https://meditropics.com/zilebesiran-the-first-sirna-based-drug-for-hypertension/

^*Preeti Kumari,

^*Post-graduate Resident, Department Of Medicine LHMC, New Delhi

ABSTRACT

Arterial hypertension is the most widespread cardiovascular risk factor worldwide. Over the past 30 years, the incidence of hypertension has doubled. Despite the availability of numerous antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), a large proportion of hypertensive patients still have uncontrolled blood pressure (BP), which hampers optimal cardiovascular risk management. Antihypertensive treatments have shown cardioprotective effects, with a reduction in systolic BP by 5 mm Hg decreasing the risk of cardiovascular events by 9% in primary prevention and by 11% in secondary cardiovascular disease (CVD) prevention. The main reasons for poor BP control include lack of adherence to treatment, persistence, and therapeutic inertia. Therefore, new treatment options are being explored to improve BP control. Zilebesiran, the first drug based on small interference RNA (siRNA) technology for treating hypertension, is currently in phase II clinical trials (KARDIA-1 and KARDIA-2). Phase I trial results demonstrated that a single dose of zilebesiran could sustain a reduction in systolic BP by 22 mm Hg and diastolic BP by 10 mm Hg for up to six months. Zilebesiran’s unique mechanism of action involves silencing the angiotensinogen (AGT) gene in the liver, reducing serum AGT levels by over 90%. In clinical trials, zilebesiran showed a satisfactory safety profile and was well tolerated by patients. The infrequent dosing of zilebesiran, potentially only twice a year, is expected to significantly improve patient adherence and persistence, leading to better blood pressure control. This article reviews the mechanism of action, effectiveness, and safety of zilebesiran, and argues for its introduction into clinical practice.

EPIDEMIOLOGY OF HYPERTENSION-CURRENT SCENARIO

For many years, arterial hypertension has been the most common risk factor for cardiovascular disease (CVD), which is the leading cause of premature death globally [1]. An analysis involving 104 million people revealed that the number of individuals aged 30–79 with hypertension doubled from 1990 to 2019, increasing from 331 million women and 317 million men  in 1990 to 626 million women  and 652 million men in 2019 [2]. This brings the global total of hypertension patients to 1.3 billion. In 2019, high systolic blood pressure (BP) was linked to 10.8 million deaths, representing over 19% of all deaths [3]. The high prevalence of hypertension can be attributed to its often asymptomatic onset, low awareness of risk factors, and ongoing societal changes, such as increased exposure to air pollution, environmental noise, poor-quality food, and excessive body weight.

THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS) — THE MAIN CAUSE OF HYPERTENSION AND ITS COMPLICATIONS

The renin–angiotensin–aldosterone system (RAAS) is a pivotal regulator of blood pressure (BP). Its upregulation increases BP by altering vascular tone, blood volume, electrolyte balance, and aldosterone synthesis, consequently leading to tissue remodelling and end-organ damage [39, 40]. RAAS-targeting drugs are effective in lowering BP, reducing cardiovascular disease (CVD) risk, and extending life. A meta-analysis involving 158,998 patients from randomized clinical trials found that ACE inhibitors (ACEI) were associated with a 10% reduction in all-cause mortality [4]. RAAS inhibitors, primarily ACEI, are considered the gold standard in hypertension treatment .In light of this and the goal of enhancing adherence through less frequent drug administration, a novel approach to targeting hypertension involves silencing the AGT gene in the liver using RNA technology-based drugs, which require less frequent administration compared to traditional antihypertensive medications. This method effectively reduces the production of Ang I and Ang II, thereby attenuating signalling mediated by Ang II type 1 (AT1R) and Ang II type 2 (AT2R) receptors.

ZILEBISERAN-MECHANISM OF ACTION

Zilebesiran is the first drug based on small interfering RNA (siRNA) technology for the treatment of hypertension Zilebesiran comprises double-stranded RNA, consisting of a non-guide strand and a guide strand, conjugated with N-acetylgalactosamine (GalNAc). This conjugation enables selective uptake of zilebesiran by hepatocytes, facilitated by the asialoglycoprotein receptor (ASGPR) present exclusively on their surface. Upon endocytosis into hepatocytes, the ASGPR is recycled to the cell membrane, while the drug escapes from the endosome and binds to the RNA-induced silencing complex (RISC) in the cytoplasm. Within the RISC, the guide strand of zilebesiran directs the cleavage of complementary target mRNA, specifically targeting AGT mRNA, thereby silencing the AGT gene [5]

This mechanism of action is also utilized by other lipidology drugs such as olpasiran, zerlasiran, lepodisiran (which target the apolipoprotein (a) — LPA gene), and inklisiran (which targets the PCSK9 gene) . Unlike standard RAAS inhibitors (ACEi or ARB) which may lead to RAAS escape due to compensatory increases in renin and Ang I levels over time, zilebesiran’s ability to potentially deplete AGT levels could mitigate this phenomenon [6]

ZILEBESIRAN — SAFETY AND EFFICACY:

Results of clinical trials in a randomized phase I clinical trial by Huang et al., the effectiveness and safety of various doses of zilebesiran versus placebo were assessed in a group of 60 mild to moderate hypertension patients. Patients were randomized to a single dose of zilebesiran (10 mg, 25 mg, 50 mg, 100 mg, or 200 mg) or placebo subcutaneously. After 8 weeks of observation, serum AGT levels decreased > 90% at the 100 and 200 mg doses of zilebesiran (Fig. 3). This effect lasted for 12 weeks. Single doses of 100 mg or 200 mg of zilebesiran reduced mean 24- hour systolic BP by 10 mm Hg at week 8 after administration. No symptomatic hypotension, treatment-related severe adverse events, or clinically significant elevations in blood creatinine or potassium were seen [7].

