Single Injection Reduces Blood Pressure for 6 Months

A single injection of the investigational antihypertensive agent zilebesiran (Alnylam Pharmaceuticals) effectively lowered blood pressure in adults with mild to moderate hypertension for up to 6 months, with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.

“Our study demonstrates that either quarterly or bi-annual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator, George Bakris, MD.

“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine, added.

The KARDIA-1 study was presented on November 11 at the recent American Heart Association (AHA) Scientific Sessions 2023, held in Philadelphia.

Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.

Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues. 

The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic blood pressure of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.

The study included 394 such patients (average baseline systolic blood pressure was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).

Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.

Ambulatory systolic blood pressure measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.

Patients receiving zilebesiran were more likely to achieve 24-hour average systolic blood pressure measurements ≤ 130 mm Hg at 6 months.

In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic blood pressure.

There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of blood pressure elevation, and one of injection site reaction.

Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Bakris reported.

There was one death due to cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.

Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.

Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at Mayo Clinic, Rochester, Minnesota, said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”

Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.

Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University School of Medicine, New Orleans, said that this study “suggests we can now target the first step in the renin angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”

Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”

Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, United Kingdom, noted that hypertension affects 1 in 3 adults worldwide, but only around 20% of people have it under control.

“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.

Bakris has received consulting fees from Alnylam Pharmaceuticals.

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