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known to elevate Ca2+

in a multitude of

organs have successfully been tested in airway epithelia.4

The latest

development, denufosol (INS37217), failed to improve lung function in CF patients as demonstrated in a recent phase III trial.5

proven to be safe when inhaled6

Lancovutide (Moli1901),

a compound directly acting on Ca2+, has but no

study has demonstrated a substantial clinical effect. Taken together, despite the large number of potential target proteins that might be able to restore anion transport when CFTR is absent, none of the compounds designed to activate these proteins demonstrated substantial clinical efficacy.

Putting CFTR into the membrane Most CF patients have a mutation that results in deletion of a phenylalanine in position 508 of the CFTR gene (F508del) that results in a folding defect and subsequent degradation of the protein shortly after synthesis. The mutated protein per se is partly functional (albeit to a much lesser degree than the wild-type) when incorporated in artificial systems. Because of the high prevalence of F508del, it is unsurprising that many attempts have been made to pharmacologically alter the cellular quality control system and thereby increase surface membrane expression of the misfolded protein. Compounds that act through such a mechanism are generally referred to as ‘correctors’. Clearly, tampering with the cell’s quality control system has risks, which render most compounds unfit for clinical practice. Few substances have an acceptable risk–benefit ratio, most of which are currently in early stages of development. One of these compounds, VX-809, was promising enough to be tested in patients homozygous for F508del.7

Membrane-resident CFTR Some CFTR mutations result in an almost normal surface membrane expression of a protein that is either only partially functional or not at all. An example for such a mutation (class III) is G551D, where a glycine in position 551 is replaced by an aspartate resulting in a channel activity that is about 100 times lower than that of wild-type CFTR.8


2–5% of all CF patients carry G551D on at least one allele and most of these patients have a severe phenotype.

The fact that G551D CFTR is delivered to the membrane makes it an ideal target for chemical compounds that restore defective channel function while not interfering with intracellular quality control mechanisms or protein channel trafficking. Substances that fit such a profile are called ‘potentiators’ because of their potential to augment the defective channel’s open probability after stimulation through physiological agonists. This approach led to an unprecedented success in treating the basic defect in CF. Prompted by the lack of targeted therapies in the field of CF, the North American CF Foundation (CFF) decided to make a significant investment to fund the development of new drugs to fight the disease.9

In 1998,

the charity approached a number of pharmaceutical companies offering financial help for preclinical development of compounds acting on the CFTR protein. While most declined, a small biotech firm named Aurora Biosciences accepted. The company specialised in fluorimetric high- throughput screening decided to utilise its knowledge on ion channel assays to develop chemical compounds to rescue defective CFTR. Aurora Biosciences was

least one G551D mutation and at the same time demonstrated effects on the nasal potential difference, sweat Cl-

concentration and predicted forced expiratory volume in one second (FEV1) of these patients.11

These data, published

at the end of 2010, by far exceeded the expectations of the scientific community for a small molecule as a treatment option in CF patients and prompted the initiation of two randomised, double blind, placebo-controlled phase III trials. Both trials aimed to demonstrate the efficacy of ivacaftor 150mg given twice daily to CF patients with the G551D mutation. While the STRIVE study of ivacaftor was conducted in CF subjects aged 12 years and older with the G551D mutation,12

the ENVISION trial

was designed to study the effect in patients aged six to 11 years. Patients from both trials were included in an ongoing open-label, rollover study to evaluate the long-term safety and efficacy of ivacaftor (PERSIST). The STRIVE trial showed a 10.6% increase in FEV1 in patients that received ivacaftor over the control group after 24 weeks of treatment. The effect on lung function persisted throughout the duration of the trial. In addition, >70% in the verum

“For someone who has spent half of his lifetime waiting for a drug that treats the basic defect in CF, ivacaftor is a major leap forward”

acquired by Vertex some three years later, but the fruitful collaboration with the CFF continued. After screening more than 200,000 different chemical substances, Vertex announced the first developmental compound that demonstrated activity in cells expressing recombinant G551D CFTR in 2004. VX-770 was the first small molecule able to increase Cl-

conductivity of the mutated protein tenfold or

approximately half of what is observed in cells expressing wild-type CFTR.10 The compound that received the International noneproprietary name ivacaftor was a dihydroquinoline derivative and had a sufficiently high oral bioavailability to make it a good candidate for clinical testing. A phase I trial demonstrating clinical safety was completed soon after the first in vitro results had been published. The results of the phase II trial confirmed that ivacaftor was safe in patients carrying at

group remained free of exacerbations until week 48 compared with 41% in the control group. It was not only lung function that was improved in the treatment group; a significant proportion of patients treated with ivacaftor experienced a gain in weight and reported an increase in the quality of life as assessed by the revised version of the CF questionnaire. The positive results of these trials were sufficient to convince the US Food and Drug Administration to approve ivacaftor for the treatment of CF patients with the G551D mutation a few months later.13 The drug, marketed under the brand name KalydecoTM

by the European Medicines Agency and has been available in some European countries since September 2012.

Pharmacoeconomic impact Under the assumption that roughly 4% of the 70,000 patients with CF carry the

, also received approval


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