Cystic Fibrosis, Therapies in Pipeline

By KAITE A. O’DELL | UMKC | Pharm.D. Candidate

Cystic fibrosis is an autosomal recessive disorder that is the most common deadly genetic disorder found in Caucasians. It affects 70,000 people worldwide with 30,000 being in the United States (1). In 1949, Lowe et al. proposed that cystic fibrosis must be caused by a defect in a single gene due to the autosomal recessive pattern of the inheritance of the disease.

In 1986, Quinton found that sweat ducts in patients with cystic fibrosis are impermeable to chloride. This led to the hypothesis that a defective chloride channel found in the lungs accounted for the respiratory failure and other clinical manifestations of cystic fibrosis. Later in 1989, the gene was identified and named the cystic fibrosis transmembrane conductance regulator (CFTR) (2).

The CFTR protein is responsible for conducting chloride across the cell membrane. It is found in the lungs, pancreas, gastrointestinal tract, sweat glands, liver, and reproductive tract. Mutations in the CFTR gene cause patients with cystic fibrosis to have defective or missing CFTR proteins at their cell surfaces, and results in poor chloride ion and water flow across cell membranes. This causes the body to produce abnormally thick and sticky mucus that leads to chronic life threatening lung infections. The thick mucus disrupts mucociliary clearance, causes neutrophil dominant inflammation, and bacterial colonization resulting in chronic infection. The clinical course of cystic fibrosis is one of episodic exacerbations of pulmonary infection and inflammation interspersed with periods of relative stability (1).

Approximately 4 percent of all Caucasians carry a single CFTR mutation. When 2 mutations are present the CFTR protein does not function. There are 6 different types of mutations of the CFTR protein. Class 1 mutations are caused by premature termination of mRNA translation and result in truncated, nonfunctional CFTR protein. This mutation occurs in around 10 percent of all cystic fibrosis cases. A class 2 mutation is caused by CFTR that is misfolded and then degraded before reaching the apical surface of the cell membrane. The delta F508 mutation is a class 2 mutation and it is the most common mutation found in cystic fibrosis occurs in more than 90% of all patients with cystic fibrosis in the United States. The third class of mutation happens when the channel is unable to use ATP to speed chloride ion transport. The G551D mutation is a class 3 mutation and occurs in 4 to 5% of patients with cystic fibrosis. Mutations of these first three classes have more severe disease manifestations (1).

Until now, medications for cystic fibrosis have not targeted the underlying cause of the disease. Existing medications used for cystic fibrosis include those that increase the airway surface liquid such as inhaled hypertonic saline, anti-inflammatory medications such as steroids and NSayss, antioxidants such as N-acetylcysteine, and inhaled antibiotics such as tobramycin and colistimethate (1). Implementation of these therapies have improved the quality of life of cystic fibrosis patients and increased the median survival age from 11 to 37 years over the past 40 years. However, these therapies only treat the symptoms of cystic fibrosis (3).

Among the new investigational drugs, ivacaftor (Kalydeco or VX-770) is the first medication for cystic fibrosis to work on the CFTR protein that causes the disease. It works by augmenting the chloride-transport activity allowing for an increase in time that the activated CFTR channels at the cell surface remain open in patients with the G551D mutation (4). The maker of ivacaftor, Vertex Pharmaceuticals submitted a new drug application in October of 2011 with a request for Priority Review.

A phase 2 trial (5) by Accurso et al., tested the safety and efficacy of ivacaftor in a 2 phase trial comparing ivacaftor to placebo after 14 days and then after 28 day of treatment. Ivacaftor was found to cause an improvement in lung function after 14 and 28 day treatment regimens compared to placebo. The mean relative change from baseline in the percentage of predicted FEV1 was 10.5% for ivacaftor 150mg every 12 hours after 14 days and 8.7% after 28 days. The frequency of adverse events was similar between the groups.

STRIVE is a phase 3 trial (4) completed by Ramsey et al. and published in the New England Journal of Medicine found that ivacaftor was associated with an improvement in lung function at 2 weeks that remained throughout the 48 week study. The percent predicted FEV1 was increased by 10.6% in the ivacaftor group compared to the placebo group after 24 weeks. Other improvements were also seen in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. Patients receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than placebo over the 48 weeks. Subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire. By 48 weeks, subjects had also gained an average of 2.7 kg more weight than the placebo group. The concentration of sweat chloride was -48.1 mmol per liter with ivacaftor compared to placebo at 48 weeks. The incidence of adverse events was similar with between groups with a lower proportion of serious adverse events with ivacaftor.

ENVISION is another phase 3 trial that studied the use of ivacaftor in children ages 6-11 years. A press release by Vertex Pharmaceuticals state that children who received ivacaftor experienced rapid and sustained improvements in lung function, weight gain, and reduction of sweat chloride throughout 48 weeks. The mean absolute improvement in lung function for children treated with ivacaftor was 10% compared to placebo and a relative mean improvement was 15.1% from baseline compared to placebo. Adverse effects were comparable between treatment groups(6).

PERSIST is a phase 3, open-label 96 week extension study of both the ENVISION and STRIVE trials. Vertex Pharmaceuticals released data from the first 12 weeks of the study in a press release. They found that the improvement in lung function was sustained through week 12 of the study for a total of 60 weeks of treatment. Adverse events were similar to those observed in the STRIVE trial (6).

Ivacaftor also stimulates activity in the delta F508-CFTR, the most common mutation in cystic fibrosis patients. However, it is much less active on the delta F508 than the G551D CFTR gene and clinical benefit in these patients is unknown. It is also not yet evident as to whether ivacaftor will stop the progression of deterioration in lung function in patients with cystic fibrosis (3).

There are other drugs being developed currently for cystic fibrosis as well. A promising candidate is the combination of VX-770 (ivacaftor) and VX-809 which will be used to treat patients with the most common mutation, the delta F508 mutation (1). The combination drug is currently in a phase 2 trial, in which Vertex Pharmaceuticals released a statement that at 28 days the combination was well tolerated and had a statistically significant change in sweat chloride suggesting increased CFTR activity (7). The findings of these studies represent an important milestone in the development of treatments designed to tackle the underlying cause of cystic fibrosis.


1. Anderson P. Emerging Therapies in Cystic Fibrosis. Ther Adv Resp Dis. 2010; 4: 177-185.

2. Rowe SM, Miller S, Sorscher EJ. Cystic Fibrosis. N Engl J Med 2005; 352: 1992-2001.

3. Davis PB. Therapy for Cystic Fibrosis – The End of the Beginning? N Engl J Med 2011; 365: 1734-1735.

4. Ramsey BW, Davies J, McElvaney G, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med 2011; 365: 1663-1672.

5. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in Persons with Cystic Fibrosis and the G5512-CFTR Mutation. N Engl J Med 2010; 363: 1991-2003.

6. Partridge M, Pike , Osborne M. Phase 3 Study of KALYDECO (ivacaftor) in Children Ages 6-11 with a Specific Type of Cystic Fibrosis Showed Significant Improvements in Lung Function and Other Measures of Disease Sustained Through 48 Weeks. Vertex Pharmaceuticals Incorporated. November 3, 2011. Retrieved Nov 14, 2011 from

7. Patridge M, Pike L, Osborne M et al. Interim Phase 2 Data Showed a Combination of VX-770 and VX-809 Improved Function of the Defective Protein that Causes Cystic Fibrosis in People With the Most Common Form of the Disease. Vertex Pharmaceuticals Incorporated. June 9, 2011. Retrieved Nov 14, 2011 from:

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