Zilebesiran

Last updated

Zilebesiran
Zilebesiran structure.svg
Clinical data
Other namesAD-85481, ALN-85481, ALN-AGT01
Legal status
Legal status
  • Investigational
Identifiers
  • sodium;[(2S,4R)-1-[12-[[1-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]-3-[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-methyloxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]propan-2-yl]amino]-12-oxododecanoyl]-4-hydroxypyrrolidin-2-yl]methyl [(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-2-(hydroxymethyl)-4-methoxyoxolan-3-yl] phosphate
CAS Number
PubChem CID
UNII
Chemical and physical data
Formula C89H152N16NaO36P
Molar mass 2076.235 g·mol−1
3D model (JSmol)
  • C[C@@H]1[C@@H]([C@@H]([C@H]([C@@H](O1)OCCCCC(=O)NCCCNC(=O)CCOCC(COCCC(=O)NCCCNC(=O)CCCCO[C@H]2[C@@H]([C@H]([C@H]([C@H](O2)CO)O)O)NC(=O)C)(COCCC(=O)NCCCNC(=O)CCCCO[C@H]3[C@@H]([C@H]([C@H]([C@H](O3)CO)O)O)NC(=O)C)NC(=O)CCCCCCCCCCC(=O)N4C[C@@H](C[C@H]4COP(=O)([O-])O[C@@H]5[C@H](O[C@H]([C@@H]5OC)N6C=NC7=C(N=CN=C76)N)CO)O)NC(=O)C)O)O.[Na+]
  • InChI=InChI=1S/C89H153N16O36P.Na/c1-54-75(121)78(124)71(100-55(2)109)86(137-54)133-37-17-14-23-63(113)91-31-20-34-94-66(116)28-40-130-49-89(50-131-41-29-67(117)95-35-21-32-92-64(114)24-15-18-38-134-87-72(101-56(3)110)79(125)76(122)60(45-106)139-87,51-132-42-30-68(118)96-36-22-33-93-65(115)25-16-19-39-135-88-73(102-57(4)111)80(126)77(123)61(46-107)140-88)103-69(119)26-12-10-8-6-7-9-11-13-27-70(120)104-44-59(112)43-58(104)48-136-142(127,128)141-81-62(47-108)138-85(82(81)129-5)105-53-99-74-83(90)97-52-98-84(74)105;/h52-54,58-62,71-73,75-82,85-88,106-108,112,121-126H,6-51H2,1-5H3,(H,91,113)(H,92,114)(H,93,115)(H,94,116)(H,95,117)(H,96,118)(H,100,109)(H,101,110)(H,102,111)(H,103,119)(H,127,128)(H2,90,97,98);/q;+1/p-1/t54-,58+,59-,60-,61-,62-,71-,72-,73-,75+,76+,77+,78-,79-,80-,81-,82-,85-,86-,87-,88-;/m1./s1
  • Key:FUHMXNACFUZXIQ-ZHSRMXMESA-M

Zilebesiran (development code ALN-AGT01) is an investigational RNA interference (RNAi) therapeutic agent being developed by Roche and Alnylam Pharmaceuticals for the treatment of hypertension. [1] [2]

Contents

It is small interfering RNA that is administered subcutaneously twice annually to lower blood pressure in people already taking other antihypertensive drugs. [3] [4] [5] The drug is designed to inhibit hepatic angiotensinogen synthesis through targeted silencing of the angiotensinogen gene, offering the potential for prolonged blood pressure control with infrequent dosing. [1] [6] [7]

Mechanism of action

Zilebesiran works by targeting the hepatic production of angiotensinogen, which is the sole precursor of angiotensin peptides and plays a key role in the pathogenesis of hypertension. [1] The drug utilizes small interfering RNA (siRNA) technology to post-transcriptionally silence the angiotensinogen (AGT) gene in liver cells. [8]

The mechanism involves several steps: zilebesiran, conjugated with GalNAc (N-acetylgalactosamine), binds to the asialoglycoprotein receptor (ASGPR) on hepatocytes, enters endosomes, and releases the siRNA component which then binds to the RNA-induced silencing complex (RISC). [9] The siRNA guide strand hybridizes with AGT mRNA, leading to its degradation and ultimately reducing angiotensinogen protein synthesis. [9]

