zilebesiran (ALN-AGT) / Alnylam, Roche - LARVOL DELTA

Efficacy and safety of zilebesiran in adults with hypertension: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Eur J Clin Pharmacol) - "Overall, zilebesiran produced significant and consistent BP reductions, especially in ambulatory measures, with a favorable safety profile. However, evidence remains limited by small sample sizes and reliance on placebo comparators, and larger trials with active antihypertensive controls are needed to validate long-term efficacy and safety."

Clinical • Journal • Retrospective data • Review • Cardiovascular • Hypertension

Hopes and doubts about zilebesiran, a new antihypertensive drug. (PubMed, Wiad Lek) - "A large study, KARDIA 3, is currently underway to assess the antihypertensive efficacy and reduction of cardiovascular complications. Despite the promising results of previous studies further observation are still necessary regarding long-term hypotensive effectiveness, reduction of risk cardiovascular complication and side effects."

Journal • Review • Cardiovascular • Hypertension • Hypotension

Angiotensinogen-Targeting RNA Interference with Zilebesiran for Hypertension: A Systematic Review and Meta-Analysis of Randomized Trials (AHA 2026) - "Abstract is embargoed at this time."

Retrospective data • Review • Cardiovascular • Hypertension

Zilebesiran in combination with a diuretic in patients with uncontrolled hypertension: a subgroup analysis from the Phase 2 KARDIA-3 trial (ESC 2026) - P3 | "Conclusions These post hoc results suggest complementary effects on BP reduction when combining zilebesiran with a diuretic-containing standard of care regimen in patients with uncontrolled HTN. This analysis informed the design of ZENITH (NCT07181109), an ongoing global Phase 3 CV outcomes trial of zilebesiran in patients with HTN receiving ≥2 antihypertensives, including a diuretic, systolic BP ≥140 mmHg at randomization, and CVD or high CV risk."

Clinical • Combination therapy • P2 data • Cardiovascular • Hypertension • Hypotension

Dose-response and efficacy ceiling of zilebesiran: a bayesian non-linear spline meta-analysis of phase 1 and KARDIA phase 2 trials (ESC 2026) - "Integrating Phase 1 and KARDIA Phase 2 data, zilebesiran demonstrates durable, dose-proportional BP reduction that plateaus at 300–600 mg. These findings consolidate zilebesiran as a first-in-class long-acting RNAi antihypertensive and support the selection of 300 mg as the optimal therapeutic dose for future cardiovascular outcome trials."

P1 data • P2 data • Retrospective data • Cardiovascular • Hypertension

Efficacy and safety of zilebesiran for inadequately controlled hypertension: a systematic review and meta-analysis (ESC 2026) - "The placebo-adjusted least-squares mean difference in SBP reduction ranged from -4.0 mmHg (95% CI -7.6 to -0.3) in the olmesartan cohort to 12.1 mmHg (95% CI - 16.5 to -7.6) in the indapamide cohort. Single-dose subcutaneous zilebesiran as an add-on therapy provides significant antihypertensive efficacy in adults with uncontrolled hypertension. However, this benefit is accompanied by increased risks of hyperkalaemia and renal function decline. These findings highlight the potential of RNA interference therapeutics but underscore the need for careful monitoring of renal parameters."

Retrospective data • Review • Cardiovascular • Hypertension • Hypotension

Zilebesiran, a Small Interfering RNA Therapeutic Targeting Angiotensinogen: Mechanism, Clinical Evidence, Safety, and Implementation Considerations. (PubMed, Life (Basel)) - "Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway."

Journal • Review • Cardiovascular • Hypertension

Emerging Pharmacological Therapies for Hypertension. (PubMed, Curr Hypertens Rev) - "This review provides a general overview of the physiological effects and pharmacokinetic properties that affect the absorption, distribution, metabolism, and elimination of recently developed antihypertensive drugs, such as fimasartan, azilsartan, zilebesiran, aprocitentan, and esaxerenone. Mechanistic differences among these agents are also highlighted; for instance, fimasartan and azilsartan inhibit the angiotensin II receptor, whereas other medications alter mineralocorticoid activity or endothelial pathways. The review further discusses the clinical implications of these mechanisms in hypertension management and supports informed therapeutic decisionmaking by providing a detailed understanding of the pharmacological and mechanistic profiles of these emerging antihypertensive therapies."

