Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension
Authors, Journal, Affiliations, Type, DOI
- Authors: Akshay S. Desai, David J. Webb, Jorg Taubel, Sarah Casey, Yansong Cheng, Gabriel J. Robbie, Don Foster, Stephen A. Huang, Sean Rhyee, Marianne T. Sweetser, and George L. Bakris
- Journal: New England Journal of Medicine, 2023;389(3):228-238 (July 20, 2023)
- Affiliations: Brigham and Women's Hospital, Boston, and Alnylam Pharmaceuticals, Cambridge, Massachusetts; University of Edinburgh; Richmond Pharmacology and St George's University of London; Medicines Evaluation Unit, Manchester University NHS Foundation Trust; University of Chicago Medicine — four United Kingdom sites
- Type: Four-part first-in-human phase 1 study. Parts A (single ascending dose) and B (fixed dose under controlled salt intake) were double-blind, randomised, placebo-controlled; Part E (fixed dose with irbesartan coadministration) was open-label. Sponsored by Alnylam, which designed the study, collected and analysed the data, and took part in interpreting them.
- DOI: https://doi.org/10.1056/NEJMoa2208391
Overview
Zilebesiran is a GalNAc-conjugated small interfering RNA that binds the hepatic asialoglycoprotein receptor and silences angiotensinogen mRNA — the sole precursor of all angiotensin peptides — from a subcutaneous injection. In 107 patients with stage 1–2 hypertension, single doses produced dose-dependent falls in serum angiotensinogen (r = −0.56 at week 8) and in 24-hour ambulatory blood pressure, with doses of 200 mg or more lowering systolic pressure by more than 10 mmHg and diastolic by more than 5 mmHg by week 8 and sustaining that effect to 24 weeks. The study was designed for safety and mechanism, not efficacy: no hypothesis was tested, follow-up was 24 weeks, and the population excluded exactly the patients who dominate clinical practice. Its importance is that it demonstrates a quarterly-or-less-frequent, adherence-independent route to RAAS suppression.
Keywords
Hypertension; RNA interference; small interfering RNA; angiotensinogen; renin–angiotensin–aldosterone system; ambulatory blood pressure monitoring; dietary sodium; zilebesiran
Key Takeaways
Background
- Nearly half of patients with hypertension do not reach guideline targets, partly through physician inertia and partly through non-adherence to daily oral therapy; office measurements also conceal variability across the diurnal cycle and over time.
- The RAAS is central to blood-pressure regulation, but ACE inhibition and ARB blockade are blunted by compensatory angiotensin reactivation and aldosterone escape, and more aggressive dual blockade risks hyperkalaemia and renal deterioration.
- Targeting hepatic angiotensinogen — upstream of every angiotensin metabolite, and with liver-restricted delivery intended to spare renal angiotensinogen — offers a way to suppress the system without the compensatory escape, in a formulation that could be given quarterly or twice yearly.
Methods
- Parts reported: A (single ascending dose), B (800 mg under low- and high-salt diets) and E (800 mg with add-on irbesartan). Part C was planned as a multidose phase but removed by protocol amendment; Part D is ongoing.
- Population: adults 18–65 years with treated or untreated hypertension, seated systolic pressure >130 to 165 mmHg (>135 to 165 mmHg in Part E) and 24-hour ambulatory systolic pressure ≥130 mmHg after at least 2 weeks of antihypertensive washout. Exclusions included secondary hypertension, postural hypotension, diabetes, previous cardiovascular events, and current or anticipated beta-blocker therapy.
- Part A: 12 patients per cohort, randomised 2:1 to a single subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400 or 800 mg) or placebo; add-on antihypertensive therapy permitted from week 8 for uncontrolled pressure.
- Part B: after a low-salt diet (0.23 g/day) then a high-salt diet (5.75 g/day), patients were randomised 2:1 to 800 mg zilebesiran or placebo and rechallenged with the same dietary sequence from days 43 to 56, timed to the expected peak drug effect.
- Part E: all patients received 800 mg; those with 24-hour ambulatory systolic pressure ≥120 mmHg at week 6 received irbesartan 300 mg daily for 2 weeks.
- End points: the primary end point was the frequency of adverse events; secondary end points were change in serum angiotensinogen and pharmacokinetics; blood-pressure change on 24-hour ambulatory monitoring was exploratory.
- Statistics: no power calculation and no formal hypothesis testing; descriptive statistics, with confidence intervals not adjusted for multiplicity.
Results
Population
- 107 patients enrolled (May 2019 to January 2022): 84 in Part A (56 zilebesiran, 28 placebo), 12 in Part B (8 vs 4) and 16 in Part E (5 of whom had received placebo in Part A).
- Mean age 53.5 years (range 35–65); 62% men; 25% Black; mean 24-hour systolic pressure 140.3 ± 9.0 mmHg. Patients over 65 years were excluded.
