Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy)

Abstract

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e. we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20-mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.

Trial registration: ClinicalTrials.gov identifier: NCT01994889.

• Senile systemic amyloidosis
• wild-type TTR amyloid cardiomyopathy
• Vyndaqel

Acknowledgements

We thank those scientists whose work enabled us to do this clinical study with tafamidis.

Declaration of interest

This work was supported by the National Institutes of Health grant DK046335 (J.W.K.), National Institute on Aging grant AG036778 (M.S.M.) as well as the Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation. J.W.K. is a shareholder and a paid consultant for Pfizer who sells tafamidis. Dr. M.S.M.’s institution, Columbia University Medical Center, received funding for research studies of tafamidis and for consultation for Dr. M.S.M.’s role as co-chair of the steering committee for the ATTR-cardiomyopathy trial.

Supplementary material available online

Figures S1 and S2