Journal • Cardiovascular • Hypertension

Alnylam to Present New Data Reinforcing Strength in RNAi-Powered TTR Silencing and Continued Progress in Hypertension at ESC Congress 2026 (Businesswire) - "These presentations add to the existing and growing body of evidence demonstrating strength in RNAi-powered transthyretin (TTR) silencing with AMVUTTRA (vutrisiran) and underscore the potential of zilebesiran as an innovative treatment approach for hypertension, the leading preventable risk factor for cardiovascular disease (CVD) worldwide....The Company will also present new data from its hypertension program, including a subgroup analysis of the KARDIA-3 Phase 2 study evaluating zilebesiran in combination with a diuretic in patients with uncontrolled hypertension."

Clinical data • P2 data • Cardiovascular • Hypertension

Zilebesiran in Hypertension: Reversibility, Acute Illness, and Therapeutic Flexibility. (PubMed, Am J Cardiovasc Drugs) - "Early reversal strategies are conceptually important, but current approaches appear better suited to planned de-escalation than emergency rescue. Future work should define vulnerable phenotypes, clarify whether acute-care pathways require protocol adaptation, and determine how reversibility can be operationalized as phase 3 development advances."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Infectious Disease • Septic Shock

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Alnylam Pharmaceuticals | N=3962 ➔ 11000

Adverse events • Enrollment change • Trial initiation date • Cardiovascular • Congestive Heart Failure • Hypertension

Breakthrough drugs in the treatment of hypertension-related disease. (PubMed, Hypertens Res) - "This review summarizes recent advances in the treatment of hypertension-related disease, with a focus on emerging pharmacotherapies such as zilebesiran, aldosterone synthase inhibitors and on established or repurposed agents including mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, GLP-1 receptor agonists, a dual GIP/GLP-1 receptor agonist, and SGLT2 inhibitors. We discuss their clinical implications, particularly in relation to adherence, pathophysiological heterogeneity, and the future of personalized hypertension management aimed at improving long-term outcomes."

Journal • Review • Cardiovascular • Hypertension • Nephrology • Renal Disease

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Alnylam Pharmaceuticals

Adverse events • Trial initiation date • Cardiovascular • Congestive Heart Failure • Hypertension

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=3962 | Recruiting | Sponsor: Alnylam Pharmaceuticals

Adverse events • New P3 trial • Cardiovascular • Congestive Heart Failure • Hypertension

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Alnylam Pharmaceuticals | N=3982 ➔ 11000

Adverse events • Enrollment change • Trial initiation date • Cardiovascular • Congestive Heart Failure • Hypertension

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Alnylam Pharmaceuticals

Adverse events • New P3 trial • Cardiovascular • Congestive Heart Failure • Hypertension

New Drugs on the Horizon for Hypertension. (PubMed, Adv Kidney Dis Health) - "This includes the nonselective endothelin receptor antagonist aprocitentan, which was Food and Drug Administration approved in 2024 for uncontrolled hypertension. Aldosterone synthase inhibitors including baxdrostat, lorundrostat, and vicadrostat are in phase 1 or 2 trials for hypertension or chronic kidney disease with evidence of significant blood pressure lowering. Finally, the novel small-interfering RNA-based zilebesiran targeting angiotensinogen represents a new class of antihypertensive medications with durable blood pressure-lowering dosing only every 3 or 6 months. Each of these medications has unique properties that can potentially contribute to improvement in blood pressure control for individual patients and at the population level. Development of these novel antihypertensives promises a welcome set of new options for the treatment of hypertension."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Hypertension • Nephrology • Renal Disease

Hypertension at an Inflection Point: Aggressive Targets Meet Novel Mechanisms for Cardiovascular Prevention. (PubMed, J Am Coll Cardiol) - "This review synthesizes these converging developments and frames them within an emerging phenotype-driven framework that matches therapy to the dominant driver of uncontrolled or difficult-to-treat hypertension. The implications for cardiovascular disease prevention are substantial: more aggressive targets are now achievable through more precise therapies, and the coming years will require a shift from 1-size-fits-all stepped care toward individualized precision management."

