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Modulating and correcting cystic fibrosis

Improvements in the treatment of paediatric cystic fibrosis (CF), the building of a world-class National Centre for Adult Cystic Fibrosis at St Vincent’s University Hospital (SVUH), Dublin, as well as availability of new and better medicines that can modulate and correct the impact of CF, have provided renewed hope for treatment of the condition in Ireland. These developments mean that people like Prof Edward McKone, Consultant Respiratory Physician at SVUH, are expecting to see a 65 per cent reduction in the number of adults with CF over the next decade.

Clinical research into CF is growing in Ireland and elsewhere. In fact, with many trials ongoing, doctors treating CF face a problem in respect to the ‘over-saturation effect’. In other words, they have been forced to look at only a certain number of new therapies in their clinics, while leaving others aside.


Recent years have seen the advent of CF modulation therapies that did not exist up to five years ago, said Prof McKone. These modulators work by targeting the root causes of CF. There are also anti-inflammatory drugs coming on stream for the treatment of CF, with three drugs currently in early-phase clinical trials. Added to this are a large number of anti-infectives for CF in development, which work by attempting to prevent the spread or kill  the bacterial types that cause CF-related infection. In children aged under 10 years with CF, the most common bacteria isolated from the sputum are Staphylococcus aureus and Haemophilus influenzae, but over the age of 10 and onwards, Pseudomonas aeruginosa is the most prevalent.

Enzyme replacement therapies can work well for CF, where the person with CF has their pancreatic ducts blocked, outlined Prof McKone. This blockage prevents digestive enzymes made by the pancreas reaching the intestines, where they are required for digestion. The replacement therapies help the person with CF to absorb fat and proteins properly, which improves nutrition, reduces fatty stools and enables people with CF to eat the same foods as anyone else. Vitamin products can also be beneficial in respect of CF. Supplements can help to replace vitamins A, D, E and K, which are crucial for normal growth and nutrition and which people with CF have trouble absorbing because they are fat soluble. 

People with CF also need to make sure that they get enough water-soluble vitamin C and B-complex, which includes folic acid, biotin and pantothenic acid.

However, Prof McKone said the biggest recent change in how physicians look at CF has come through the development of ‘corrector therapies’, which are genetically-specific, personalised medicines.

The availability of lumacaftor/ivacaftor (Orkambi) for patients in Ireland has been a big boost, as have promising trials of gene therapy undertaken recently in the UK.


CF is a recessive condition which requires both parents to have the gene and for the child to inherit it from both parents. It is the most common genetic condition affecting the lungs of Caucasians globally, with an estimate of 70,000 people with CF worldwide. However, that figure may well prove an underestimate, as CF is likely under-diagnosed in countries where it is not as common as in Ireland.

The number of people in Ireland with the condition is about 1,200, while in the UK, it is estimated at around 10,000, said Prof McKone. One-in-19 Irish people carry the gene, while it is one-in-25 in the UK, one-in-30 in the US, one-in-65 in Africa, and one-in-90 in Asia.

The gene that causes CF — the cystic fibrosis transmembrane conductance regulator (CFTR) gene — is found on chromosome 7 and is a very big gene, said Prof McKone. The gene codes for salt content and sweat glands in the body, so if it is not working, there is a problem in these respects.

There are many mutations of CFTR that can result in CF, but the most common of these is F508del, according to Prof McKone. If a person has two mutations of this gene, then they will get ‘classic CF’. In Ireland, 60 per cent of people with CF have two mutations of F508del. At this stage, scientists have discovered 1,800 mutations affecting the CFTR gene that can cause CF, outlined Prof McKone, but in Ireland just seven mutations are responsible for 80 per cent of the cases of CF. He said that on a positive note, the three most common mutations in Ireland appear to be responsive to drug therapy and this is the reason why pharmaceutical companies decide to hold many of their CF trials in this country.


Professor Edward McKone

The CFTR gene produces a protein which can be thought of as acting like a ‘revolving door’, carrying salt in and out of the cell and across cell membranes, said Prof McKone. That protein is called the cystic fibrosis transmembrane conductance regulator, and it acts as a channel across the membrane of cells that produce mucus, sweat, saliva, tears and digestive enzymes.

The mutations that cause CFTR to malfunction in this role are classified according to the nature of the disruption they produce. Class 1 mutations mean the regulator protein doesn’t get made at all, said Prof McKone.

In the case of Class 2 mutations, which are common in Ireland, he said that the regulator protein does get made, but that the ‘assembly line’ producing it recognises that there is something wrong and the regulator gets broken up inside the cell, before it gets a chance to reach the cell surface and ‘do its job’.

In Class 3 mutations, said Prof McKone, the regulator protein gets to the surface of the cell but because it has been disrupted by the mutation of its encoding gene, it doesn’t work and “the revolving door is shut”.

In Class 4 mutations, the regulator protein again gets to the surface, Prof McKone said, but this time “the door is slightly ajar”, so some of the protein functions correctly. In Class 5 mutations, he said that an extremely reduced amount of normal protein is expressed on the cell surface. Meanwhile, in Class 6 mutations, the protein reaches the cell surface but while functional, it is unstable and degraded and is removed by the cellular machinery.


