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ATLANTA -- The novel RNA silencer zilebesiran reduced blood pressure (BP) when added to a diuretic, calcium channel blocker, or maximum-dose angiotensin receptor blocker, the phase II KARDIA-2 trial showed.

At 3 months, the addition of zilebesiran reduced mean 24-hour ambulatory systolic BP by 4.0 mm Hg more than olmesartan alone, 9.7 mm Hg more than with amlodipine alone, and 12.1 mm Hg more atop indapamide, which were all statistically significant compared with adding placebo, reported Akshay Desai, MD, MPH, of Brigham and Women's Hospital in Boston, at the American College of Cardiology (ACC) annual meeting.

At the 6-month mark when patients would be due for another dose, BP effects were "somewhat attenuated" in the olmesartan-combo group, such that the ambulatory BP differential compared with the olmesartan-placebo group lost significance, although in-office BP remained 4.6 mm Hg lower (P<0.001).

Zilebesiran was associated with increased rates of mild hyperkalemia, hypotension, and liver function decline, "but most episodes were non-serious, transient, and resolved without intervention," Desai said.

"Though the trial was not adequately powered to ensure long-term safety, these results support the potential for combining biannual dosing of zilebesiran with standard-of-care antihypertensives to achieve additive blood pressure reductions," he concluded at the late-breaking clinical trial session.

These findings follow the presentation of the KARDIA-1 trial in people with mild to moderate hypertension taken off antihypertensive treatment. In that study, quarterly and biannual injections of the drug showed 24-hour mean ambulatory systolic BP reductions ranging from 14.1- to 16.7-mm Hg greater than with placebo, depending on the dose, from baseline to 6-month follow-up.

However, guidelines note that most patients need more than one antihypertensive to get to goal.

Kim Williams Sr., MD, of the University of Louisville in Kentucky, an ACC press conference study discussant, pointed to the greater efficacy with a multiple drug regimen across different mechanisms.

"So I think we've got a powerful opportunity here, particularly with the indapamide group," he noted. He said that it was striking that the combination of zilebesiran with the angiotensin II receptor blocker did get a response, "but you don't get as much response as you did with the calcium channel blocker or the one that just in our brains seems to be more complementary, which is the diuretic, and that seemed to be really three different responses."

Zilebesiran is an investigational small interfering RNA therapeutic that targets hepatic synthesis of angiotensinogen, the most upstream precursor of the renin-angiotensin-aldosterone (RAS) system that regulates BP.

Comparisons across the drug combination groups, not just against placebo, would be helpful, Williams said, "because it looked like at least the indapamide group did substantially better than the olmesartan group."

That diuretic was also associated with the lowest rate of hyperkalemia, he pointed out. Potassium elevations over 5.5 nmol/L occurred in 3.2% of that group compared with 6.8% in the amlodipine and 6.7% in the olmesartan combination groups.

Desai emphasized that "olmesartan is one of the more potent angiotensin receptor blockers out, and we intentionally tested the effect against a maximal dose to see if there was residual treatment effect that might be seen and to examine the safety, since there has been a legacy of concern about dual RAS antagonism from the predicate experience."

The trial randomized 1,500 patients ages 18 to 75 who had either a seated office systolic BP of 155-180 mm Hg if untreated or 145-180 mm Hg despite taking one or two antihypertensives. They were randomized to indapamide 2.5 mg daily, amlodipine 5 mg daily, or olmesartan 40 mg daily. After passing a 4-week run-in period with a 24-hour mean ambulatory systolic BP of 130-160 mm Hg and at least 80% adherence to protocol-specified background antihypertensive therapy, each group (130 on indapamide, 241 on amlodipine, and 301 on olmesartan) was randomized to add a single 600-mg shot of zilebesiran or placebo. Rescue antihypertensive medication was allowed to be added after month 3.

Mean baseline systolic BP was 143 mm Hg. Mean age was 58-59, about 57% were men, 61-70% were white, and 80% were enrolled in the U.S.

ACC session moderator Pamela Bowe Morris, MD, of the Medical University of South Carolina in Charleston, pointed to patient concerns about side effects with long-acting drugs that could take months to go away.

Adverse events were mainly injection site reactions, which occurred in 3-4% of patients, said Desai. "We haven't seen a lot of other tolerability issues with the drug."

Hypotension or orthostatic hypotension occurred in none of the indapamide-treated patients; 8% and 5.9% of the amlodipine-placebo and amlodipine-combo group patients, respectively; and 2.0% and 4.7% of the olmesartan group who got placebo and zilebesiran, respectively.

Serious hypotension hasn't happened so far, Desai noted. "The reassurance I can provide at this point is that we did see, in that phase I experience, salt-responsiveness to rescue the blood pressure-lowering effect of zilebesiran. Volume resuscitation is also effective. And because we are antagonizing only one key axis for blood pressure support, it stands to reason that pressors that agonize other axes that are important in blood pressure control, so sympathomimetics, should still be effective, as is, in the preclinical models, direct infusion of angiotensin II. So we think apart from the reversal agent program ... that is under development, there are reasons to believe we should be able to maintain rescue strategies for hypotension."

He noted that an adequately powered phase III cardiovascular outcomes trial is intended once the dosing, safety, and target population are better defined.

Subcutaneous injection isn't likely to be much of a barrier to use, Desai suggested, and could actually be preferable.

"I think the willingness of patients to self-administer a subcutaneous therapy has increased. Some of this is overcoming the perception that it is a long needle and a deep injection and educating patients around the ease. I think it's an overcomable barrier," he said. "If we could overcome challenges not only with adherence but provide some baseline of blood pressure control against which the regimen could be reconstructed, that would be fantastic."

ACC session study discussant Nanette Wenger, MD, of Emory University School of Medicine in Atlanta, agreed.

"I'm very excited by this new approach to therapy," she said. "Only about a fourth of the patients in our country have control of their blood pressure. Some of it may be a clinician issue of not adequate titration, but I think a great deal is that asymptomatic patients get bored with medication taking and don't continue to take it on a regular basis. ... Every-6-month therapy may be a way to conquer some of the problems that we see."

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