Ivacaftor: a quantum leap in treating cystic fibrosis?

Pharmacy, University Medical Center Freiburg

Freiburg, Germany

Email: [email protected]

Cystic fibrosis (CF) is an autosomal recessive disorder characterised by highly viscous mucus that impairs the airway clearance, thereby paving the way to recurrent infections of the respiratory tract. Organs of the gastrointestinal tract, such as the small and large intestine, the bile duct and the pancreas, are also severely affected in most patients suffering from CF. The therapeutic mainstay so far has been merely symptomatic. Mucolytic agents such as N-acetylcysteine, osmolytes and recombinant DNAse are aimed to liquify the sticky mucus whereas oral, parenteral and inhaled antibiotics are used to treat the bacterial infection. Orally administered pancreatic enzyme preparations support the otherwise insufficient digestion of nutrients. These drugs are not able to cure the disease but the combination of these therapeutic regimens helps to increase the lifespan and decrease some of the burden of patients with CF.

Soon after the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein was discovered by positional cloning,(1) hopes were raised that a cure for CF was nearby. Unfortunately, attempts to correct the genetic defect using viral and non-viral gene transfer vectors had been inconclusive and, in some cases, even potentially dangerous to the patients.(2) Gene therapy has not been completely abandoned, but other strategies have evolved. The latter are either aimed to restore CFTR function or to bypass the defective protein entirely by activation of other anion channels.

Anion transport requires the concerted action of ion channels in combination with active and passive transporters. For decades scientists have been searching for epithelial anion channels that could complement the function of CFTR. Because no other cAMP-dependent anion channel had been found as yet, most research has focused on channels that can be activated through elevation of the intracellular Ca2+ concentration (CaCC). Recently, proteins such as the anoctamins (TMEM16) and bestrophins(3) have been implicated to play a role in transepithelial ion transport. Most approaches to activate CaCCs are aimed at increasing intracellular Ca2+ via direct or indirect mechanisms. Compounds that bind to P2YX2 receptors that are 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) Lancovutide (Moli1901), a compound directly acting on Ca2+, has proven to be safe when inhaled(6) 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.

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)

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)

Approximately 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 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 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 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, also received approval by the European Medicines Agency and has been available in some European countries since September 2012.

Under the assumption that roughly 4% of the 70,000 patients with CF carry the G551D mutation, only approximately 3000 patients might be able to benefit from the new drug. The costs for one year of treatment with KalydecoTM is $294,000 in the US or €306,000 (reference price in Germany) respectively, making it pricey. The time between the discovery of ivacaftor and the marketing authorisation was short, but filled with complexities. The development was partly sponsored by a charity. Even if we assume a total cost of development for KalydecoTM of one billion US$ and that only every third CF patient with a G551D mutation would in fact receive the branded drug, the return on investment would be reached within three years. Clearly, some of the sales returns will be used as royalties to the CFF and to help developing other compounds directed against the remaining 96% of mutations found in those CF patients who may not benefit from ivacaftor. But questions might be raised whether the public insurance systems are willing to support a lifelong therapy with orphan drugs such as KalydecoTM. Countries such as Germany and the UK require that an added benefit for every newly approved drug over pre-existing therapies is demonstrated in order for it to be reimbursed through the public insurance system.

The future will tell whether ivacaftor is, in fact, the quantum leap innovation to justify the costs. However, from the perspective of someone who has spent half of his lifetime waiting for a drug that treats the basic defect in CF, ivacaftor is certainly a major leap forward.

• Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator. The molecular defect results in a lack of anion transport.
• CF is characterised by impaired airway mucus clearance and insufficient digestion in the gastrointestinal tract.
• Until recently, the treatment of CF has been symptomatic and comprised frequent use of antibiotics, mucolytics and enzyme supplements.
• Drugs aimed at activating alternative anion channels have failed to demonstrate clinical efficacy.
• Ivacaftor (VX-770; Kalydeco™) demonstrates positive effects on the function of both the lung and the gastrointestinal tract but only helps a small subset of CF patients.

1. Kerem B et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245(4922):1073–80.
2. Griesenbach U, Geddes DM, Alton EWFW. Gene therapy progress and prospects: cystic fibrosis. Gene Ther 2006;13(14):1061–7.
3. Kunzelmann K et al. Role of the Ca2+-activated Cl- channels bestrophin and anoctamin in epithelial cells. Biol. Chem 2011;392(1–2):125–34.
4. Erlinge D. P2Y receptors in health and disease. Adv Pharmacol 2011;61:417–39.
5. Ratjen F et al. Long term effects of denufosol tetrasodium in patients with cystic fibrosis. J Cyst Fibros 2012;11(6):539–49.
6. Grasemann H et al. Inhalation of Moli1901 in patients with cystic fibrosis. Chest 2007;131(5):1461–6.
7. Clancy JP et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012;67(1):12–18.
8. Bompadre SG, Sohma Y, Li M, Hwang T-C. G551D and G1349D, Two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol 2007;129(4):285–98.
9. Beall R. Straight talk with… Robert Beall. Interviewed by Elie Dolgin. Nat Med 2012;18(3):335.
10. Van Goor F et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 2009;106(44):18825–30.
11. Accurso FJ et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010;363(21):1991–2003.
12. Ramsey BW et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18):1663–72.
13. Gever J. FDA approves cystic fibrosis drug. www.medpagetoday.com/article.cfm?tbid=30936 (accessed 22 January 2013).