the highest dose of zilebesiran had a mean 23/11 mm Hg decline in mean 24-hour BP at 24 weeks. No change in BP was observed in the placebo arm at 12 weeks. In the second step of the trial, the greatest decline in BP was among those receiving zilebesiran while on a low-sodium diet. In the third step of the study, more than half of participants (63%) had systolic BPs ≥120 mm Hg at 6 weeks and received add-on irbesartan, per protocol, which provided additional incremental BP lowering by a mean 6/3 mm Hg without affecting creatinine or potassium levels. Limitations of the study include relatively small sample size, limited duration of follow-up, and exclusion of key patient groups, including older patients and those with multiple comorbidities. As this was a phase 1 study of zilebesiran, there are no prior clinical studies for comparison. For some context, the FDA has approved inclisiran, another small interfering RNA that inhibits production of proprotein convertase subtilisin/kexin type 9 (PCSK9). Given subcutaneously every 6 months, inclisiran reduces low-density lipoprotein cholesterol levels by about 50%.8Ray K.K. Wright R.S. Kallend D. et al.Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.N Engl J Med. 2020; 382: 1507-1519https://doi.org/10.1056/NEJMoa1912387Crossref PubMed Scopus (775) Google Scholar Similar to zilebesiran, the only treatment-related adverse event was injection-site reaction, which occurred in 3%-5% of trial participants. Antihypertensive agents that inhibit the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, are susceptible to causing angiotensin II and aldosterone escape (ie, return to normal or elevated levels despite blocking the renin-angiotensin pathway upstream), which may contribute to refractory hypertension and target organ damage.9Te Riet L. van Esch J.H. Roks A.J. van den Meiracker A.H. Danser A.H. Hypertension: renin-angiotensin-aldosterone system alterations.Circ Res. 2015; 116: 960-975https://doi.org/10.1161/CIRCRESAHA.116.303587Crossref PubMed Scopus (535) Google Scholar Upstream inhibition of the renin-angiotensin system has been proposed as a way to avert angiotensin II and aldosterone escape. Unfortunately, this did not yield better efficacy or tolerability in the case of direct renin inhibitors compared to or in combination with downstream inhibitors of the renin-angiotensin system.3Harel Z. Gilbert C. Wald R. et al.The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis.BMJ. 2012; 344: e42https://doi.org/10.1136/bmj.e42Crossref PubMed Scopus (113) Google Scholar,4Wang G.M. Li L.J. Tang W.L. Wright J.M. Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension.Cochrane Database Syst Rev. 2020; 10: CD012569https://doi.org/10.1002/14651858.CD012569.pub2Crossref PubMed Scopus (2) Google Scholar This may, in part, be due to incidental upstream inhibition of counter-regulatory pathways in the renin-angiotensin system that reduce inflammation, oxidative stress, and fibrosis.10Paz Ocaranza M. Riquelme J.A. Garcia L. et al.Counter-regulatory renin-angiotensin system in cardiovascular disease.Nat Rev Cardiol. 2020; 17: 116-129https://doi.org/10.1038/s41569-019-0244-8Crossref PubMed Scopus (365) Google Scholar Preclinical animal studies demonstrated that a single administration of zilebesiran had similar antihypertensive efficacy to once daily angiotensin receptor blockade and similarly did not affect plasma or renal angiotensin II levels.6Uijl E. Mirabito Colafella K.M. Sun Y. et al.Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen.Hypertension. 2019; 73: 1249-1257https://doi.org/10.1161/HYPERTENSIONAHA.119.12703Crossref PubMed Scopus (64) Google Scholar However, when combined, zilebesiran and angiotensin receptor blockade had a synergistic effect on BP that was greater than that observed when angiotensin-converting enzyme inhibition was combined with angiotensin receptor blockade. This dual renin-angiotensin system blockade did result in a decline in plasma and renal angiotensin II levels but also yielded an increase in potassium levels with no change in creatinine (in the setting of normal baseline kidney function), somewhat reminiscent of prior studies of dual renin-angiotensin system blockade.11Makani H. Bangalore S. Desouza K.A. Shah A. Messerli F.H. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials.BMJ. 2013; 346: f360https://doi.org/10.1136/bmj.f360Crossref PubMed Scopus (194) Google Scholar These findings suggest attenuation of angiotensin II escape. Nonetheless, zilebesiran specifically targets the hepatic asialoglycoprotein receptor, which is responsible for most, but not all, of the body's angiotensinogen synthesis. Angiotensinogen is produced by several other organs, including the brain, kidneys, heart, adrenal glands, and adipose tissue. Murine studies suggest that extrahepatic angiotensinogen does not significantly affect BP,12Cruz-Lopez E.O. Ye D. Wu C. et al.Angiotensinogen suppression: a new tool to treat cardiovascular and renal disease.Hypertension. 