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Breathing life

Compounds in development bring hope for a cystic fibrosis cure

A 3D image of someone's lungsWorldwide around 70,000 people are affected by cystic fibrosis (CF), an inherited disease which is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene encodes for the CFTR chloride channel, which regulates ion transport across epithelial cells. In patients with CF this protein does not function correctly, resulting in the production of thick mucus particularly in the lungs and pancreas. Current treatment regimes include physical measures such as airway clearance techniques to remove mucus from the lungs, anti-inflammatory compounds and use of antibiotics to treat lung infections. However, to date, advances in treatments for CF have only extended the average life expectancy of CF patients to around 37 years and there is a clear need for research into therapeutics both to alleviate the symptoms of the disease and to enable a potential cure.

Cystic fibrosis symptoms can be treated using agents to make it easier to clear the thick mucus from the lungs. Genentech's Pulmozyme (dornase alpha) is a recombinant DNase enzyme that hydrolyses the large DNA strands, which contribute to making the mucus thick and sticky. This DNA cleavage reduces the viscosity of mucus secretions enabling easier removal. However, not all patients respond to treatment with Pulmozyme. Other treatment options are thus necessary. Increasing hydration, for example, is another way to improve mucus clearance. Hypertonic saline can be used to increase hydration, as can mannitol. Pharmaxis is developing an inhaled dry powder formulation of mannitol (Bronchitol), which is an osmolytic agent designed to increase movement of water across the lung surface.

Other methods under investigation to improve mucus hydration and clearance include targeting different proteins to control the transport of salt within cells. Need for the CFTR protein may be abrogated if modulation of the activity of other proteins can provide sufficient hydration. Inspire Pharmaceuticals is developing denufosol, which has been granted fast track status by the US FDA. Denufosol is a purinergic P2Y2 receptor agonist that is able to activate mucosal hydration and mucociliary clearance in the respiratory tract. In the phase III TIGER-1 trial, a significant improvement in FEV1, a measure of lung function, was observed.

Results from a second phase III trial, TIGER-2, are expected in late 2010. Another chloride channel agonist in clinical trials is lancovutide (Moli 1901, duramycin). Lancovutide is thought to normalise mucus composition in the lung by activating an alternative salt channel in the airway. Phase II trials have been completed and Lantibio and AOP Orphan Pharmaceuticals, the European licensee, expect to begin phase III trials soon.

Another approach to restore hydration is to use epithelial sodium channel inhibitors to prevent sodium absorption. Parion Sciences has taken their epithelial sodium channel inhibitor P-552 (552-02) into phase II proof of concept trials in patients with cystic fibrosis and have a second generation compound in the pipeline, GS9411, which has been licensed to Gilead. GS9411 has been studied in healthy volunteers and, in December 2009, a phase I trial was initiated in patients with cystic fibrosis.

Gene therapy potential
CF may seem an ideal disease candidate for gene therapy as mutations in the CFTR gene are known to cause the condition, hence transfer of a functioning gene encoding for the CFTR protein should, in theory, correct the condition. Unfortunately, the mechanics of this process are not straightforward and problems in delivery and expression have meant that results so far have been less than spectacular.

Copernicus Therapeutics' gene therapy programme is one of the most advanced as it has had a prototype therapy in phase Ia trials. Copernicus's product is intended to deliver compacted non-viral DNA into the lungs. However, there is debate as to whether this, or any therapy, has delivered clinically meaningful gene expression. Copernicus is reformulating its PLASmin nanoparticle therapy with support from the Cystic Fibrosis Foundation Therapeutics.

Another approach is being pursued by PTC Therapeutics. This company is developing a compound, ataluren, which corrects the processing of the CFTR gene. Ataluren (PTC124), an oxadiazole, is designed to treat a sub-group of CF patients with what is known as a nonsense mutation. A nonsense mutation occurs when a point mutation in the DNA introduces a premature stop codon, resulting in a truncated protein. Ataluren promotes read through of premature stop codons in mRNA, hopefully enabling the translation of full-length functional CFTR protein. In phase II trials, orally administrated ataluren resulted in improvements in nasal transepithelial potential difference, a marker for CFTR protein production. PTC Therapeutics and Genzyme have initiated a phase III trial to evaluate the safety and efficacy, in terms of lung function, of ataluren in patients with nonsense mutation CF.

Ensuring a functioning CFTR protein can also be achieved by modulating the defective protein directly. Vertex Pharmaceuticals has two compounds in clinical development that act in different fashions to restore activity. VX-770 is described as a 'potentiator' and is designed to increase the gating ability of the defective CFTR ion channel. VX-770 has shown promise in phase II trials in CF patients with the G551D CFTR mutation and has now entered phase III development. The ENDEAVOR registration clinical programme, initiated in 2009, consists of two phase III trials of VX-770 in patients with the G551D mutation and a phase II trial in patients homozygous with the ∆F508 mutation, the most common CFTR mutation. Vertex's second compound in clinical development is a 'corrector' molecule. VX-809 acts to increase the amount of CFTR on the surface of airway cell membranes, which may improve function and lead to an increase in net chloride transport across the cell surface. VX-809 is being studied in phase II trials in CF patients with the ∆F508 mutation. 

With several compounds in phase III trials for CF it will be interesting to see what therapeutic approach, if any, will be the key to alleviating this disease. Indeed several different drugs may be needed to target different mutations of the CFTR gene and emerging drugs may be used together in treatment regimes. Compounds that are orally available, such as ataluren and the two Vertex molecules, have an advantage over inhaled or aerosol therapies in development because of the potential ease of administration in conjunction with current treatments such as Pulmozyme.

However, it is quite possible that in the future an emerging inhaled salt modulator, such as denufosol, may be used in conjunction with oral CFTR modulators. Among the compounds discussed, Bronchitol appears most likely to make it first to the market, but the CFTR modulators offer particularly exciting potential for the treatment of CF. As increased knowledge about protein misfolding in CFTR is gained, the rational design of CFTR modulators will only get better and this should result in an improved ability of these molecules to restore functional activity of the CFTR protein. As well as Vertex and PTC Therapeutics, several other companies have preclinical research programmes investigating CFTR modulators, referred to by some as molecular chaperones. The next few years may well prove to be a major turning point for CF therapies, the potential for a cure as opposed to just treating the symptoms, appears tantalisingly within reach.


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The Author
Pipeline was written by Tori Muir of Adis International - Wolters Kluwer Health - using data derived from Adis R&D Insight and Clinical Trials Insight.

For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)20 7981 0714 or email:

To comment on this article, email

9th February 2010


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