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Acoramidis

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Acoramidis
Clinical data
Pronunciationə-corAM-i-dis
Trade namesAttruby
Other namesAG10
AHFS/Drugs.comAttruby
License data
Routes of
administration		By mouth
Drug classAmyloidogenesis suppressant
ATC code
  • None
Legal status
Legal status
Identifiers
  • 3-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC15H17FN2O3
Molar mass292.310 g·mol−1
3D model (JSmol)
  • CC1=C(C(=NN1)C)CCCOC2=C(C=CC(=C2)C(=O)O)F
  • InChI=1S/C15H17FN2O3/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20)
  • Key:WBFUHHBPNXWNCC-UHFFFAOYSA-N

  • InChI=1S/C15H17FN2O3.ClH/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16;/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20);1H
  • Key:MGFZEARHINUOMX-UHFFFAOYSA-N

Acoramidis, sold under the brand name Attruby, is a medication used for the treatment of cardiomyopathy.[1] It is a near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation,[2][3] to treat transthyretin amyloid cardiomyopathy. It is taken by mouth.[1]

The most common adverse reactions include diarrhea and upper abdominal pain.[4]

Acoramidis was approved for medical use in the United States in November 2024.[4][5]

Medical uses

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Acoramidis is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization.[1][4][6]

ATTR-CM is a rare and serious disease that affects the heart muscle.[4] In people with ATTR-CM, there is a build-up of protein deposits in the heart, causing the walls of the heart to become stiff, and making the left ventricle unable to properly relax and fill with blood (called cardiomyopathy).[4] As the condition progresses, the heart can become unable to pump blood out adequately, causing heart failure.[4] There are two types of ATTR-CM, hereditary ATTR-CM (hATTR-CM) and wild-type ATTR-CM (wATTR-CM).[4] In hATTR-CM, which can run in families, there's a variant in the transthyretin gene, which results in protein deposits in the heart. In wATTR-CM, there is no variant in the transthyretin gene.[4]

Side effects

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The most common side effects are diarrhea and abdominal pain.[7]

History

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The efficacy and safety of acoramidis were evaluated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult participants with wild-type or hereditary (variant) ATTR-CM (NCT03860935).[4]

Clinical trials

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Phase I data indicated acoramidis achieved near-complete (>90%) TTR stabilization across the entire dosing interval at steady state.[8]

Phase II and the Open-Label Extension (OLE) data indicated after a median of 38 months, long-term treatment with acoramidis was generally well tolerated and resulted in a median decline in NT-proBNP levels, normalization of serum TTR, and sustained stabilization of TTR in individuals with ATTR-CM. [9]

Phase III data from ATTRibute-CM indicated acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo at 30 months in participants with ATTR-CM. Adverse events were similar in the two groups.[10]

Other analyses from ATTRibute-CM indicated a 50% reduction in cumulative cardiovascular hospitalizations (CVH), a 42% reduction in all-cause mortality (ACM) and recurrent CVH, and a 3-month time-to-separation of the Kaplan Meier curves for ACM or CVH. No other treatment has demonstrated this degree of treatment effect this quickly in participants with ATTR-CM.[11][12][13]

In vitro data indicated acoramidis exhibits near-complete (>90%) TTR stabilization at therapeutic trough concentrations, and its TTR stabilization exceeds that of tafamidis' across a range of destabilizing TTR mutations.[14]

Society and culture

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[edit]

Acoramidis was approved for medical use in the United States in November 2024.[4][15][16] The approval was granted to BridgeBio Pharma.[6]

Names

[edit]

During development, acoramidis was known as AG10 (the Alhamadsheh-Graef molecule 10).[17]

Acoramidis is the international nonproprietary name (INN).[18]

