New RNA Interference-Based Therapy for Hypertension

By Michael H. Crawford, MD, Editor

SYNOPSIS: A randomized, double-blind, placebo-controlled trial of a range of doses of a new ribonucleic acid (RNA) interference drug that reduces hepatic angiotensinogen levels has shown significant mean 24-hour systolic blood pressure reductions at three months after a single subcutaneous injection.

SOURCE: Bakris GL, Saxena M, Gupta A, et al. RNA interference with zilebesiran for mild to moderate hypertension: The KARDIA-1 randomized clinical trial. JAMA 2024;331:740-749.

Zilebesiran (Zbs) is a ribonucleic acid (RNA) interference drug that targets hepatic synthesis of angiotensinogen (the predominant precursor of angiotensin peptides), which are key regulators of systemic blood pressure (BP). A Phase I study of one subcutaneous (subq) dose of Zbs produced a dose-dependent reduction in angiotensinogen and 24-hour ambulatory BP at 24 weeks.

This Phase II study assessed the antihypertensive effect and safety of four different quarterly and semiannually administered subq doses of Zbs vs. placebo after six months in patients with mild to moderate hypertension (HTN) not taking antihypertensive medications: 150 mg every six months; 300 mg every six months; 300 mg every three months; and 600 mg every six months vs. placebo every three months.

Those receiving Zbs every six months received the placebo at three months to maintain the blinding. The primary endpoint was the change from baseline to three months in mean 24-hour ambulatory systolic BP (SBP). Secondary endpoints included office BP, six-month change in BP, and angiotensinogen serum levels. Safety endpoints included adverse effects, weight, and laboratory tests. Also, various subgroups, such as age older or younger than 65 years, baseline mean ambulatory SBP more or less than 145 mmHg, and normal or abnormal renal function, were analyzed separately.

Of the 377 patients randomized, 75 patients received placebo injections and 92% completed the six-month study period (mean age 57 years, 44% women,
25% Black). Mean baseline ambulatory BP was 142/82 mmHg. The primary endpoint was -7 mmHg for 150 mg of Zbs every six months; -10 mmHg for 300 mg every three or six months; -9 mmHg for 600 mg every six months; and +7 mmHg for placebo (P < 0.001 for all comparisons). These results were consistent across all prespecified subgroups.

Office and six-month SBP followed a similar statistically significant pattern. Serum angiotensinogen levels were reduced more than 90%, which persisted six months after both a 300-mg and 600-mg dose of Zbs. Serious adverse effects occurred in 4% of the Zbs patients and in 7% of the placebo patients, but none were deemed to be the result of drug therapy. Of the mild to moderate reactions in the Zbs groups, injection site reactions (6%) and hyperkalemia (5%) were the most frequent. Hepatic reactions occurred in 5% of the Zbs patients and 1% of the placebo patients but were transient and resolved during therapy. The authors concluded that treatment with Zbs in patients with mild to moderate hypertension across a range of doses sig-nificantly reduced mean ambulatory SBP at three months.

COMMENTARY

The long-term management of hypertension is challenging because of the usual necessity of multiple drugs dosed daily, which can increase the frequency of adverse effects. Not surprisingly, adherence is a major issue, and many patients are not at guideline-recommended target SBP levels. Thus, this report of a new RNA interference drug that can be administered at intervals of months is of interest. The Bakris et al study demonstrated that quarterly or biannual subq injections significantly decreased SBP in patients with mild to moderate hypertension. The most common adverse effects were predictable — injection site reactions and hyperkalemia, both of which were mild, were transitory, and did not result in study discontinuation.

Strengths of the study include that the patients were typical adult hypertensives: the majority were obese, almost one-quarter had type II diabetes, and most were receiving more than one antihypertensive drug prior to the study. Also, ambulatory BP was the endpoint that is considered the gold standard for hypertension studies. In addition, they obtained serum angiotensinogen levels, which substantiated the mechanism of BP lowering. Finally, considerable effort went into keeping the study double-blinded.

There are limitations to consider in this study. Part of the differences observed were because of the increase in SBP in the placebo group, which could have been the result of delayed recovery from discontinuing the patients’ antihypertensive medications. Also, the patients had mild to moderate hypertension and the results may not apply to those with severe hypertension. In addition, the six-month duration is short and a longer follow-up period would be necessary to confirm the long-term efficacy and safety of Zbs. Finally, outcomes were not assessed in this relatively short period, but the magnitude of SBP reduction has been shown in other trials to reduce adverse outcomes.

There is a theoretical risk of refractory hypotension if too large a dose of Zbs is administered or if the renin-angiotensin system response to volume depletion, bleeding, sepsis, or cardiac dysfunction is attenuated. However, it is possible that the standard treatment of such conditions would be adequate to successfully mitigate the effects of Zbs. Also, the sympathetic system would still be intact. There is interest, though, in developing a reversal agent. In addition, the interactions between Zbs and other drugs for hypertension need to be studied, since the likelihood that Zbs will always be successful as monotherapy is unknown.

In summary, this is a major new development in the treatment of hypertension that could increase compliance with therapy and reduce the need for polypharmacy.