Drug combination for cystic fibrosis looks promising

"A 'groundbreaking' new therapy for cystic fibrosis could hugely improve patients' quality of life," The Daily Telegraph reports after a combination of two drugs – lumacaftor and ivacaftor – was found to improve lung function.

The headline is prompted by a trial looking at a new treatment protocol for cystic fibrosis, a genetic condition caused by a mutation in a gene that normally creates a protein that controls salt balance in a cell. This leads to thick mucus build-up in the lungs and other organs, causing a persistent cough, poor weight gain and regular lung infections.

The prognosis for cystic fibrosis has improved dramatically over the past few decades, but the condition is still life-limiting. This new drug combination works together to make the faulty cell protein work better.

More than 1,000 people with cystic fibrosis were given the new protocol or a placebo for 24 weeks. The treatment led to meaningful improvements in lung function compared with the placebo. It also reduced the number of lung infections, improved quality of life, and helped people gain weight.

Further study of the drugs' effects in the longer term will be needed, in addition to collecting more information on side effects.

But this treatment won't work for all people with cystic fibrosis. There are various gene mutations, and this treatment only targeted the most common one, which affects half of people with the condition.  

Where did the story come from?

The study was carried out by researchers from various international institutions, including the University of Queensland School of Medicine in Australia, and Queens University Belfast.

There were various sources of funding, including Vertex Pharmaceuticals, which makes the new treatment.

The study was published in the peer-reviewed New England Journal of Medicine.

The UK media provided balanced reporting of the study, including cautions that the treatment should work in around half of people with cystic fibrosis. Researchers were quoted as saying that although they hope this could improve survival for people with cystic fibrosis, they don't know this for sure.

However, some of the reporting focusing on the quality of life improvements does not take note of the researchers' caution that, overall, these improvements fell short of what was considered meaningful.

The media also debated the cost of the treatment protocol. The Guardian reports one year's course of lumacaftor alone costs around £159,000. The new treatment protocol is being assessed by the National Institute for Health and Care Excellence (NICE) to see if it is a cost effective use of resources.  

What kind of research was this?

This was a randomised controlled trial (RCT) aiming to investigate the effects of a new treatment for cystic fibrosis.

Cystic fibrosis is a hereditary disease caused by mutations in a gene called cystic fibrosis transmembrane conductance regulator (CFTR). The protein made by the CFTR gene affects the balance of chloride and sodium inside the cells.

In people with cystic fibrosis, the CFTR protein does not work. This causes mucus secretions in the lungs and other parts of the body to be too thick, leading to symptoms such as a persistent cough and frequent chest infections.

There is no cure for cystic fibrosis, and current management focuses on breaking down mucus and controlling the symptoms with treatments such as physiotherapy and inhaled medicines.

We have two copies of all of our genes – one inherited from each parent. To develop cystic fibrosis, you need to inherit two abnormal copies of the CFTR gene. One in 25 people carry a copy of the abnormal CFTR gene. If two people carrying an abnormal gene have a child and the child receives the abnormal gene from both parents, they will develop cystic fibrosis.

This trial looked at the effects of a treatment that helps the abnormal CFTR protein work better, called lumacaftor. It was tested in combination with another treatment called ivacaftor, which also boosts the activity of CFTR proteins.

There are various different types of CFTR gene mutations. One, called Phe508del, is the most common and affects 45% of people with the condition. Lumacaftor specifically corrects the abnormality caused by the Phe508del mutation, so this trial only included people with this mutation. An RCT is the best way of examining the safety and effectiveness of a new treatment. 

What did the research involve?

This study reports the pooled results of two identical RCTs that have investigated the effects of two different doses of lumacaftor, in combination with ivacaftor, for people with cystic fibrosis who have two copies of the Phe508del CFTR mutation.

