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

A single subcutaneous dose of zilebesiran in combination with indapamide, amlodipine, or olmesartan demonstrated significant reductions in both ambulatory and office systolic blood pressure (SBP) at month 3. Moreover, the novel blood pressure-lowering drug showed a promising safety profile, suggesting its potential as a novel treatment strategy for hypertension.

“Despite the availability of effective therapies, many patients with hypertension do not achieve guideline-recommended blood pressure targets, leaving them at an unattended risk for cardiovascular events,” said Dr Akshay Desai (Brigham and Women's Hospital, MA, USA) [1]. In part, this may be due to poor adherence to complex multidrug oral treatment regimens.

Zilebesiran, an investigational RNA interference therapeutic, significantly reduced 24-hour mean ambulatory SBP at 3 months with a single subcutaneous injection compared with placebo in the phase 2 KARDIA-1 study [2]. Building on this, the phase 2 KARDIA-2 study (NCT05103332) aimed to assess zilebesiran’s efficacy in combination with standard-of-care anti-hypertensive therapy [1].

The study enrolled 1,500 adults with mild-to-moderate hypertension, who were randomised to receive once-daily oral treatment with indapamide, amlodipine, or olmesartan 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 LS mean differences 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; see Figure). 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).

Figure: Change from baseline to month 3 in 24-hour mean ambulatory SBP [1]



CI, confidence interval; LSM, least-square mean; LSMD, LSM difference; SBP, systolic blood pressure.

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 nor 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. 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.
   2. Bakris GL, et al. JAMA. 2024;331(9):740-749.

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Posted on 16 May 202413 June 2024