Clinical studies have shown that zilebesiran reduces serum angiotensinogen levels by more than 90%, leading to downstream reductions in the vasoconstrictor angiotensin II. [2] This approach targets the renin-angiotensin-aldosterone system at its most upstream point, potentially offering more comprehensive blockade than traditional ACE inhibitors or ARBs. [10]

Clinical development

Phase 1 studies

The first-in-human Phase 1 study of zilebesiran was a randomized, double-blind, placebo-controlled trial conducted in 107 patients with mild-to-moderate hypertension. [1] Results published in the New England Journal of Medicine in July 2023 demonstrated that single subcutaneous doses of zilebesiran led to dose-dependent decreases in both serum angiotensinogen levels and 24-hour ambulatory blood pressure that were maintained for up to 24 weeks. [1]

The study showed that doses of 200 mg or higher achieved sustained blood pressure reductions, with the 800 mg dose producing mean reductions in 24-hour systolic blood pressure of greater than 20 mmHg at six months. [11] Patients experienced consistent and sustained lowering of both daytime and nighttime systolic blood pressure throughout the six-month observation period. [11]

Phase 2 studies

KARDIA-1 trial

The KARDIA-1 Phase 2 trial was a randomized, double-blind, placebo-controlled, multicenter global dose-ranging study designed to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. [12] The study enrolled 394 adults representing a diverse population and evaluated multiple dose levels of zilebesiran compared to placebo. [12] [13]

KARDIA-2 trial

The KARDIA-2 study evaluated zilebesiran as an add-on therapy to standard of care antihypertensive medications. [10] Results announced in March 2024 demonstrated clinically significant blood pressure reductions when zilebesiran was added to existing antihypertensive regimens. [10] [14]

KARDIA-3 trial

The KARDIA-3 Phase 2 study is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of zilebesiran used as an add-on therapy in adult patients with high cardiovascular risk. [15] [10] [16] Enrollment was completed in 2025, with the study evaluating zilebesiran in combination with at least two antihypertensives in patients with uncontrolled hypertension. [16]

Phase 3 studies

In September 2025, Roche and Alnylam advanced zilebesiran into a global phase III cardiovascular outcomes trial for people with uncontrolled hypertension. [17]

Clinical efficacy

Clinical trials have demonstrated that zilebesiran provides dose-dependent and sustained blood pressure reductions lasting up to 24 weeks after a single subcutaneous injection. [1] The KARDIA clinical program has enrolled more than 600 patients across Phase 2 trials, demonstrating clinically significant blood pressure reductions with encouraging safety profiles both as monotherapy and as add-on therapy. [18]

The drug achieves tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained for months after a single dose. [19] This prolonged duration of action represents a potential paradigm shift in hypertension management, offering the possibility of infrequent dosing schedules compared to daily oral medications. [20]

Safety profile

Clinical trials have reported that zilebesiran has a satisfactory safety profile and is well tolerated by patients. [2] The most commonly observed adverse events were mild injection-site reactions at the subcutaneous injection site. [1] No serious adverse events directly attributable to zilebesiran have been reported in published studies. [1]

The safety profile appears favorable across the dose ranges studied, with higher doses showing proportionally greater efficacy without significant increases in adverse events. [18] The infrequent dosing schedule may also contribute to improved patient tolerability and adherence compared to daily oral antihypertensive medications. [20]

Technology platform

Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables targeted delivery to liver cells and enhanced stability of the siRNA molecule. [10] The GalNAc conjugation allows for specific uptake by hepatocytes through the asialoglycoprotein receptor, ensuring targeted delivery to the site of angiotensinogen synthesis. [9]

This technology platform represents an advancement in RNAi therapeutics, providing prolonged duration of action that distinguishes zilebesiran from traditional small molecule drugs targeting the renin-angiotensin-aldosterone system. [21]

Regulatory status

As of September 2025, zilebesiran remains an investigational drug that has not received approval from regulatory agencies. [16] The compound has completed through Phase 2 clinical development as part of the KARDIA clinical program, with plans for Phase 3 studies based on the positive results from earlier trials. [16]

