Biannual zilebesiran associated with substantial BP reductions 

In the phase 2 KARDIA-1 study, a single subcutaneous dose of zilebesiran demonstrated encouraging reductions in systolic blood pressure (BP) in hypertensive patients at 3 and 6 months of follow-up compared with placebo.

“Despite the availability of effective therapies to reduce hypertension, many patients remain untreated or have uncontrolled disease,” said Prof. George Bakris (University of Chicago, IL, USA) [1]. The subcutaneously administered investigational agent zilebesiran delivered promising efficacy data at 24 weeks after 1 infusion of this agent in a phase 1 study [2].

Prof. Bakris presented the results of the phase 2 KARDIA-1 study (NCT04936035), which randomised 394 participants with mild-to-moderate hypertension 1:1:1:1:1 to 1 of 4 dose-levels of the RNA-interference therapeutic zilebesiran (ranging from 150 mg once every 6 months to 600 mg once every 6 months) or a placebo [1,2]. The primary endpoint was the change in 24-hour mean ambulatory systolic BP from baseline to 3 months.

“At 3 months, all zilebesiran dose levels were associated with significantly larger reductions in 24-hour mean ambulatory systolic BP than placebo,” said Prof. Bakris. In the lowest-dose group, the reduction was -14.1 mmHg compared with placebo (P<0.0001), and the reduction was -15.7 mmHg compared with placebo in the highest-dose group (P<0.0001). These reductions appeared to be maintained at 6 months, with corresponding reductions of -11.1 mmHg for the lowest-dose group and -14.2 for the highest-dose group.

“The agent also displayed a favourable safety profile,” according to Prof. Bakris. No serious or severe drug-related adverse events were reported. However, the rates of hyperkalaemia and hypotension were higher in the zilebesiran groups (6% vs 3%; 4% vs 1%); although these cases were mostly mild or moderate and did not lead to treatment discontinuations.

These results support the quarterly or biannual dosing of subcutaneous zilebesiran to reduce the BP of patients with hypertension. The investigational agent zilebesiran is further assessed as an add-on therapy for patients with hypertension in the KARDIA-2 trial.

1. 
   
   1. Bakris G, et al. Sustained blood pressure reduction with the RNA interference therapeutic zilebesiran: primary results from Kardia-1, a phase 2 study in patients with hypertension. LB04, AHA Scientific Sessions 2023, 11–13 November, Philadelphia, USA.
   2. Desai AS, et al. N Engl J Med 2023;389:228­–238.

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Posted on 29 January 202413 June 2024