Journal • Review • Cardiovascular • Hypertension • Nephrology

Zilebesiran as Add-on Treatment to RAAS Inhibitors for Patients with Hypertension: Data From KARDIA-2 and KARDIA-3 Phase 2 Trials (ERA 2026) - P2, P3 | "ZENITH (NCT07181109), an ongoing global CV outcomes trial, is now enrolling patients with HTN and established CV disease or high CV risk. Image"

Clinical • P2 data • Cardiovascular • Hypertension

Zilebesiran as Add-on Treatment to RAAS Inhibitors for Patients with Hypertension: Data from the KARDIA-2 and KARDIA-3 Phase 2 Trials (ERA 2026) - No abstract available

Clinical • P2 data • Cardiovascular • Hypertension

A Study to Evaluate ALN-AGT01 RVR in Adult Patients With Mild to Moderate Hypertension Pretreated With Zilebesiran (clinicaltrials.gov) - P2 | N=93 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Hypertension

A Study to Evaluate ALN-AGT01 RVR in Adult Patients With Mild to Moderate Hypertension Pretreated With Zilebesiran (clinicaltrials.gov) - P2 | N=93 | Not yet recruiting | Sponsor: Alnylam Pharmaceuticals

New P2 trial • Cardiovascular • Hypertension

Resistant Hypertension: Pathophysiology, Diagnostic Approaches, and Emerging Therapeutic Strategies. (PubMed, Curr Hypertens Rev) - "Resistant hypertension represents a multifactorial condition requiring a multidimensional diagnostic and therapeutic approach. Integrating lifestyle changes, optimized pharmacotherapy, and emerging options, including aldosterone synthase inhibition, dual endothelin receptor antagonism, small-interfering RNA strategies, and refined device-based approaches, offers incremental BP reductions in carefully selected patients. The synthesis emphasizes a pragmatic, stepwise strategy that couples adherence and secondary cause assessment with evidence-based pharmacologic intensification (notably mineralocorticoid receptor antagonists) and selective device therapy. This integrated approach may be critical for achieving durable BP control and reducing cardiovascular risk in patients with resistant hypertension."

Journal • Cardiovascular • Chronic Kidney Disease • Endocrine Disorders • Hypertension • Nephrology • Obstructive Sleep Apnea • Renal Disease • Respiratory Diseases • Sleep Disorder

Angiotensinogen Reconsidered: Evolving Perspectives in Hypertension Research. (PubMed, Hypertension) - "Recent translational advances, including RNA-based therapeutics such as small interfering RNAs (zilebesiran) and antisense oligonucleotides (tonlamarsen), demonstrate promising blood pressure reductions and favorable safety profiles in clinical trials. AGT also shows potential as a biomarker for hypertensive nephropathy and treatment responsiveness. This review underscores the value of AGT as an upstream therapeutic target and diagnostic marker, offering new avenues for precision medicine and long-acting strategies in the management of both conventional and resistant hypertension while possibly addressing medication adherence-related obstacles."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Genetic Disorders • Hypertension • Inflammation • Nephrology • Obesity • Renal Disease

POOLED SAFETY ANALYSIS OF ZILEBESIRAN, AN INVESTIGATIONAL LONG-ACTING RNA INTERFERENCE THERAPEUTIC, FROM PHASE 2 STUDIES IN PATIENTS WITH HYPERTENSION (ACC 2026) - "In KARDIA-2, patients with inadequately controlled HTN on indapamide, amlodipine, or olmesartan received add-on zilebesiran 600 mg or placebo. In 890 patients from the Phase 2 KARDIA studies who were treated with zilebesiran as monotherapy or as add-on to other antihypertensives, including oral RAAS inhibitors, overall rates of clinically relevant safety events over 6 months were low. Alongside previously reported efficacy findings, this supports the advancement of the Phase 3 ZENITH CV outcomes trial in patients with uncontrolled HTN and high CV risk."

Clinical • P2 data • Cardiovascular • Hypertension • Hypotension