References

[edit]
  1. ^ a b c d "Attruby- acoramidis hydrochloride tablet, film coated". DailyMed. 26 November 2024. Retrieved 28 November 2024.
  2. ^ Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, et al. (June 2013). "AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin". Proceedings of the National Academy of Sciences of the United States of America. 110 (24): 9992–9997. doi:10.1073/pnas.1300761110. PMC 3683741. PMID 23716704.
  3. ^ Miller M, Pal A, Albusairi W, Joo H, Pappas B, Haque Tuhin MT, et al. (September 2018). "Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis". Journal of Medicinal Chemistry. 61 (17): 7862–7876. doi:10.1021/acs.jmedchem.8b00817. PMC 6276790. PMID 30133284.
  4. ^ a b c d e f g h i j "FDA approves drug for heart disorder caused by transthyretin-mediated". U.S. Food and Drug Administration. 1 October 2024. Retrieved 27 November 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ "FDA approves BridgeBio Pharma's Attruby to treat rare heart disease ATTR-CM". PMLiVE. 25 November 2024. Retrieved 25 November 2024.
  6. ^ a b LeMieux J (25 November 2024). "Bridgebio's Attruby, to Treat Heart Condition ATTR-CM, Receives FDA Approval". Genetic Engineering and Biotechnology News. Retrieved 25 November 2024.
  7. ^ "FDA approves BridgeBio's Attruby for ATTR-CM treatment". Pharmaceutical Technology. 25 November 2024. Retrieved 25 November 2024.
  8. ^ Fox JC, Hellawell JL, Rao S, O'Reilly T, Lumpkin R, Jernelius J, et al. (January 2020). "First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers". Clinical Pharmacology in Drug Development. 9 (1): 115–129. doi:10.1002/cpdd.700. PMC 7003869. PMID 31172685.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ^ Masri A, Aras M, Falk RH, Grogan M, Jacoby D, Judge DP, et al. (March 2022). "Long-Term Safety and Tolerability of Acoramidis (Ag10) in Symptomatic Transthyretin Amyloid Cardiomyopathy: Updated Analysis from an Ongoing Phase 2 Open-Label Extension Study". Journal of the American College of Cardiology. 79 (9): 227. doi:10.1016/S0735-1097(22)01218-9.
  10. ^ Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, et al. (January 2024). "Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy". The New England Journal of Medicine. 390 (2): 132–142. doi:10.1056/NEJMoa2305434. PMID 38197816.{{cite journal}}: CS1 maint: overridden setting (link)
  11. ^ "Program Planner". www.abstractsonline.com. Archived from the original on 6 February 2021. Retrieved 19 October 2024.
  12. ^ Alexander K, Judge D, Cappelli F, Fontana M, Garcia-Pavia P, Grogan M, et al. (6 May 2024). Acoramidis Achieves Early Reduction in Cardiovascular Death or Hospitalization in Transthyretin Amyloid Cardiomyopathy (ATTR-CM): Results from the ATTRibute-CM Clinical Trial OC7 (#281) (Report). doi:10.26226/m.65f9bf8ae6f73964e1d4f069.
  13. ^ "BridgeBio Shares Recurrent Event Analysis of ATTRibute-CM, Demonstrating a 42% Reduction by Acoramidis on the Composite Endpoint of All-Cause Mortality and Recurrent Cardiovascular-related Hospitalization Events". HFSA. Retrieved 19 October 2024.
  14. ^ Ji A, Wong P, Judge DP, Graef IA, Fox J, Sinha U (November 2023). "Acoramidis produces near-complete TTR stabilization in blood samples from patients with variant transthyretin amyloidosis that is greater than that achieved with tafamidis". European Heart Journal. 44 (Supplement_2). doi:10.1093/eurheartj/ehad655.989. ISSN 0195-668X.
  15. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
  16. ^ "Attruby (acoramidis), a Near Complete TTR Stabilizer (≥90%), approved by FDA to Reduce Cardiovascular Death and Cardiovascular-related Hospitalization in ATTR-CM Patients" (Press release). BridgeBio Pharma. 23 November 2024. Archived from the original on 25 November 2024. Retrieved 28 November 2024 – via GlobeNewswire.
  17. ^ "FDA approves Stanford Medicine-developed drug that treats rare heart disease". Stanford. 27 November 2024. Retrieved 29 November 2024.
  18. ^ World Health Organization (2024). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83". WHO Drug Information. 38 (1). hdl:10665/378096.

Further reading

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[edit]
  • Clinical trial number NCT03860935 for "Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM)" at ClinicalTrials.gov
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