Adam R. Looker

Chapter Twenty-Four – Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with Cystic Fibrosis and the G551D-CFTR Mutation

Abstract Cystic fibrosis (CF) is caused by mutations in the CFTR gene of an epithelial ion channel, the CF transmembrane conductance regulator (CFTR). We initiated efforts to discover potentiators of mutated CFTR. Potentiators are small molecules that increase the flow of ions through activated CFTR in the cell membrane. In-house HTS campaigns led to the identification of multiple hits. Extensive medicinal chemistry efforts driven by phenotypic assays led to the discovery of VX-770 (ivacaftor). VX-770 was found to be a potent, selective, orally bioavailable potentiator of G551D -CFTR, displaying excellent pharmacokinetic and safety profiles in rodents and nonrodents. Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of VX-770 suitable for clinical development. After successful clinical trials, ivacaftor was approved by the FDA in 2012 for the treatment of people with CF who have a G551D mutation in the CFTR gene.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies

ABSTRACT The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium‐led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions. Graphical abstract Figure. No caption available. HighlightsICH M7 Option 4 permits the use of predicted purges in lieu of analytical testing of mutagenic impurities.Predicted purge factors derived from expert knowledge or experimental data can be derived for stages in a synthesis.Thresholds of the predicted purge over the required purges can ensure a negligible risk from a mutagenic impurity.The level of scientific support needed to defend a purge estimate has been proposed.

The Delivery of Flexibility from the Application of QbD to API Development

This paper by IQ consortium member companies will describe how the application of the ICH Q11 vision for enhanced QbD development can lead to flexibility through differentiated outcomes for elements of API manufacture, such as the control strategy and lifecycle change management. Two further articles, in addition to this introductory paper, will present a series of case histories which address such flexibility and exemplify opportunities for the further development of the ICH Q11 vision.