2022; 79: 2115-2126https://doi.org/10.1161/HYPERTENSIONAHA.122.18731Crossref PubMed Scopus (20) Google Scholar but further research is needed to understand if these findings translate to humans. Zilebesiran is at an earlier stage of investigation than several other novel antihypertensive agents, including nonsteroidal mineralocorticoid receptor antagonists such as finerenone and esaxerenone,13Epstein M. Kovesdy C.P. Clase C.M. Sood M.M. Pecoits-Filho R. Aldosterone, mineralocorticoid receptor activation, and CKD: a review of evolving treatment paradigms.Am J Kidney Dis. 2022; 80: 658-666https://doi.org/10.1053/j.ajkd.2022.04.016Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar highly selective aldosterone synthase (CYP11B2) inhibitors such as baxdrostat14Freeman M.W. Halvorsen Y.D. Marshall W. et al.Phase 2 trial of baxdrostat for treatment-resistant hypertension.N Engl J Med. 2023; 388: 395-405https://doi.org/10.1056/NEJMoa2213169Crossref PubMed Scopus (103) Google Scholar and lorundrostat,15Laffin L.J. Rodman D. Luther J.M. et al.Aldosterone synthase inhibition with lorundrostat for uncontrolled hypertension: the Target-HTN randomized clinical trial.JAMA. 2023; 330: 1140-1150https://doi.org/10.1001/jama.2023.16029Crossref PubMed Scopus (24) Google Scholar angiotensin receptor–neprilysin inhibitors such as sacubitril-valsartan,16Kario K. Williams B. Angiotensin receptor-neprilysin inhibitors for hypertension-hemodynamic effects and relevance to hypertensive heart disease.Hypertens Res. 2022; 45: 1097-1110https://doi.org/10.1038/s41440-022-00923-2Crossref PubMed Scopus (15) Google Scholar and the dual endothelin receptor antagonist aprocitentan.17Schlaich M.P. Bellet M. Weber M.A. et al.Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.Lancet. 2022; 400: 1927-1937https://doi.org/10.1016/S0140-6736(22)02034-7Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Distinct from nonsteroidal mineralocorticoid receptor antagonists, which selectively block aldosterone from binding to mineralocorticoid receptors in the heart and kidneys, aldosterone synthase inhibitors prevent adrenal aldosterone synthesis altogether. In the recent phase 2 trial of baxdrostat,14Freeman M.W. Halvorsen Y.D. Marshall W. et al.Phase 2 trial of baxdrostat for treatment-resistant hypertension.N Engl J Med. 2023; 388: 395-405https://doi.org/10.1056/NEJMoa2213169Crossref PubMed Scopus (103) Google Scholar 248 participants with resistant hypertension were randomized to 1 of 3 doses of baxdrostat vs placebo for 12 weeks. The higher dose of baxdrostat (2 mg) lowered office systolic BP, the primary end point, by 11 mm Hg more than placebo. With regard to safety, 2 participants had to temporarily hold baxdrostat owing to serum potassium levels elevated to 6 mmol/L, which did not recur after restarting the medication. Endothelin-1 is a potent vasoconstrictive peptide that acts on type A and B endothelin receptors in endothelial and vascular smooth muscle cells.18Schiffrin E.L. State-of-the-art lecture. Role of endothelin-1 in hypertension.Hypertension. 1999; 34: 876-881https://doi.org/10.1161/01.hyp.34.4.876Crossref PubMed Scopus (173) Google Scholar Unlike some prior endothelin receptor antagonists that were more selective and susceptible to poorer efficacy and safety, aprocitentan targets both endothelin A and B receptors and has a better safety profile.19Heidari Nejad S. Azzam O. Schlaich M.P. Dual endothelin antagonism with aprocitentan as a novel therapeutic approach for resistant hypertension.Curr Hypertens Rep. 2023; https://doi.org/10.1007/s11906-023-01259-zCrossref PubMed Scopus (2) Google Scholar In the recent phase 3 trial of aprocitentan,17Schlaich M.P. Bellet M. Weber M.A. et al.Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.Lancet. 2022; 400: 1927-1937https://doi.org/10.1016/S0140-6736(22)02034-7Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar 730 participants with resistant hypertension were randomized to 1 of 2 doses of aprocitentan vs placebo for 4 weeks followed by single-blinded administration of high-dose aprocitentan (25 mg) for 32 weeks followed by randomization to high-dose aprocitentan vs placebo for an additional 12 weeks. The higher dose of aprocitentan lowered office systolic BP, the primary endpoint, by 4 mm Hg more than placebo. Of note, aprocitentan had a slightly greater effect on night-time ambulatory BP (7 mm Hg lower than placebo) than daytime BP (5 mm Hg lower than placebo), which is not typically observed with antihypertensive therapies. Aprocitentan also reduced albuminuria by about 30%, and had the most pronounced BP lowering among participants with albuminuria and CKD stages 3 and 4. However, 18% of participants on the higher dose experienced fluid retention, which was severe enough in 7 participants to stop the medication. Zilebesiran's BP-lowering properties are impressive and may be larger in magnitude than currently available daily renin-angiotensin system targeting agents. Zilebesiran may be even better tolerated and likely only requires dosing once every 6 months. Considering the many barriers to achieving BP control, particularly nonadherence, excessive pill burden, and difficulty attaining antihypertensive therapy, zilebesiran has the potential to be a game changer. Nonetheless, as this was a phase 1 trial, zilebesiran is far from ready for clinical use. Additional studies are needed to determine zilebesiran's full magnitude and duration of action, dosing intervals, tolerability after multiple doses, and BP-lowering and antiproteinuric efficacy. Larger studies in more diverse populations are needed, particularly including older participants and those with CKD. More research is needed to understand how this drug will behave in individuals in need of angiotensinogen, such as those in shock or during pregnancy, and whether protocols that restore hepatic angiotensinogen levels in a murine model20Uijl E. Ye D. Ren L. et al.Conventional vasopressor and vasopressor-sparing strategies to counteract the blood pressure-lowering effect of small interfering RNA targeting angiotensinogen.J Am Heart Assoc. 2022; 11e026426https://doi.org/10.1161/JAHA.122.026426Crossref PubMed Scopus (18) Google Scholar are practical and effective in humans. Regardless of the remaining barriers, we are undoubtedly entering a new era of antihypertensive therapy. Jordana B. Cohen, MD, MSCE, and Adam P. Bress, PharmD, MS. Dr Cohen's ORCiD is 0000-0003-4649-079X. None. The authors declare that they have no relevant financial interests. Received August 28, 2023, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form September 24, 2023.