Is zilebesiran a novel effective and uniquely administered agent for an expanding therapeutic armamentarium for blood pressure control?

Hypertension is a growing as well as a resource-consuming threat to global public health that affects more than one billion adults worldwide (1). The risk for cardiovascular-renal events and premature mortality begins to escalate at incrementally higher blood pressure (BP) levels that are well within the normal range (2) and also below levels of BP where most hypertensives qualify for antihypertensive drug therapy (3).

Worldwide, treatment rates for adults with hypertension are 38% (men) and 47% (women) with control rates (<140/90 mmHg) approximating 20% in both; improvements in control rates have almost exclusively occurred in high-income countries with virtually no change in low- and middle-income countries (4). In the United States (US), approximately 76% of US adults with hypertension are treated with antihypertensive drugs (5). The majority of adults with hypertension do not achieve adequate control (<130/80 mmHg) (6). Furthermore, at least in the US, control of BP amongst drug-treated adults with hypertension began to decline ~2011–2012 coincident with a fall in treatment rates (7). The majority of drug-treated patients with hypertension require multiple antihypertensive drugs to achieve control. Yet, ~40% of drug-treated adults with hypertension are treated with a single antihypertensive drug, ~40% of uncontrolled drug-treated patients have been prescribed a single drug, and fewer than 25% of drug-treated patients have been prescribed more than two drugs (8).

Hypertension control optimally protects against premature mortality and cardiovascular-renal events when BP is, on average, at levels well below the hypertensive range. Hypertension control rates in drug-treated patients can be influenced by patient, provider, system, disease condition and societal influences (9). Patient characteristics such as obesity (10), as well as depressed kidney function and albuminuria (micro and macro) (11), appear to confer physiological resistance to the BP lowering effect of antihypertensive drugs. Prescription of insufficiently intense drug therapy and therapeutic inertia are important provider factors negatively impacting hypertension control rates. Non-adherence to prescribed antihypertensive drug therapy is a critical patient-related factor negatively influencing hypertension control rates. Once antihypertensive medication has been prescribed, 12% of patients will never fill their prescription (12). One observational study (13) in treatment naïve adults with uncomplicated hypertension started on an angiotensin receptor blocker (ARB) reported persistence of ~60% at 6 months and just under 50% at 12 months on the initially prescribed ARB. A cross-sectional study by Jung and colleagues (14) used toxicological urine analysis to objectively measure medication adherence in patients with apparent treatment-resistant hypertension (prescribed an average of 5 BP lowering drugs). They reported that 53% were non-adherent (70% incomplete/30% complete) with 85% of those with incomplete adherence having taken <50% of prescribed medication. These studies highlight the substantive contribution of medication non-adherence to poor BP control across the spectrum of hypertension severity.

The renin-angiotensin-aldosterone (RAS) system has an important role in regulation of BP. Zilebesiran is a small interfering RNA agent that antagonizes hepatic angiotensinogen mRNA activity resulting in prolonged reductions in serum angiotensinogen levels (15,16). Specificity to the liver site of action, as well as its prolonged effect, is attributable to the conjugation of zilebesiran with N-acetylgalactosmine (GaINAc) which binds to the hepatocyte asialoglycoprotein receptor (ASGPR). Angiotensinogen is the only known precursor of all angiotensin peptides. A small phase I study of zilebesiran in patients with hypertension showed prolonged (24 weeks) dose-related reductions in BP as well as in serum angiotensinogen (~90%) along with slightly lower plasma renin activity, aldosterone, angiotensin I and angiotensin II with doses >200 mg (17). Interestingly, there was a delayed peak effect on SBP lowering, specifically at the highest dose (800 mg) SBP was 5.7 mmHg or 34% lower at week 24 than that at week 18. The observed BP lowering while on a low-salt diet (0.23 g/d) was reversed over 5–7 days while consuming a high-salt (5.75 g/d) diet, even after doses of 800 mg/d of zilebesiran (17). The addition of irbesartan, an ARB, conferred additional BP lowering.

