Ivacaftor: A Novel Gene-Based Therapeutic Approach for Cystic Fibrosis

Abstract

Ivacaftor is a new therapeutic agent that acts at the cystic fibrosis transmembrane conductance regulator (CFTR) channel to alter activity. It is approved for use in patients 6 years and older with cystic fibrosis who have at least 1 G551D mutation in the CFTR gene. It is unlike any other current pharmacologic agent for cystic fibrosis in that it specifically targets the gene defect associated with cystic fibrosis as opposed to treating resulting symptomology. Mucoactive agents, antibiotics, inhaled beta agonists, and other anti-inflammatory agents are currently the mainstay of cystic fibrosis treatment but can be associated with several side effects in addition to cumbersome frequency of administration. Ivacaftor's oral dosing regimen offers a more convenient treatment option. However, it is associated with significant drug-drug interactions.

High‐Throughput Assays to Assess the Functional Impact of Genetic Variants: A Road Towards Genomic‐Driven Medicine

“…Ivacaftor is a CFTR potentiator because it can alter the activity of the channel by increasing the opening probability and flow of ions. The development of ivacaftor for use in G551D variant carriers provides a further example of how high‐throughput functional assays can facilitate identification of actionable drug targets and development of targeted therapeutics …”

Economics

“…The recent introduction of new pharmaceutical therapies comes at substantial annual cost, ranging from approximately $90 thousand per year for pulmonary fibrosis to more than $300 thousand per year for cystic fibrosis. These therapies may increase the cost‐saving potential of lung transplant in these disease groups if they are used in candidates who are sick enough to be considered for transplant . For example, it is possible that lung transplant will become immediately cost‐saving in Medicare‐covered cystic fibrosis patients if these therapies become widely used in the patients who are simultaneously listed for lung transplant, even if use results in decreased pulmonary exacerbations requiring hospitalizations and/or prolonged use of intravenous antibiotics.…”

Ion channels as therapeutic antibody targets

“…12 Despite the initial successes in identifying ion channel modulators, only two novel ion channel drugs have been approved by the US Food and Drug Administration (FDA) since the 1990s, despite vastly improved screening tools for small molecule/compound libraries. 13 The most recently approved drugs are ivacaftor (Kalydeco), which potentiates the cystic fibrosis CFTR chloride channel 14 and crofelemer (Mytesi), a proanthocyanidin oligomer, which inhibits both CFTR and the calcium-activated chloride channel TMEM16A. 15 As with the vast majority of other drugs targeting ion channels, ivacaftor and crofelemer are both small molecule chemical entities.…”