By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: One dose of a new RNA-based drug administered by subcutaneous injection, which blocks hepatic angiotensinogen production, resulted in sustained reductions in blood pressure in patients with hypertension for up to 24 weeks without any serious adverse effects.
SOURCE: Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Eng J Med 2023;389:228-238.
Desai et al recently reported on a potential new treatment for hypertension — Zilebesiran (Zb), described in their paper as a small interfering RNA (siRNA) covalently linked to an N-acetylgalactosamine ligand designed to bind to the hepatic asialoglycoprotein receptor, which reduces hepatic angiotensinogen messenger RNA (mRNA) levels. The authors explained this action limits the production of angiotensinogen, which is the sole precursor of all angiotensin peptides. This approach may limit any compensatory production of angiotensin by angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Also, by targeting hepatic angiotensin production, extra-hepatic angiotensinogen expression may be preserved, limiting off-target effects in the kidney and other tissues. The prolonged pharmacodynamic effects of siRNAs offer the potential for blood pressure-lowering for months, with twice-yearly or quarterly subcutaneous administration.
Armed with this knowledge, Desai et al detailed the results of a Phase I study of the safety as well as the pharmacokinetic and pharmacodynamic effects of Zb in patients with hypertension under low- and high-dietary salt intake and in combination with irbesartan. The study included one ascending dose of Zb (10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, or placebo), a single fixed dose of Zb (800 mg) during low- and high-salt diets, and an open-label study of that fixed dose of Zb plus daily irbesartan. The study was conducted at four sites in the United Kingdom. Inclusion criteria were age 18-65 years, treated or untreated hypertension, systolic blood pressure (SBP) 130 mmHg to 165 mmHg, and a mean SBP of 130 mmHg or higher on 24-hour ambulatory BP monitoring after withdrawal of antihypertensive medications for at least two weeks. The authors excluded those with secondary hypertension, postural hypotension, diabetes, previous cardiovascular events, or anticipated treatment with beta-blockers.
After completing the study protocol, all patients were entered into an extended safety study. The primary endpoint of all three segments of the study was the change from baseline in SBP and diastolic BP (DBP) by 24-hour ambulatory BP monitoring and serum angiotensinogen levels. From 2019 through 2021, 107 patients were enrolled (84 in part one, 12 in part two, and 16 in part three — five of whom received placebo in part one). Mean age was 54 years, 62% were men, and 25% were Black.
At single doses of 200 mg or higher, the authors observed decreases in SBP of more than 10 mmHg and decreases in DBP of more than 5 mmHg by eight weeks, which continued for 24 weeks. A high-salt diet attenuated these effects, and co-administration of irbesartan potentiated them. Five patients experienced mild transient injection site reactions. No patient experienced hypotension, hyperkalemia, or worsening renal function. The authors concluded a single subcutaneous injection of Zb of 200 mg or more produced dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory BP, which were sustained for up to 24 weeks. No serious drug-related adverse effects were noted.
COMMENTARY
As predicted by many, the novel COVID vaccines are going to usher in a new era of RNA-based therapeutics. Zb is one of the first to arrive, focusing on one of the major risk factors for cardiovascular disease. It has been estimated that despite the availability of effective therapeutic agents, almost half of patients with hypertension do not achieve BP targets recommended by guidelines.1 One common reason is poor adherence to prescribed daily oral medications. Thus, the possibility of a once-every-four-to-six-months subcutaneous shot that controls BP throughout the 24-hour circadian cycle is exciting.
Some will say patients do not like shots and will be just as noncompliant or worse than they are with pills. They will point to the cholesterol-lowering injectable medications, which have not exactly taken off in my practice. However, up until recently, these shots needed to be injected every two to four weeks; for Zb, we are talking about every four to six months. This has to be an easier sell. Also, there were patients who were afraid of the RNA-based COVID-19 vaccine because they thought it was going to alter their DNA. Hopefully, long-term data will help dissuade them of this notion. In addition, I predict Zb is going to be used predominantly by an older population, who could be more amenable to the convenience of shots and less afraid of new technologies affecting their genes. Finally, the adverse effects were largely limited to injection site irritation. There were no negative effects on the kidneys or electrolytes.
Before we get too excited, this is a Phase I study, which carries several limitations. It was a small study of highly selected patients. They were free of cardiovascular disease and diabetes, and none were > age 65 years. Also, the highest baseline SBP permitted was 165 mmHg. In addition, those with postural hypotension or current or anticipated treatment with beta-blockers were excluded. Although women of childbearing age were permitted in the study, there are insufficient data to comment on whether the teratogenic effects of other renin-angiotensin system inhibitors can be seen with Zb. However, studies of siRNA in rat models of preeclampsia showed that Zb did not cross the placenta and did not show deleterious effects on the pups, according to Desai et al. Finally, a high-salt diet attenuated the effects of Zb on BP. Given our proclivity for salt, this may be the Achilles’ heel of Zb. Not surprisingly, Phase II studies are underway (KARDIA-1 and KARDIA-2).2,3
REFERENCES
1. Abegaz TM, Shehab A, Gebreyohannes EA, et al. Nonadherence to antihypertensive drugs: A systematic review and meta-analysis. Medicine (Baltimore) 2017;96:e5641.
2. ClinicalTrials.gov. A study to evaluate efficacy and safety of ALN-AGT01 in patients with mild-to-moderate hypertension (KARDIA-1).
3. ClinicalTrials.gov. Zilebesiran as add-on therapy in patients with hypertension not adequately controlled by a standard of care antihypertensive medication (KARDIA-2).
One dose of a new RNA-based drug administered by subcutaneous injection, which blocks hepatic angiotensinogen production, resulted in sustained reductions in blood pressure in patients with hypertension for up to 24 weeks without any serious adverse effects.
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