For those that have Class 3 mutations with the G55ID mutation, the normal situation is that the regulator protein gets to the cell surface but it doesn’t work once there and “the revolving door” for salt is locked. However, when the drug ivacaftor (Kalydeco) is added, that ‘door swings open’ and there is a 50 per cent increase in regulator protein activity at the cell surface, said Prof McKone.

There is a 10 per cent increase in lung function within two weeks of the start of ivacaftor therapy, said Prof McKone. Clinical trials have shown that after that huge initial jump, lung functioning plateaus.

When people on this therapy are doing a sweat test, their chlorides fall well below 60mEq/L after two weeks. This means that defective chloride channels are starting to function again.

Prof McKone was interested to know whether ivacaftor altered the rate of decline in lung function that people with CF would experience over the years, or if it just postponed the inevitable lung transplant. To test this, he set up a comparative study, which showed that the rate of decline in lung function in people using ivacaftor over time was about half that of those who went without the drug. This showed ivacaftor was a disease-modifying treatment, he said.

Ivacaftor is associated with improved lung function, increased weight, a decrease in infections and improved sweat chloride for those with the G55ID mutation, said Prof McKone. There was a question as to whether these effects were sustained over the long term, but further studies have found that there is an improved impact on lung function over three years, and that the rate of CF exacerbations didn’t change over the three-year period either, outlined Prof McKone.

There have been studies done on the impact of ivacaftor on CF in people with some of the other Class 3 mutations, and for these too “the door spins open”, said Prof McKone. This beneficial effect led the US and European authorities to extend the drug license for ivacaftor to include people with these other Class 3 mutations in February 2014. Since then, he said, everyone with “gated mutations” in Ireland have had access to ivacaftor.

Ivacaftor also benefits people with Class 4, 5 and 6 mutations, said Prof McKone. For example, he said people with the R117H mutation can benefit and this makes up 25 per cent of the people with CF in Ireland, with an even greater proportion in Northern Ireland. A trial involving people with the R117H mutation over 24 weeks demonstrated this benefit, said Prof McKone, with one group given ivacaftor and the other group a dummy. There were 69 patients involved.

The trial found that there was a 5 per cent improvement in lung function in adults over 18, but a less marked impact on children aged between six and 11 years, perhaps because they had less lung function impairment than the older group, said Prof McKone. He said the question for the European Medicines Agency is whether it will limit the license for ivacaftor for the people with the R117H mutation to the group over 18, or simply to the genetic subgroup. If it is the latter, then children might get access to the drug too, he said.

It has also been found that ivacaftor works well for people with R117H who have advanced CF, said Prof McKone. He said that some people who were very sick under his care did well on this drug. Ivacaftor has been licensed in Ireland to treat people with various mutations of the CFTR gene, but not the R117H. The US FDA has extended the licence to include R117H and it is likely that the same will happen here. This would provide a new treatment option for another group of the Irish population with CF.


Prof McKone said that for Class 2 mutations, where the mutation is F508del, there is an abnormal regulator protein produced by the CTFR gene. The cell recognises that the protein is abnormal and it gets broken up before it has a chance to even get to the cell surface. The first challenge is to get the abnormal protein to the surface of the cell, and the second is to get it working properly once it is in place there, he said.

In those with two copies of the F508del mutation, the drug lumacaftor works to bring the abnormal protein to the surface, and ivacaftor then activates it on the surface. The combination of lumacaftor and ivacaftor (Orkambi) is regarded as a corrector therapy for CF.

A huge worldwide, multi-centre trial of lumacaftor/ivacaftor took place over 24 weeks, with about 1,000 people enrolled in the study. Lung function was seen to improve by 3 per cent on average and this result was reliable, given the large numbers in the study. That level of improvement wasn’t enough to bring about a change in quality of life that was noticeable to many patients, said Prof McKone. However, he said the improvement was important because it was seen consistently across all CF groups.

Those on the lumacaftor/ivacaftor trial needed less intravenous medications and their rate of infections dropped by one-third. “Overall, there was a modest improvement in lung function,” said Prof McKone, “but a good impact on reducing infections. This is a big first step, as it is the first corrector therapy.”

There are other CFTR correctors in development, including VX661, which is a new version of ivacaftor, said Prof McKone. This is being studied for all CTFR genotypes, he said, and there are a number of clinical trials happening in Ireland. He said it may prove to be the case that VX661 is added to what is already available to get more regulator protein activity on the cell surface.


The question of how long people with CF will live is still dependent on the type of mutation they have, said Prof McKone. The mortality for those with severe mutations is twice that for those with milder forms, he said. The mean survival age overall for people with CF is 37, but for those with partial functioning of the CFTR gene, the average survival is 55. There is a big difference in survival, therefore, between people with 2 or 3 per cent functioning of their CFTR gene, compared to those with 13 to 14 per cent, he outlined.

The cost of developing ivacaftor was very high, said Prof McKone, so it is good to see Novartis and Pfizer involved with developing CF correctors that might in the coming decades bring about bigger effects and improvements for CF patients, he said.

Meanwhile, there are many research groups working on the various genetic subgroups of CF to find the right combination of drugs that will work for each, said Prof McKone. There is also gene therapy work underway, which might offer hope for those who do not respond to existing therapies. The UK Gene Therapy Consortium did a small phase 2b clinical trial, which produced data that was promising enough to be now under consideration for a larger phase 3 trial, he noted.

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