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Zilebesiran: Novel siRNA Therapy for Hypertension

Zilebesiran is an investigational small interfering RNA (siRNA) therapeutic that targets hepatic angiotensinogen synthesis to provide sustained blood pressure reduction lasting up to 6 months with subcutaneous dosing every 3-6 months, demonstrating clinically significant reductions of 10-17 mmHg in systolic blood pressure compared to placebo. 1, 2

Mechanism of Action

• Zilebesiran uses RNA interference technology conjugated to N-acetylgalactosamine (GalNAc) to achieve liver-specific delivery to hepatocytes, where it inhibits angiotensinogen mRNA translation 3, 4
• The drug produces >90% reductions in circulating angiotensinogen levels, thereby suppressing the entire renin-angiotensin-aldosterone system at its most upstream point 4
• This GalNAc conjugation enables the same predictable pharmacokinetic profile seen with other approved GalNAc-siRNA therapeutics (givosiran, lumasiran, inclisiran), with plasma Tmax of 4-6 hours and elimination half-lives of 5-10 hours 5

Clinical Efficacy Data

KARDIA-1 Trial Results (Phase 2)

• In 377 adults with mild to moderate hypertension (daytime ambulatory SBP 135-160 mmHg), zilebesiran achieved statistically significant reductions in 24-hour mean ambulatory SBP at 3 months across all dosing regimens 2
• Specific reductions versus placebo at month 3:
  • 150 mg every 6 months: -14.1 mmHg (95% CI -19.2 to -9.0; P<0.001) 2
  • 300 mg every 3 months: -16.7 mmHg (95% CI -21.2 to -12.3; P<0.001) 2
  • 300 mg every 6 months: -16.7 mmHg (95% CI -21.2 to -12.3; P<0.001) 2
  • 600 mg every 6 months: -15.7 mmHg (95% CI -20.8 to -10.6; P<0.001) 2

KARDIA-2 Trial Results

• When used as adjunctive therapy to standard antihypertensive medications, zilebesiran produced an additional 12.1 mmHg reduction in systolic blood pressure at 3 months 3

Duration of Effect

• Single subcutaneous doses ≥200 mg produce clinically significant blood pressure reductions (>10/5 mmHg systolic/diastolic) within 8 weeks, with effects persisting for up to 6 months 4, 6
• The 300 mg dose administered every 6 months resulted in sustained reductions exceeding 15 mmHg at 3 months 3

Optimal Dosing

Based on meta-analysis and clinical trial data, the optimal dosing range appears to be 250-500 mg, with the 300 mg dose every 6 months providing the best balance of efficacy and convenience 1, 2

Safety Profile

• Over 6 months, 60.9% of zilebesiran-treated patients experienced adverse events versus 50.7% with placebo, with serious adverse events occurring less frequently in the treatment group (3.6% vs 6.7%) 2
• Drug-related adverse events occurred in 16.9% of zilebesiran patients versus 8.0% with placebo, primarily consisting of mild injection site reactions and transient mild hyperkalemia 4, 2
• No serious hypotension or renal impairment attributable to RAAS suppression has been observed in short-term studies 4
• The safety profile mirrors that of other approved GalNAc-siRNA therapeutics, where plasma protein binding (>90% for givosiran, 77-85% for lumasiran, ~87% for inclisiran) has minimal impact on hepatocellular uptake and disposition 5

Clinical Applications Under Investigation

Primary Indications

• Monotherapy for patients with essential mild to moderate hypertension who struggle with daily medication adherence 3, 4
• Adjunctive therapy for patients with resistant or uncontrolled hypertension despite standard treatment 3

Potential Advantages

• Bi-annual or quarterly dosing addresses the critical unmet need of medication nonadherence, which contributes to suboptimal blood pressure control in less than half of treated hypertensive patients 6
• Provides 24-hour tonic blood pressure control, potentially reducing nighttime blood pressure more effectively than conventional daily medications 6
• May offer target organ protection for heart, kidneys, and retina beyond blood pressure reduction alone 3

Important Clinical Considerations

Ongoing Research

• KARDIA-3 is currently evaluating zilebesiran in a larger global population to assess its impact on major cardiovascular outcomes, which will be critical for determining its role in reducing cardiovascular morbidity and mortality 3

Reversibility

• Studies are evaluating the reversibility of angiotensinogen knockdown, which is relevant for clinical scenarios requiring rapid restoration of RAAS activity 6

Population-Specific Responses

• The KARDIA-1 trial included 24.7% Black patients, but further research is needed to characterize patient-specific responses across diverse populations to optimize therapeutic efficacy 2, 3

Comparison to Other siRNA Therapeutics

• Unlike inclisiran (which targets PCSK9 for lipid lowering and has shown exploratory cardiovascular benefits with 26% reduction in composite MACE), zilebesiran targets a different pathway but employs the same GalNAc-conjugation technology for liver-specific delivery 5
• The predictable pharmacokinetics of GalNAc-siRNA therapeutics suggest zilebesiran's effects should be similarly reliable across patients 5