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Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

Authors Burton A, Castaño A, Bruno M, Riley S, Schumacher J, Sultan MB, See Tai S, Judge DP, Patel JK, Kelly JW

Received 31 October 2020

Accepted for publication 20 January 2021

Published 18 March 2021 Volume 2021:15 Pages 1225—1243


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Manfred Ogris

Arianna Burton,1 Adam Castaño,1 Marianna Bruno,1 Steve Riley,2 Jennifer Schumacher,1 Marla B Sultan,3 Sandi See Tai,4 Daniel P Judge,5 Jignesh K Patel,6 Jeffery W Kelly7

1Medical Affairs, Pfizer Inc, New York, NY, USA; 2Clinical Pharmacology, Pfizer Inc, Groton, CT, USA; 3Global Product Development, Pfizer Inc, New York, NY, USA; 4Global Product Development, Pfizer Inc, Collegeville, PA, USA; 5Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; 6Department of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA; 7Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

Correspondence: Adam Castaño Email [email protected]

Abstract: Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Keywords: amyloidosis, cardiomyopathy, heart failure, transthyretin, treatment, Vyndaqel/Vyndamax

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