False dawn for cystic fibrosis disease modifiers?Recent results have cast doubt over how effective a breakthrough class of cystic fibrosis drugs can be in patients with the most common form of the disease.

David Holmes

In 2012, treatment approaches for cystic fibrosis (CF) were poised for transformation following the US approval of Vertex’s ivacaftor for a small subset of CF patients. Experts hoped that this first disease- modifying breakthrough would lead a wave of treatments that would eventually help the subset of CF patients with the most common disease-causing mutations. But recent results from trials that combine ivacaftor with Vertex’s lumacaftor, a second disease-modifying drug intended for use in this subset, now paint a mixed picture. Question marks loom over whether these drugs will fulfil their promise.

CF is an autosomal-recessive genetic disorder that impairs the clearance of airway secretions, resulting in chronic and potentially fatal respiratory infections and other complications. It is caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), with mutations classed in six groups based on how they affect the production, trafficking, function or stability of CFTR. The most common mutations are class II mutations, which stop CFTR from being trafficked to the cell surface after production, and the most common class II mutation is F508del. Almost 90% of individuals with CF in the world (in total about 1 in 3,000 births in Europe and the

USA) have this mutation in at least one CFTR gene, and roughly 50% of these individuals are homozygous, with two F508del mutations. At present, the only treatments available to these patients are for symptoms, and the median age of survival for a person with CF is just over 33 years.

Ivacaftor, a small-molecule potentiator compound, works by keeping the CFTR channels open at the cell surface. It is particularly good at activating class III gating-mutant CFTRs such as the G551D mutant, and was approved in 2012 for the treatment of CF in patients with the G551D mutation. Unfortunately, misfolded F508del CFTR rarely makes it to the cell surface, and is instead usually retained and degraded in the endoplasmic reticulum. Consequently, ivacaftor alone would be of no clinical benefit to CF patients with the F508del mutation. Instead, Vertex pinned its hopes on combining ivacaftor with a ‘corrector’ compound, such as lumacaftor, that corrects the misfolding of F508del CFTR and increases the likelihood of it reaching the cell surface.

In June this year Vertex released data from the TRAFFIC and TRANSPORT Phase III trials, which treated F508del-homozygous CF patients with ivacaftor and lumacaftor in combination. The 559- and 563-patient studies both met their primary end point: an improvement in lung function as measured by forced expiratory volume in 1 second at

24 weeks. Pulmonary exacerbations, a secondary end point, were also significantly reduced by treatment. On the basis of the results, Vertex is expected to submit a new drug application in the United States and a marketing authorization application in Europe later this year for people with CF who are aged 12 or older and homozygous for the F508del mutation.

Although some hailed the results as a success, prompting blockbuster sales predictions, the improvements in lung function (2.6–4%) were modest compared with the success achieved with ivacaftor alone in G551D mutation patients (10.6–12.5%). The drug-induced improvements looked more like the gains patients have experienced in studies of treatments that target the symptoms of the disease. Questions about the underwhelming results were reinforced in July, when a 125-patient 8-week Phase II trial of the combination missed its primary end point in F508del heterozygous patients.

Now, new preclinical data point to yet more concerns about the potential for the ivacaftor and lumacaftor combination to treat CF effectively.

Using human primary airway epithelial cells to examine the effects of chronic use of lumacaftor and ivacaftor at the molecular level, one group reported in July that ivacaftor inhibits the beneficial effects of lumacaftor (Sci. Transl. Med. 6, 246ra96; 2014). “We found

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that ivacaftor causes instability of the target protein CFTR, which counteracts its correction by lumacaftor in CF patients who carry the F508del mutation,” says Martina Gentzsch — Director of the CFTR Correction Core at the Marsico Lung Institute at the University of North Carolina Chapel Hill, USA — a co-author of the study. “Our data explain the moderate outcome [of the TRAFFIC and TRANSPORT trials],” she adds. Another group independently reported that ivacaftor lowers the folding efficiency and function of F508del CFTR (Sci. Transl. Med. 6, 246ra97; 2014).

The moderate improvements seen in the TRAFFIC and TRANSPORT trials could in fact have had more to do with the off-target effects of ivacaftor than the effect of the drug on CFTR functioning, adds Gentzsch. Ivacaftor has been shown to increase lung hydration and to have antibacterial activity independently of its ability to potentiate CFTR. In addition to measuring clinical end points, “testing the effect of the ivacaftor and lumacaftor combination on CFTR function and maturation in patients is absolutely crucial,” she explains.

“While these and other preclinical experiments represent interesting cell biology that can inform our research efforts, what doctors and patients care about — and what we’re focused on — is the benefit the combination has on people with CF,” said Vertex in response to questions about the preclinical data. It pointed to published clinical and preclinical studies that have “consistently shown that a combination of lumacaftor and ivacaftor, or VX-661 and ivacaftor, results in improved function of the defective protein that causes CF” as evidence of efficacy.

Nevertheless, the preclinical and clinical findings cumulatively “raise serious questions that need to be addressed,” says Brian O’Sullivan, of the University of Massachusetts Medical School in Worcester, USA. “It would be fascinating, and disappointing, if ivacaftor really does interfere with lumacaftor when administered over a prolonged period,” O’Sullivan says. Perhaps even more disappointing for Vertex and the CF community is the fact that Gentzsch’s results show that ivacaftor also inhibits correction of F508del-mutant CFTR by Vertex’s VX-661, a follow-up corrector compound that is currently in Phase II trials in combination with ivacaftor.

“More work will need to be done before we can realize the full potential of these drugs,” says Gentzsch. If investigators can understand exactly how the drugs interfere with one another, for example, they may be able to optimize better next-generation correctors and potentiators. The similarities between lumacaftor and VX-661 mean that “there may be a need for a more distinctly different corrector than VX-661 to do the job well,” says O’Sullivan. Vertex expects to begin clinical development of a next-generation corrector compound that could fit the bill in early 2015.

Because of the complexity of the F508del CFTR defect and the redundancy of the quality-control mechanisms that detect and degrade the mutant protein, truly effective disease-modifying treatments for F508del patients might also require the combination of potentiators like ivacaftor with two or more corrector compounds. Vertex, however, have yet to announce any plans to test a three-drug regimen. “Eventually, there will be next-generation CFTR correctors which will be added to the ivacaftor and lumacaftor combination to increase efficacy,” predicts Michael Boyle, of the Johns Hopkins Medical Institutions in Baltimore, USA.

Although other disease-modifying compounds such as PTC Therapeutics’ ataluren are in development for some of the rarer classes of CFTR mutations, at present the only other compound in Phase II development for F508del patients is N30 Pharmaceuticals’ N-6022, an intravenously administered drug that is the first of a new class of compounds developed to conserve S-nitrosoglutathione (GSNO), a signalling molecule that is involved in CF pathogenesis. Preclinical studies have shown that N-6022 acts as both a corrector of abnormal chloride-channel function and as an anti-inflammatory. N30 are hoping to start clinical testing of an oral form of the drug later this year.

It would be fascinating, and disappointing, if ivacaftor really does interfere with lumacaftor when administered over a prolonged period

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