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 a pattern of encouraging side effects, as part of the phase 2 study of KARDIA. -1 study.
“Our study demonstrates that quarterly or semiannual doses of zilebesiran can safely and effectively lower blood pressure in patients with uncontrolled hypertension,” said the study’s principal investigator, George Bakris, MD.
“Based on these results, zilebesiran has the potential to improve treatment compliance, which will in turn reduce cardiovascular risk in people with hypertension,” said Bakris, professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago. , 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 that, despite the availability of effective antihypertensive medications, many adults with hypertension go untreated, up to 80% of them are suffering from uncontrolled illness, both globally and in the United States.
Zilebesiran is a subcutaneous RNA interference therapeutic agent that binds with high affinity to the hepatic asialoglycoprotein receptor, resulting in a reduction in the synthesis of angiotensinogen, the sole precursor of all peptides of the angiotensin. It is hoped that its hepatocyte-targeted delivery will preserve extrahepatic expression of angiotensinogen, which could limit off-target effects in the kidney and other tissues.
The KARDIA-1 trial studied the safety and effectiveness of different doses of zilebesiran in patients with mild to moderate hypertension (systolic blood pressure 135 to 160 mm Hg), who are either untreated or taking a stable treatment including up to two antihypertensive medications.
The study included 394 patients (mean baseline systolic blood pressure was 142 mm Hg) who were randomly assigned to receive one of four different doses of zilebesiran (150 mg, 300 mg, or 600 mg once every 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 approximately 10 mm Hg in the three maximum doses studied and approximately 14 mm Hg compared to placebo.
Patients receiving zilebesiran were more likely to achieve 24-hour mean systolic blood pressure measurements ≤130 mm Hg at 6 months.
Additionally, participants in all four zilebesiran groups consistently experienced significantly greater reductions in daytime and nighttime systolic blood pressure.
Four non-serious adverse events led to treatment discontinuation in the zilebesiran groups: two cases of orthostatic hypotension, one case of elevated blood pressure, and one case of injection site reaction.
Most hyperkalemia-related adverse events, occurring in 6% of patients, were mild, did not require intervention, and usually resolved with repeated measurements; none were associated with acute kidney injury or led to discontinuation of study drug. The incidence of hypotensive events was low and no clinically relevant changes in renal or hepatic function were observed, Bakris reported.
One death due to cardiopulmonary arrest was recorded in a patient receiving 300 mg zilebesiran every 3 months, but this death was not classified as drug-related.
Zilebesiran is being evaluated as an add-on therapy for the treatment of hypertension in the ongoing phase 2 KARDIA-2 study.
Moderating an AHA news conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, said that “having an injectable drug that allows “Reducing blood pressure long term is extremely exciting.”
Taler noted that some patients may not return for subsequent doses, but added that with subcutaneous administration, home administration could be a possibility.
Also speaking at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University School of Medicine in New Orleans, said this study “suggests that we can now target the first step in the renin-angiotensin system – angiotensinogen – which appears next. to lead to a robust and continuous drop in blood pressure for up to 6 months, which should improve compliance.
Noting that only 50% of patients continue to take antihypertensive medications after a year, Ferdinand added: “If we can increase compliance, we will increase effectiveness and perhaps protect against some end-organ damage.” »
Anna Dominiczak, MD, University of Glasgow, UK, designated presenter of the KARDIA-1 study at the AHA’s late-breaking clinical trials session, noted that hypertension affects 1 in 3 adults in the world, but only about 20% of people suffer from it. control.
“An increase in the number of patients effectively treated for hypertension to the levels seen in the best-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks and 17 million cases of hypertension. “heart failure by 2050,” she said. .
Bakris has received consulting fees from Alnylam Pharmaceuticals.
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