The study recruited 1,122 people aged 12 or older; 559 in one of the trials and 563 in the other. Participants in both trials were randomly assigned to one of three study groups:

  • 600mg of lumacaftor every 24 hours in combination with 250mg of ivacaftor every 12 hours
  • 400mg of lumacaftor every 12 hours in combination with 250mg of ivacaftor every 12 hours
  • placebo pills every 12 hours

The placebo pills looked just like the lumacaftor and ivacaftor pills and were taken in the same way, so researchers and participants could not tell whether they were taking placebo or not. All treatments were taken for 24 weeks.

The main outcome examined was how well the participants' lungs worked, measured as a change in percentage of predicted forced expiratory volume (FEV1). This is the amount of air that can be forcibly exhaled in the first second after a full in-breath, which provides a well-validated method of assessing lung health and function.

The percentage of predicted FEV1 shows how much you exhale as a percentage of what you would be expected to, based on your age, sex and height.

The researchers also looked at the change in body mass index (BMI) and in people's quality of life in terms of their lung function, as reported in the patient-reported Cystic Fibrosis Questionnaire – Revised (CFQ-R).

The study analysis included all patients who received at least one dose of the study drug, which was 99% of all participants.  

What were the basic results?

At the start of the study, the average FEV1 of participants was 61% of what was predicted (what it ought to be). There were no differences between the randomised groups in terms of age, sex, lung function, BMI or current cystic fibrosis treatments used.

Lumacaftor-ivacaftor significantly improved how well the participants' lungs worked compared with placebo in both trials, and at both doses. The change in percentage of predicted FEV1 ranged between 2.6% and 4.0% across the two trials compared with placebo over the 24 weeks.

There were also significant improvements compared with placebo in BMI (range of improvement 0.13 to 0.41 units), and respiratory quality of life (1.5 to 3.9 points on the CFQ-R). There was also a reduced rate of lung infections in the treatment groups.

There was similar reporting of side effects across the two treatment groups and placebo groups (around a quarter of participants experienced side effects). The most common adverse effect participants experienced was lung infections.

However, the proportion of participants who stopped taking part in the study as a result of side effects was slightly higher among the drug treatment groups (4.2%) compared with placebo groups (1.6%).

The specific reasons for discontinuation varied between individuals – for example, a couple stopped because of shortness of breath or wheezing; some stopped because of blood in their sputum; some because of a rash; and so on. 

How did the researchers interpret the results?

The researchers concluded that, "These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis [who carried two copies of] the Phe508del CFTR mutation." 


This trial has demonstrated that this new treatment combination could be effective in improving lung function for people with cystic fibrosis who have two copies of the common Phe508del CFTR mutation.

The trial has many strengths, including its large sample size and the fact it captured outcomes at six months for almost all participants. The improvements in lung function were seen while the participants continued to use their standard cystic fibrosis treatments. As the researchers suggest, this indicates the treatment could be a beneficial add-on to normal care to further improve symptoms.

The results seem very promising, but there are limitations that should be addressed. Though lung function improvements were said to be clinically meaningful, improvements in quality of life relating to lung function fell short of what is considered to be meaningful clinically (four points and above on the CFQ-R scale).

The trial only included people with well-controlled cystic fibrosis, and effects of the treatment might not be as good for people with poorer disease control. The treatment combination would also only be suitable for people with the Phe508del CFTR mutation.

This trial only included people with two copies of this mutation, which is only the case in around 45% of people with the condition. Whether the treatment would benefit people who carry one copy of the Phe508del mutation and a different second CFTR mutation is not yet clear, and people with two non-Phe508del mutations would not be expected to benefit from this treatment.

The effects of this treatment combination will need to be studied in the longer term, beyond six months – for example, to see whether it could prolong life. Further information will need to be collected on side effects and how commonly they cause people to stop treatment.

Though this treatment targets the abnormal protein that causes symptoms, as one of the study authors notes in The Guardian, it is not a cure. The lead researcher, Professor Stuart Elborn, was quoted as saying: "It is not a cure, but it is as remarkable and effective a drug as I have seen in my lifetime."

Overall, the results of this trial show promise for this new treatment for people with cystic fibrosis who carry two copies of this specific gene mutation.

NHS Attribution