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

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

Abbreviations

ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTR amyloidosis, transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTR-PN, transthyretin amyloid polyneuropathy; ATTRv, variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BL, baseline; CI, confidence interval; CV, cardiovascular; EE, efficacy evaluable; ITT, intent-to-treat; KPS, Karnofsky Performance Status score; LS, least-squares; mITT, modified intent-to-treat; mo, month; N/A, not available; NIS-LL, Neuropathy Impairment Score in the Lower Limbs; Norfolk QoL-DN, Norfolk Quality of Life-Diabetic Neuropathy questionnaire; NSAID, nonsteroidal anti-inflammatory drugs; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; pts, patients; QoL, quality of life; SD, standard deviation; SE, standard error; T₄, thyroxine; THAOS, Transthyretin Amyloidosis Outcomes Survey; TQoL, Total Quality of Life score from the Norfolk Quality of Life-Diabetic Neuropathy questionnaire; TRACS, Transthyretin Amyloidosis Cardiac Study; TTR, transthyretin; wk, week; y, year.

Disclosure

Medical writing support for this article was provided by Donna McGuire of Engage Scientific Solutions and was funded by Pfizer. AC, MB, SR, JS, MBS, and SST are full-time employees of Pfizer and may hold Pfizer stock and/or stock options. AB is a paid consultant to Pfizer in connection with the development of this manuscript.  DPJ has received consultancy fees from Alnylam, Blade Therapeutics, GSK, and Pfizer and research grants from Array Biopharma, Eidos, and Pfizer. JWK discovered tafamidis at the Scripps Research Institute; is a shareholder of FoldRx Pharmaceuticals, acquired by Pfizer Inc in October 2010 (the companies that developed tafamidis into a drug); and receives royalty payments from tafamidis patents and sales. JP has received grant/research support from Akcea, Alnylam, Alexion, Eidos, and Pfizer; served as a consultant for Akcea, Alnylam, Cytokinetics, and Pfizer; and served on the speaker’s bureau for Akcea and Alnylam. The authors report no other conflicts of interest related to this work.