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 in the TTR amyloidosis. Hence we measure the TTR tetramer dissociation rate (kinetic stability) in the patients’ plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tells 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.

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

“…Interestingly, no significant difference was found between the two tested doses (20 mg vs. 80 mg), while in‐vitro results suggested the need for doses of 60 mg daily to achieve complete kinetic stabilization, especially in more advanced cases …”

Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis

“…Thus, early administration of tafamidis seems to be important for its efficacy. Additionally, all previous trials employed a dose of 20 mg but an 80 mg dose is being tested in an ongoing phase III trial, with biochemical data suggesting that a higher dose may be required for TTR stabilization 136 . Five year safety data in a small cohort has been reassuring in that tafamidis was generally well tolerated at 20 mg, though efficacy data showed few patients with ATTR-CA were clinically stabilized at 3.5 years.…”

Transthyretin cardiac amyloidosis: an update on diagnosis and treatment

“…80 In a Phase 3 multicentre randomized ATTR-ACT trial (NCT01994889), 441 patients with ATTR-CA (wild type or variant) were randomly assigned in a 2:1:2 ratio to receive tafamidis 80 mg, 20 mg, or placebo orally every 24 h for 30 months. 82 Thus, tailoring of the tafamidis Transthyretin cardiac amyloidosis dose to the patients in NYHA class III might need to achieve maximum kinetic stabilization. Tafamidis reduced all-cause mortality and cardiovascularrelated hospitalizations compared with placebo.…”