The way ahead for cystic fibrosis

Cystic fibrosis is an inherited disease that eventually leads to severe damage in the lungs. It is caused by a mutation of the gene responsible for the cystic fibrosis transmembrane conductance regulator (CTFR) protein. This results in a defective protein, preventing cells handling the movement of chloride ions properly, and among other manifestations, leading to the airways becoming congested with thick mucus. More than 2,000 mutations have been identified, many of which may give rise to cystic fibrosis. Worldwide, roughly 70,000 people are affected, with thousands of new cases identified each year. It is one of the most widespread life-shortening genetic diseases.

Until recently, pulmonary treatment relied on helping to remove mucus from the lungs and tackling infections. Life expectancy for sufferers is reduced, and in some cases lung transplants have proved effective. However, in the last decade treatment has seen a potential revolution with the emergence of CFTR modulators, a new class of drugs that work by improving the function of the defective protein.

Treatment revolution 
In 2012, Kalydeco (ivacaftor; Vertex Pharma), was approved in the EU and US. It was the first therapy to address the underlying cause of CF, and was found to be effective in those with a specific mutation (G551D). According to an analysis of Phase III and long-term extension studies in sufferers who have the G551D mutation, treatment with ivacaftor halves the annual loss of lung function over three years, compared to similar untreated patients. A separate long term analysis shows the annual risk of death, organ transplantation, hospitalisation due to any reason and frequency of pulmonary exacerbations were all significantly lower in the ivacaftor-treated group. 

The initial indication covered about 2000 patients in the USA; however, since then the drug’s indication has been extended to include up to 10 other mutations – covering some 8% of the affected population. In 2015, Vertex Pharma submitted a supplemental New Drug Application for the use of Kalydeco in cystic fibrosis patients who have one of 23 residual function mutations, though the FDA announced it cannot approve the application in its current form. 

Vertex has also looked to expand its potential market through combining ivacaftor with other treatments, and hopes to increase availability. In 2015, the FDA approved Orkambi (combination lumacaftor plus ivacaftor; Vertex) for people with CF who have two copies of the most common mutation, F508del, representing about half of those with the disease. The total number with this mutation status in the USA is nearly 11,000. In a recent Phase III study in children aged 6–11 years, the combination treatment met its primary endpoint – the absolute change in lung clearance index – and Vertex now plans to submit an application in the EU for Orkambi in the first half of 2017.

There have been problems with Orkambi however. Data show that within three months of therapy initiation, about 15% of patients discontinued treatment following respiratory problems. If discontinuation rates prove higher, the utility of the drug will be impacted. In addition, the high cost of treatment has caused issues, and NICE (National Institute for Health and Care Excellence [UK]) has not recommended it, primarily due to its price.

On the horizon 
Translarna (ataluren; PTC therapeutics) is a small molecular agent that was filed for approval in the EU in 2015, and is targeted at nonsense mutation CF. Approximately 10% of cystic fibrosis patients have their disease as a result of a nonsense mutation, which can cause one of the most severe forms of cystic fibrosis. If approved, ataluren would be the first oral protein restoration treatment for this form of CF. In a phase III study, investigators found no significant differences in FEV1 or pulmonary exacerbations between the ataluren and placebo groups, although a posthoc analysis determined that ataluren appeared to benefit patients who were not using chronic inhaled tobramycin. Phase III trials in patients not receiving this antibiotic are currently underway.

VX-661 (tezacaftor) combined with ivacaftor is now in Phase III trials for CF patients with at least one copy of the F508del mutation. Studies show that tezacaftor has a more favourable pharmacokinetic profile than lumacaftor, which means once-daily dosing is possible. The drug also shows fewer interactions with ivacaftor, which means concomitant use of lower dose ivacaftor is an option. Vertex plans to submit a New Drug Application (NDA) to the FDA for combination tezacaftor plus ivacaftor in the second half of 2017, pending data from current studies. However, it is already clear that the combination does not work in patients with one copy of the delF508 mutation along with a mutation that allows for only minimal CFTR function. 

Hope for these patients, and others like them, could lie with alternative combinations of therapy. For example, in October 2015 Vertex announced that it is advancing two next-generation CFTR therapies into clinical development. Known as VX-152 and VX-440, they are designed to further improve processing and trafficking of the CFTR protein to the cell surface. These are being evaluated alone and in combination with tezacaftor plus ivacaftor in Phase II studies in people with CF. Studies of triple combination therapies (VX-152/tezacaftor/ivacaftor and VX-440/tezacaftor/ivacaftor) were also planned to start in late 2016.

These trials are expected to enrol people with CF who have two copies of the F508del mutation, and people who have one copy of the F508del mutation and a second mutation that results in minimal CFTR function – a combination which has proved difficult to treat. The first data from this study are expected in the second half of 2017.

Beyond the horizon 
Adempas (riociguat; Bayer Healthcare), formerly BAY63-2521, is currently being assessed in a Phase II trial in cystic fibrosis patients who are homozygous for the F508del mutation; research indicates that it may act as a disease modifier. Other CFTR modulators in early development and testing include N9115 (Nivalis) and QR 010 (ProQR). Finally, recent positive topline results from the Saphira 1 Phase II trial of GLPG 1837 (Abbvie/Galapagos), indicate that this therapy could eventually offer an alternative to ivacaftor in patients with the G551D mutation.

Further Reading

Quon BS & Rowe SM. New and emerging targeted therapies for cystic fibrosis. BMJ 2016; 352; 30 March 2016.

Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nature Reviews Genetics 16, 45–56; 2015.