Acoramidis

Acoramidis
Clinical data
ATC code
  • None
Identifiers
  • 3-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
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

Acoramidis /ə-corAM’-i-dis/ (formerly AG10, named for "Alhamadsheh-Graef molecule 10") is an investigational, near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation,[1][2] to treat transthyretin amyloid cardiomyopathy. It is delivered by mouth. An alternative treatment is tafamidis.[3][4][5] Acoramidis is pending FDA approval (PDUFA Nov. 29, 2024) for the treatment of both wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) to reduce cardiovascular death and hospitalization.

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.[6]

Phase 1 data indicated acoramidis achieved near-complete (>90%) TTR stabilization across the entire dosing interval at steady state.[7]

Phase 2 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. [8]

Phase 3 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 patients with ATTR-CM. Adverse events were similar in the two groups.[9]

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 patients with ATTR-CM.[10][11][12][13]

References

[edit]
  1. ^ Penchala, Sravan; Connelly, Stephen; Wang, Yu; Park, Miki; Zhao, Lei; Baranczak, Aleksandra; Rappley, Irit; Vogel, Hannes; Liedtke, Michaela; Witteles, Ronald; Powers, Evan; Reixach, Natàlia; Chan, William; Wilson, Ian; Kelly, Jeffery; Graef, Isabella; Alhamadsheh, Mamoun (2013-05-28). "AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin". Proceedings of the National Academy of Sciences. 110 (24): 9992–9997. doi:10.1073/pnas.1300761110. PMC 3683741. PMID 23716704.
  2. ^ Miller, Mark; Pal, Arindom; Albusairi, Wabel; Joo, Hyun; Pappas, Beverly; Haque Tuhin, Md Tariqul; Liang, Dengpan; Jampala, Raghavendra; Liu, Fang; Khan, Jared; Faaij, Marjon; Park, Miki; Chan, William; Graef, Isabella; Zamboni, Robert; Kumar, Neil; Fox, Jonathan; Sinha, Uma; Alhamadsheh, Mamoun (2018-09-13). "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. ISSN 0022-2623. PMC 6276790. PMID 30133284.
  3. ^ "Trial demonstrates potential of acoramidis for transthyretin amyloid cardiomyopathy". www.escardio.org.
  4. ^ Masri, Ahmad; Aras, Mandar; Falk, Rodney H.; Grogan, Martha; Jacoby, Daniel; Judge, Daniel P.; Shah, Sanjiv Jayendra; Witteles, Ronald; Ji, Alan X.; Wong, Paul W.; Cao, Xiaofan; Vanlandingham, Rebecca; Katz, Leonid; Sinha, Uma; Fox, Jonathan C.; Maurer, Mathew S. (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. S2CID 247906494.
  5. ^ Campbell, Courtney M.; Zhang, Kathleen; Lenihan, Daniel J.; Witteles, Ronald (April 2022). "Developing Therapy for Transthyretin Amyloidosis". The American Journal of Medicine. 135: S44–S48. doi:10.1016/j.amjmed.2022.01.002. PMID 35077703. S2CID 246225610.
  6. ^ Ji, A; Wong, P; Judge, D P; Graef, I A; 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.
  7. ^ Fox, Jonathan C.; Hellawell, Jennifer L.; Rao, Satish; O'Reilly, Terry; Lumpkin, Rick; Jernelius, Jesper; Gretler, Daniel; Sinha, Uma (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. ISSN 2160-763X. PMC 7003869. PMID 31172685.
  8. ^ Masri, Ahmad; Aras, Mandar; Falk, Rodney H.; Grogan, Martha; Jacoby, Daniel; Judge, Daniel P.; Shah, Sanjiv Jayendra; Witteles, Ronald; Ji, Alan X.; Wong, Paul W.; Cao, Xiaofan; Vanlandingham, Rebecca; Katz, Leonid; Sinha, Uma; Fox, Jonathan C. (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.
  9. ^ Gillmore, Julian D.; Judge, Daniel P.; Cappelli, Francesco; Fontana, Marianna; Garcia-Pavia, Pablo; Gibbs, Simon; Grogan, Martha; Hanna, Mazen; Hoffman, James; Masri, Ahmad; Maurer, Mathew S.; Nativi-Nicolau, Jose; Obici, Laura; Poulsen, Steen Hvitfeldt; Rockhold, Frank (2024-01-11). "Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy". New England Journal of Medicine. 390 (2): 132–142. doi:10.1056/NEJMoa2305434. ISSN 0028-4793. PMID 38197816.
  10. ^ "Program Planner". www.abstractsonline.com. Retrieved 2024-10-19.
  11. ^ Alexander, Kevin; Judge, Daniel; Cappelli, Francesco; Fontana, Marianna; Garcia-Pavia, Pablo; Grogan, Martha; Hanna, Mazen; Masri, Ahmad; Maurer, Mat (2024-05-06). "Acoramidis Achieves Early Reduction in Cardiovascular Death or Hospitalization in Transthyretin Amyloid Cardiomyopathy (ATTR-CM): Results from the ATTRibute-CM Clinical Trial OC7 (#281)". dx.doi.org. doi:10.26226/m.65f9bf8ae6f73964e1d4f069. Retrieved 2024-10-19.
  12. ^ Cheng, Richard; Grodin, Justin; Gordon, Robert; Schmedtje, John; Lecumberri, Ramón; berk, john; K., Margot; Mooney, Deirdre; (Martha), Xiaofan (2024-05-03). "Treatment-related Early Increase in Serum TTR is Associated With Lower Cardiovascular Hospitalization in ATTR-CM: Insights From ATTRibute-CM OC10 (#282)". dx.doi.org. doi:10.26226/m.65f9bf8ae6f73964e1d4f06f. Retrieved 2024-10-19.
  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". hfsa.org. Retrieved 2024-10-19.


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