Pharmacodynamics and Pharmacokinetics
- Serum angiotensinogen fell in proportion to dose: r = −0.56 at week 8 (95% CI −0.69 to −0.39).
- Doses of 100 mg or more lowered serum angiotensinogen by more than 90%, sustained from week 3 to week 12; 800 mg maintained >90% suppression through week 24.
- Small decreases in plasma renin activity and in aldosterone, angiotensin I and angiotensin II were seen at 200 mg or more. Irbesartan did not further lower angiotensinogen.
- Pharmacokinetics appeared dose-proportional.
Blood Pressure (Exploratory)
- Dose correlated with the fall in 24-hour ambulatory systolic pressure (r = −0.41 at week 8, 95% CI −0.58 to −0.21), and the fall in systolic pressure correlated with the degree of angiotensinogen reduction (r = 0.52, 95% CI 0.42 to 0.61).
- Doses of 200 mg or more lowered systolic pressure by >10 mmHg and diastolic by >5 mmHg at week 8, consistently across the diurnal cycle (daytime and night-time alike) and sustained to week 24.
- At 800 mg, the week-24 change was −22.5 ± 5.1 / −10.8 ± 2.7 mmHg (n=8; six without add-on therapy).
- Salt dependence (Part B): a low-salt diet alone lowered pressure by −9.1 ± 4.5 / −2.4 ± 3.1 mmHg; after 800 mg zilebesiran with the same low-salt diet the fall was −18.8 ± 4.3 / −8.4 ± 2.5 mmHg; a high-salt diet returned pressure to baseline both before and after dosing.
- Add-on effect (Part E): six patients not needing add-on therapy fell −21.8 ± 2.9 mmHg at week 6; the ten with persistent ambulatory systolic pressure ≥120 mmHg gained a further −6.3 ± 3.1 / −3.0 ± 1.9 mmHg after irbesartan.
Safety
- Adverse events occurred in 58 zilebesiran recipients (72%) and 28 placebo recipients (88%). Those reported in ≥5% were headache, injection-site reaction and upper respiratory tract infection, mostly mild or moderate.
- Injection-site reactions were the only treatment-related event reported in more than two patients — five patients, all mild and transient.
- There were no deaths and no unplanned hospitalisations, and no intervention for hypotension, hyperkalaemia or worsening renal function; no clinically significant change in potassium, sodium, creatinine or eGFR.
- Three serious adverse events occurred: ischaemic optic neuropathy in a placebo recipient, prostate cancer requiring surgery in a 200 mg recipient, and acute anaemia complicating a screening procedure before dosing in a Part E patient.
- Transient, low-titre antidrug antibodies in 2 of 80 patients (2%); no clinically significant weight change over 12 weeks.
Discussion
- The authors argue that angiotensinogen silencing upstream of the RAAS may avoid the compensatory reactivation that limits ACE inhibitors and ARBs, while hepatocyte-restricted delivery leaves renal angiotensinogen intact and limits off-target renal effects — though renal RAAS activity was not directly measured.
- They present the salt-sensitivity finding as a two-edged result: it shows the drug's effect is physiologically tuned to sodium intake, and it offers a way to reverse over-lowering in an emergency (raising salt intake alongside volume resuscitation and pressors). They also note that reversibility of this kind is a safety property when a single injection cannot be withdrawn.
- Two phase 2 studies, KARDIA-1 and KARDIA-2, were under way at the time of publication.
Limitations of the document
- No efficacy hypothesis was tested. The trial was sized for safety and mechanism; every blood-pressure estimate is exploratory, unadjusted for multiplicity, and derived from small dose cohorts.
- Small numbers and short follow-up. 107 patients and 24 weeks cannot assess uncommon serious adverse events, and single doses say nothing about chronic dosing.
- The population excludes the patients who matter most. Diabetes, prior cardiovascular events and age over 65 years were excluded; there were no patients with CKD, heart failure, resistant hypertension, or on beta-blockers. Intravenous RAAS blockade is most valuable and most hazardous in exactly those groups — hyperkalaemia and acute kidney injury risk after sustained angiotensinogen suppression in CKD is untested.
- All patients underwent a 2-week washout, so the drug's effect was measured on a relatively untreated baseline rather than as add-on therapy in patients already on multiple agents.
- High salt intake abolishes the effect. Efficacy is conditional on dietary sodium, which is neither measured nor controlled in routine practice.
- A fixed interval injection cannot be titrated. Where a daily tablet allows dose adjustment within days, a single dose that suppresses angiotensinogen for months has a long offset; the trial shows high salt can partially reverse the pressure effect but does not establish a clinical reversal strategy.
- Teratogenicity is unknown. Although preclinical angiotensinogen siRNA did not cross the placenta or harm pups, human pregnancy data do not exist for this mechanism.
- Four UK sites, a single sponsor, and sponsor-led data analysis and interpretation; no RAAS metabolite data were available to verify liver specificity in humans.
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