Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy

转甲状腺素 医学 疾病 淀粉样多发性神经病 药理学 生物信息学 内科学 生物 发病年龄
作者
Richard Labaudinière
出处
期刊:The Royal Society of Chemistry eBooks [The Royal Society of Chemistry]
卷期号:: 202-229
标识
DOI:10.1039/9781782624202-00202
摘要

Rare genetic diseases represent a unique opportunity to develop drugs on genetically validated targets and fulfil major unmet medical needs. A genetically validated target improves the chance of positive clinical outcome, a significant hurdle for half of the drug candidates under development. Tafamidis was recently the first treatment to be approved for an amyloid disease, TTR-FAP, an ultra-orphan misfolding disease. This chapter will describe the key steps and success factors in the discovery and clinical development of tafamidis, leading to its approval in 2011. Tafamidis was developed to change the energetics of transthyretin (TTR) tetramer dissociation, the rate-limiting step in amyloid formation, mimicking the biological effects of the intragenic trans-suppressors that confer a protective effect in this fatal neurodegenerative disease. A pharmacodynamic marker measuring tetramer stabilisation in plasma samples was developed to assess target engagement and to select a dose from the single- and multiple-dose ascending Phase I study, which would be studied in a pivotal 18 month Phase II/III study. Tafamidis treatment was shown to reduce neurophysiological deterioration and improve quality of life, to preserve nerve function in large and small fibres and to improve nutritional status when compared to placebo treatment.

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