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From G551D to F508del: An Inquiry Into The Development Of Targeted Therapeutics For The Treatment Of Cystic Fibrosis Open Access


Other title
Cystic Fibrosis
Type of item
Degree grantor
University of Alberta
Author or creator
Mohammad, Sohaib
Supervisor and department
Yasui, Yutaka (School of Public Health)
Examining committee member and department
Senthilselvan, Ambikaipakan (School of Public Health)
Ogbogu, Ubaka (Law)
Leung, Winnie (Pulmonary Medicine)
School of Public Health
Clinical Epidemiology
Date accepted
Graduation date
2016-06:Fall 2016
Master of Science
Degree level
Cystic Fibrosis (CF) is a fatal inherited disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein. CFTR plays an integral role in salt and water transport across the epithelial membrane of major organs, such as the lungs. CFTR-targeted therapeutic strategies can theoretically reduce the effects of CFTR ion dysfunction through potentiation, correction, or both. Potentiators work by increasing the length of time CFTR channels remain open following activation while correctors work by increasing the cell surface density of CFTR. In 2012, regulatory approval by the United Stated Food and Drug Administration (FDA) and European Medicines Agency (EMA) was granted to a potentiator compound, Ivacaftor (trade named Kalydeco). In 2015, the FDA and EMA granted regulatory approval to a corrector-potentiator combination, Lumacaftor-Ivacaftor (trade named Orkambi). The regulatory approval of these compounds has been met with both excitement and concern. For the first time since the discovery of CFTR gene in 1989, an agent which works by directly targeting the CFTR channel has been developed, and this in turn has paved the way towards a potential cure. On the other hand, Kalydeco and Orkambi are not curative, and the amount of clinical benefit seen in clinical trials ranges from, at best, an absolute improvement of 12.5% (Kalydeco) and 3.6% (Orkambi) from baseline for one measure of lung function, Percent Predicted Forced Expiratory Volume in 1 Second (FEV1% predicted). Given that they need to be taken throughout a patient’s lifetime, there has been some concern regarding the cost-effectiveness of these treatments, which range from $259,000 USD (Orkambi) to over $300,000 USD (Kalydeco) per patient per year This thesis research involves three investigations pertaining to the development of Kalydeco and Orkambi for the treatment of CF: 1) A review of Phase II/III clinical trials which have lead to the regulatory approval of Kalydeco and Orkambi; 2) An evaluation of clinical trials that have studied Ivacaftor, Lumacaftor, or their combination in patients homozygous for the F508del mutation, which affects nearly half of all CF patients; and 3) A study of gaps that existed in CF treatment when Kalydeco first received regulatory approval and which gaps remain since Orkambi’s regulatory approval. Our first study is important to understand the historical development of Kalydeco and Orkambi, and in particular, to gain a better understanding of the underlying biology of CFTR as well as the clinical endpoints used in clinical trials. The results of our second investigation suggest that, although Lumacaftor-Ivacaftor combination therapy appears to be superior to Lumacaftor monotherapy, studies of longer duration that are adequately powered towards key clinical endpoints, like FEV1% predicted, are needed to distinguish Lumacaftor-Ivacaftor as being superior to Ivacaftor monotherapy. The results of our third study indicate that several gaps in CF treatment through the use of these targeted agents have been fully or partially filled, but there are certain key gaps which remain. In particular, there is still uncertainty pertaining to the clinical benefit of Ivacaftor in certain sub-populations eligible to receive the treatment, the cost effectiveness of Ivacaftor, as well as the usefulness of sweat chloride concentration as a clinical endpoint in clinical trials.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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