Complete Stabilization of Transthyretin by Acoramidis

Transthyretin amyloidosis (ATTR) is a progressive, life-threatening disease.1 The cascade of events leading to development of the disease begins with the breakdown and dissociation of tetrameric TTR, accelerated by destabilizing TTR mutations. The mitigation of TTR destabilization is at the core of current therapeutic strategies for ATTR. Diflunisal and tafamidis are 2 TTR stabilizers that work to slow disease progression and have been investigated for clinical benefits in randomized, phase 3 clinical trials. Acoramidis (AG10) is a novel TTR stabilizer that is currently under development for the treatment of ATTR. It works by employing a unique mechanism that mimics the specific disease-protective action of T119M in stabilizing TTR.2

By mimicking the characteristics of T119M, AG10 demonstrates differential TTR binding, kinetic stability, and a higher degree of stabilization than other TTR stabilizers. To evaluate these potential differences, in this study, Alan X. Ji, PhD, and fellow investigators characterized and compared the relative TTR binding affinity of commercially available tafamidis and AG10.3,4

The thermodynamic stability of TTR interaction was determined by microscale thermophoresis, and kinetic stability was assessed by surface plasmon resonance. Immune blots were used to determine each stabilizer’s ability to mitigate accelerated tetramer dissociation alone or in combination over 72 hours at a pH of 3.8. Fluorescent probe exclusion assay was used to measure the binding site occupancy of TTR in serum. At 1 hour, target occupancy was calculated from progress curves.3 Therapeutic concentrations associated with administration of tafamidis meglumine 80 mg (trough = 16 µM; peak = 26 µM) were estimated from publicly available FDA documents.3,5,6

The affinity of AG10 for purified TTR was >3 times that of tafamidis. Kinetic stability revealed >4 times longer residence time for AG10 bound to TTR when measured against tafamidis. In vitro incubation of tafamidis alone did not entirely stabilize tetrameric TTR when evaluated at therapeutically attained plasma concentrations; however, by combining AG10 with tafamidis in vitro, complete stabilization of tetrameric TTR was achieved.3,4

The authors concluded that the extended residence time of AG10 provides enhanced TTR binding site occupancy and stabilization when compared with tafamidis. This study demonstrated that in vitro AG10 is a potent stabilizer of TTR as assessed by TTR binding affinity and kinetic stability and demonstrated complete stabilization of TTR in plasma samples with or without therapeutic concentrations of tafamidis.4 These outcomes provide strong support for the development of AG10 as a disease-modifying ATTR cardiomyopathy treatment.

References

  1. Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: an update on diagnosis and treatment. ESC Heart Fail. 2019;6:1128-1139.
  2. Miller M, Pal A, Albusairi W, et al. Enthalpy-driven stabilization of transthyretin by AG10 mimics a naturally occurring genetic variant that protects from transthyretin amyloidosis. J Med Chem. 2018;61:7862-7876.
  3. Ji A, Wong P, Betz A, Sinha U. Differential transthyretin binding, kinetic stability and additive ex vivo stabilization by AG10 compared to tafamidis. Presented at: 2020 International Symposium on Amyloidosis; September 14-18, 2020. Poster PW027.
  4. Ji A, Wong P, Betz A, Sinha U. Differential transthyretin binding, kinetic stability and additive ex vivo stabilization by AG10 compared to tafamidis. Presented at: 2020 International Symposium on Amyloidosis; September 14-18, 2020. Abstract PW027.
  5. Center for Drug Evaluation and Research. Summary review for regulatory action – NDA 211996/NDA 212161 (tafamidis meglumine/free acid). May 2, 2019. www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211996Orig1s000,%20212161Orig1s000SumR.pdf. Accessed February 26, 2021.
  6. Center for Drug Evaluation and Research. Clinical review – NDA 211996/NDA 212161 (tafamidis meglumine/free acid). November 2, 2018. www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211996Orig1s000,%20212161Orig1s000MedR.pdf. Accessed February 26, 2021.

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