KARDIA-2: Add-on zilebesiran effectively lowers blood pressure

A single subcutaneous dose of zilebesiran was associated with a clinically significant reduction in mean ambulatory and office systolic blood pressure (SBP) at month 3 when added to standard-of-care antihypertensives. Moreover, the novel BP-lowering drug showed a promising safety profile in the phase KARDIA-2 trial.

Zilebesiran, an investigational RNA interference therapeutic, has previously shown promising outcomes in hypertension management [1]. The current KARDIA-2 study (NCT05103332), presented by Dr Akshay Desai (Brigham and Women's Hospital, MA, USA), aimed to assess zilebesiran's efficacy in combination with standard-of-care antihypertensive therapy [2].

The study enrolled 1,500 adults with mild-to-moderate hypertension, who were randomised to receive once-daily oral treatment with olmesartan, amlodipine, or indapamide as background therapy. Those with a 24-hour mean SBP of 130–160 mmHg for ≥4 weeks were further randomised to receive zilebesiran 600 mg or placebo as add-on therapy.

At 3 months, participants receiving zilebesiran with either indapamide, amlodipine, or olmesartan demonstrated statistically significant reductions in 24-hour mean ambulatory SBP and office SBP compared with placebo. The least-square mean differences (LSMDs) were -12.1 mmHg for zilebesiran + indapamide, -9.7 mmHg for zilebesiran + amlodipine, and -4.0 mmHg for zilebesiran + olmesartan (all with P<0.001). At 6 months, reductions in office SBP remained significant (P<0.01 for all comparisons) for zilebesiran + indapamide (-13.6 mmHg), zilebesiran + amlodipine (-8.6 mmHg), and zilebesiran + olmesartan (-4.6 mmHg).

Safety analysis revealed a favourable profile for all combinations, with low incidences of adverse events (AEs) and rare serious AEs. Notably, hypotension/orthostatic hypotension occurred in 7 participants in each combination group but was resolved without intervention. A few participants experienced >30% reduction in eGFR, primarily in the first 3 months, which resolved upon repeat measurement.

“Although our trial was not adequately powered or of sufficient duration to ensure long-term safety and efficacy, these results do appear to support the potential for combining biannual dosing of zilebesiran with standard-of-care or any hypertensives to achieve additive blood pressure reductions”, concluded Dr Desai.

1. 
   
   1. Bakris GL, et al. JAMA. 2024;331(9):740-749.
   2. Bakris GL, et al. Zilebesiran in Combination with a Standard-of-care Antihypertensive in Patients with Inadequately Controlled Hypertension: Primary Results from the Phase 2 KARDIA-2 Study. LB2, Session 405, ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.

Medical writing support was provided by Dr Susanne Kammerer
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Posted on 10 April, 202425 April, 2024