In the effect of zilebesiran versus ibersartan was assessed in a randomized phase I clinical trial by Taubel et al., including 20 patients with hypertension and obesity. Patients were randomized to zilebesiran 800 mg subcutaneously (day 1 and 85) and daily oral placebo or sequential subcutaneous doses of saline (day 1 and 85), and daily 150 mg oral irbesartan. After 24 weeks of observation, AGT serum levels did not change with irbesartan but were reduced by 99% with zilebesiran from week 4 to week 24. Change in systolic BP from baseline to week 24 was –27 ± 8 mm Hg with zilebesiran versus –19 ± 6 mm Hg with irbesartan. Zilebesiran was generally well tolerated [8].

In a randomized phase I clinical trial by Desai et al., including 107 patients with hypertension, the effectiveness and safety of zilebesiran (after washout of antihypertensive medications for at least 2 weeks) were assessed. The study was divided into several parts. In part A, patients were randomized to a single escalating dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks. Part B analyzed the 800-mg dose of zilebesiran on BP under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. [9].Overall, 5 patients experienced mild adverse events administration of the drug. There was no hypotension, hyperkalemia or deterioration of kidney function. Zilebesiran reduced serum AGT concentrations by > 90%. A dose-dependent reduction in 24-hour BP was observed. A single dose of 800 mg of zilebesiran allowed for long-term BP control (in the 24th week of observation, the 24-hour systolic BP was reduced by 22.5 mm Hg and diastolic BP by 10,8 mm Hg) [9]. The results of this study indicate that zilebesiran had a good safety profile, and only one dose of this drug reduced systolic BP by more than 22 mm Hg and diastolic BP by more than 10 mmHg for 6 months. This indicates that using zilebesiran twice a year will allow BP control in some patients.

 During the American Heart Association (AHA) congress in 2023, Bakris et al. published the preliminary results of the placebo-controlled, randomized, double-blind, doseranging phase 2 study KARDIA-1 (NCT04936035). The study included 377 patients with mild-to-moderate hypertension who were randomized to zilebesiran (n = 302) or placebo (n = 75). After antihypertensive washout, patients with a daytime mean SBP of 135–160 mm Hg, assessed by ambulatory BP monitoring, were randomized to a zilebesiran regimen [150, 300, or 600 mg subcutaneously once every 6 months (Q6M) or 300 mg subcutaneously once every 3 months (Q3M)] or to placebo subcutaneously Q3M. Reductions in 24-hour mean SBP were 12 shown to be significantly greater for all zilebesiran regimens than placebo at month 3 and month 6  with consistent reductions in daytime and nighttime SBP.

The analysis of the safety profile allowed us to conclude that the most common side effects of zilebesiran included injection site reaction (6.3% zilebesiran, 0% placebo; all mild and transient) and hyperkalemia (5.3% zilebesiran, 1.3% placebo; most mild and transient). No renal or hepatic dysfunction was observed in patients taking zilebesiran. Thus, in this study, it was found that in patients with mild-to-moderate hypertension, a single dose of zilebesiran was characterized by a significant antihypertensive effect (24-hour SBP reduction by approximately 10 mm Hg) and an acceptable safety profile [10]. A problem related to the use of drugs based on siRNA technology is the formation of anti-drug antibodies (ADAs). In the zilebesiran study, transient, low-titer ADAs were observed in 2.5% of patients. As with all RAAS inhibitors, treatment escape is possible but was not observed over the extended follow-up period for zilebesiran[11].

Two randomized clinical trials phase II are currently underway: A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild To-Moderate Hypertension (KARDIA-1; NCT04936035; expected completion of the study: 31 Dec 2024) and Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2; NCT05103332; expected completion of the study: 31 Dec 2025).

ZILEBESIRAN — HYPERTENSION TREATMENT IN THE FUTURE

Despite the more than 100 medications approved to treat hypertension, as mentioned above, the effectiveness of antihypertensive treatment is unsatisfactory. Zilebesiran may contribute to improving BP control (improving adherence and persistence) due to the possibility of administering it twice a year. Although the safety profile of zilebesiran appears satisfactory, more extensive population-based studies in high-risk groups (chronic kidney disease, chronic kidney disease, type 2 diabetes, and heart failure) will reliably demonstrate adverse effects on kidney function, a significant concern in treatment with RAAS inhibitors. The most likely clinical safety issue is the potential need to reverse the long-acting effects of zilebesiran. Although evidence for emergency reversal agents with noradrenaline and Ang II is encouraging, these will require clinical testing. Use in women of reproductive age is likely to be an absolutecontraindication to drugs targeting AGT unless contraception can be assured, given the known teratogenic effects of RAS inhibition. Further studies will determine the effect of zilebesiran on BP in patients with hypertension and disturbed BP circadian rhythm (non-dippers) and the effectiveness and safety of combining zilebesiran with other antihypertensive drugs. In summary, according to the authors, zilebesiran is a new kid on the block and may change the face of hypertension treatment.

 

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