A report (15) of the KARDIA-1 phase 2 study by Bakris and colleagues is the subject of this commentary. The KARDIA-1 study was a phase 2 randomized (1:2:1:1) placebo-controlled clinical trial of escalating doses of subcutaneously administered zilebesiran (150, 300 mg every 3 months or every 6 months, or 600 mg every 6 months compared to placebo) in patients with average daytime ambulatory systolic BP of 135–160 mmHg (after washout of their prescribed antihypertensive drug regimen). The primary study endpoint was the change from baseline in 24-hour mean ambulatory systolic BP. At 3 months, there were statistically significant reductions in ambulatory systolic BP from baseline across the 150 mg every 6 months, 300 mg every 3 or 6 months, and 600 mg every 6 months active treatment arms that, respectively, were −14.1, −16.8, and −15.7 mmHg. Interestingly, the placebo-adjusted SBP changes for each of the zilebesiran treatment groups were considerably more than the SBP reduction from baseline because of the nearly 7 mmHg increase from baseline in systolic BP in the placebo group. Adverse events occurred more in the combined zilebesiran treatment arms than with placebo (60.9% vs. 50.7%). Non-serious drug-related adverse events—mostly hyperkalemia and injection site reactions—were about twice as common in the combined zilebesiran compared to placebo group. Serious adverse events occurred more with placebo compared to the combined zilebesiran treatment arms (6.7% vs. 3.6%).

To date, what do we know about zilebesiran, an antihypertensive agent that has not yet been tested beyond phase 2 clinical trials? First and foremost, we know that it effectively lowers BP as monotherapy when given to patients with mild to moderate hypertension. However, the time to the peak BP lowering effect with this agent appears more prolonged than with conventional antihypertensive drug therapy. A review of reversing the pressor effect of Zilebesiran (18) also confirmed that a high sodium diet reverses it’s BP lowering effect when given as monotherapy. However, in actual clinical practice, zilebesiran will almost assuredly be used in combination with other antihypertensive medications. Accordingly, in zilebesiran-treated patients experiencing non-acute low BP in ambulatory settings, the other hypertensive drugs (sans beta blockers/central adrenergic inhibitors) will likely be immediately stopped/held along with augmentation of dietary sodium intake to overcome the antihypertensive effect of zilebesiran. Interestingly, there appears to be incremental BP lowering when an ARB—another antagonist of the RAS system—is added. Also, zilebesiran does not appear to result in the activation of compensatory RAS escape mechanisms (14) that can occur during RAS drug therapy (19,20). The data from the KARDIA-1 trial suggest that the maximum dose needed might be 300 mg as there was not any further reduction in BP at the 600 mg dose. Therapeutic non-adherence is common among adult patients with hypertension. And though zilebesiran has not been specifically studied in this group, its infrequent administration that does not require daily pill taking, will almost assuredly be of particular benefit in patients who struggle with sustained adherence to conventional daily administered oral antihypertensive drugs. We also know that this agent is not as well tolerated as placebo with injection site reactions and hyperkalemia as the most common adverse drug effects, however, these adverse events infrequently resulted in study drug discontinuation.

There are also things that we do not yet know about zilebesiran. At present, we do not know the absolute contraindications to this drug though, almost assuredly it will need to be used with caution, if at all, in patients with concurrent hyperkalemia. Furthermore, this agent with its prolonged action may prove difficult to use in patients prone to episodic low BP (e.g., autonomic neuropathy). It is also not known if the combined use of zilebesiran with ARBs or angiotensin converting enzyme (ACE) inhibitors will be safe. What are the most and least effective drugs to be combined with zilebesiran for BP lowering? Another unknown relates to whether zilebesiran will confer protection to the kidney given that its site of action is in the liver; also, despite zilbesiran only inhibiting angiotensinogen production in the liver, this does not ensure that patients initiated on this drug will not experience transient deteriorations in kidney function when BP is lowered with this agent because, in patients with reduced nephron mass (chronic kidney disease), renal autoregulation of glomerular pressure is abnormal as its relationship with systemic BP is now quasi-linear rather than sigmoidal (21). Also, will zilebesiran prevent or mitigate dihydropyridine calcium antagonist lower extremity edema like ACE inhibitors and ARBs? Given the recent Food and Drug Administration (FDA) approval of two renal denervation systems, will it be advisable to treat hypertensive patients with both zilebesiran and renal denervation given the prolonged duration of BP lowering for both of these therapies? The answers to most of these questions will ultimately become known with the completion of phase III clinical trials. The totality of evidence learned will determine the ultimate place in the hypertension therapeutic armamentarium for zilebesiran, an emerging novel and promising therapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-139/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-139/coif). J.M.F. reports research grants from SonieVie, Recor Medical, Astra Zeneca, Idorsia, Mineralys, consulting fees from Recor Medical, Astra Zeneca, Idorsia, Casana, serves on the monitoring board or advisory board of NIH, acts as an expert witness for Teva, and receives royalties from UptoDate. The author has no other conflicts of interest to declare.

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