See also

References

  1. 1 2 3 4 5 6 7 8 Desai, Akshay S.; Webb, David J.; Taubel, Jorg; Casey, Sarah; Cheng, Yansong; Robbie, Gabriel J.; et al. (20 July 2023). "Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension". New England Journal of Medicine. 389 (3): 228–238. doi:10.1056/NEJMoa2208391. PMID   37467498.
  2. 1 2 3 "Zilebesiran — the first siRNA-based drug in hypertensiology: why is it needed, and will it change the treatment approach of hypertension?". Arterial Hypertension. 10 January 2024.
  3. ↑ Carvalho, Thiago (2023). "RNA interference treatment targeting angiotensinogen lowers blood pressure". Nature Medicine. 29 (12): 2962–2963. doi:10.1038/d41591-023-00091-x. ISSN   1078-8956. PMID   37845541.
  4. ↑ Khan, Rida S.; Frishman, William H. (22 February 2024). "Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis". Cardiology in Review. 33 (3): 279–284. doi:10.1097/CRD.0000000000000645. PMID   38385680.
  5. ↑ Waldron, James (5 March 2024). "2nd win for Alnylam RNAi blood pressure med strengthens Roche's $2.8B biobucks bet". Fierce Biotech. Retrieved 6 March 2024.
  6. ↑ Desai, Akshay S.; Webb, David J.; Taubel, Jorg; Casey, Sarah; Cheng, Yansong; Robbie, Gabriel J.; et al. (20 July 2023). "Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension" (PDF). New England Journal of Medicine. 389 (3): 228–238. doi:10.1056/NEJMoa2208391. hdl: 20.500.11820/9ec1c393-058a-4fe7-8e8f-df207dcdfb85 . PMID   37467498.
  7. ↑ Bakris, George L.; et al. (5 March 2024). "RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial". JAMA. 331 (9): 740–749. doi:10.1001/jama.2024.0728. PMC   10873804 . PMID   38363577.
  8. ↑ Khan, R. S.; Frishman, W. H. (2025). "Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis". Cardiology in Review. 33 (3): 279–284. doi:10.1097/CRD.0000000000000645. PMID   38385680.
  9. 1 2 3 Siddiqui, E.; Siddiqui, A. H.; Moeed, A.; Laique, F.; Najeeb, H.; Al Hasibuzzaman, M. (2025). "Advancing hypertension management: the role of zilebesiran as an siRNA therapeutic agent". PMC. 87 (2): 577–582. doi:10.1097/MS9.0000000000002696. PMC   11918631 . PMID   40110301.
  10. 1 2 3 4 5 "Alnylam Reports Positive KARDIA-2 Topline Study Results". Alnylam Pharmaceuticals. 5 March 2024.
  11. 1 2 "Alnylam Presents New Data for Zilebesiran". Alnylam Pharmaceuticals. 13 November 2021.
  12. 1 2 "Alnylam Reports Positive Topline Results from KARDIA-1 Phase 2 Dose-Ranging Study". Alnylam Pharmaceuticals. 7 September 2023.
  13. ↑ Alnylam Pharmaceuticals (20 December 2024). A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Multicenter Study to Evaluate the Efficacy and Safety of ALN-AGT01 in Patients With Mild-to-Moderate Hypertension (Report). clinicaltrials.gov.
  14. ↑ Alnylam Pharmaceuticals (19 June 2025). A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (Report). clinicaltrials.gov.
  15. ↑ Alnylam Pharmaceuticals (25 August 2025). A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Adult Patients With High Cardiovascular Risk and Hypertension Not Adequately Controlled by Standard of Care Antihypertensive Medications (Report). clinicaltrials.gov.
  16. 1 2 3 4 "Alnylam Highlights Significant Pipeline Progress". Alnylam Pharmaceuticals. 25 February 2025.
  17. ↑ "Roche and Alnylam to take zilebesiran into Phase III hypertension trial". www.thepharmaletter.com. Retrieved 3 September 2025.
  18. 1 2 "Alnylam Presents Positive Results from the KARDIA-2 Phase 2 Study". Alnylam Pharmaceuticals. 7 April 2024.
  19. ↑ "Alnylam Announces Publication of Phase 1 Study Results for Zilebesiran". Business Wire. 19 July 2023.
  20. 1 2 Lemine, M.; Almuzainy, S.; Aljubeh, R.; Alilo, A. (2024). "Zilebesiran and Hypertension: A Systematic Review and Meta-analysis". PMC. 36 (4): 420–430. PMC   11708905 . PMID   39781230.
  21. ↑ "ALN AGT 01". AdisInsight.
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