Cystic fibrosis drug

Behind the Headlines

Thursday August 21 2008

Cystic fibrosis sufferers produce a thick, sticky mucus that clogs their lungs and digestive systems

“Drug hope for cystic fibrosis sufferers” is the headline in The Daily Telegraph. The newspaper reports that a new study of a drug, known as PTC124, “bypasses a genetic defect that causes breathing problems [in cystic fibrosis sufferers], leading to a reduction of symptoms”.

Researchers say the therapy has few side effects and represents an example of personalised medicine, where a drug has been developed to target the actions of a specific gene defect identified in a group of cystic fibrosis patients by gene sequencing. This was a small phase 2 trial, which did not look at long-term clinical outcomes. The findings are significant, though larger, longer trials are needed before its approval for use by regulators. We can expect more of these types of study as genomic research, the drug development based on it and genetic sequencing in diseased groups become more established.


Where did the story come from?

Dr Eitan Kerem from the Hadassah Hebrew University Hospital, Jerusalem, and colleagues from elsewhere in Israel and the US carried out the study. The study was sponsored by the pharmaceutical company PTC Therapeutics and part-funded by the Cystic Fibrosis Foundation Therapeutics. It was published in the peer-reviewed medical journal: The Lancet.



What kind of scientific study was this?

This was a phase 2 prospective study and was not randomised. All the participants were given two 28-day treatment cycles (14 days on treatment and 14 days off treatment, so the patients acted as their own controls.


In order to be included in the trial, patients had to have a specific genetic profile of cystic fibrosis. Most of (70%) cystic fibrosis occurs because of a mutation in the gene which codes for the cystic fibrosis transmembrane regulator (CFTR) channel. This channel controls the levels of salt found in cells. In patients with cystic fibrosis, the CFTR channel doesn’t form properly and this causes, among other things, a thick mucus to build up in the airways and digestive systems of patients.

All participants in the study had two of the disease-causing CFTR mutations. One of these mutations, known as a ‘nonsense mutation’, alters a gene so that a ‘nonsense codon’ (a triplet of DNA bases forming a ‘premature stop codon’) is inserted in the gene. This occurs in about 10% of cystic fibrosis patients.

"In patients with cystic fibrosis who also have a premature stop codon in the CFTR gene, the oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by this gene.”

Eitan Kerem, lead author

The drug used in this study, PTC124, is given orally. It is a compound that was specifically developed based on knowledge about how this nonsense mutation causes cystic fibrosis. It works by making the ribosomes (which translate genetic code into protein) ‘read through’, i.e. ignore, the parts of the genetic code  created because of the nonsense codons included in the gene – the premature stop codons. Usually, these premature stop codons cause the ribosome to stop translating the genetic code too early, and this means that the CTFR protein and channel doesn’t form properly. The new drug encourages the ribosome to ignore these nonsense/premature stop codons, and use the normal stop codons, to make a more complete protein so that the CTFR channel is more likely to be formed and work correctly.

There were two cycles of treatment. Twenty-three patients completed the first cycle and 21 of the same patients completed the second cycle. The researchers measured three things:

  • The number of patients responding to the drug.
  • Changes in CFTR-mediated total chloride transport. 
  • The transepithelial nasal potential difference.

The last two measures are well-known measures of the physiological functions which are disrupted by cystic fibrosis, and are based on recording the secretion of chloride ions and voltage differences that occur across the lining of the nose. The researchers compared the readings at the start of the study with the reading after 14 days on treatment for each cycle. Statistical tests were used to estimate the significance of any difference and any side effects were recorded.


What were the results of the study?

The researchers report that the mean total chloride transport increased in the first treatment phase, measured by a fall of 7.1 mV and a fall of 3.7 mV in the second treatment phase. They also recorded a response in total chloride transport (defined as a change in nasal potential difference of −5 mV or more) in 16 of the 23 patients in the first cycle treatment phase and in eight of the 21 patients in the second and this suggested “partial restoration of CFTR function“.


Total chloride transport entered the normal range for 13 of 23 patients in the first cycle’s treatment phase and for nine of 21 in the second cycle. Two patients given the drug had constipation without intestinal blockage and four had mild stinging when passing water. No drug-related serious adverse effects were recorded.


What interpretations did the researchers draw from these results?

The researchers conclude that in patients with “cystic fibrosis who also have a premature stop codon in the CFTR gene, the oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by this gene.”


What does the NHS Knowledge Service make of this study?

This is an interesting trial for a number of reasons:

  • It provides an example of how treatments can be designed to overcome defects in gene expression, a recent possibility brought about by rapid advances in genetics and understanding of the precise action of genes in cystic fibrosis.
  • The treatment appears to produce short-term improvements so significant that sufferers’s physiological responses become comparable with those found in people without cystic fibrosis. Any long lasting improvements in the symptoms of cystic fibrosis were not demonstrated in this study and will require more research.
  • This is good news for the 10% of people with cystic fibrosis who have this mutation. However, it is not clear how easy it will be to test for this mutation in routine practice.

The study is small, and long-term outcomes were not measured, but this is to be expected for a phase 2 study as it only seeks to establish the safety and practicality of the drug’s use prior to further research. This future research will be awaited with much interest by patients and practitioners alike.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Drug hope for cystic fibrosis sufferers. The Daily Telegraph, August 21 2008

Cystic fibrosis drug. The Times, August 21 2008

Links to the science

Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; Aug 21 [Epub ahead of print]

Further reading Lee T, Southern KW. Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease. Cochrane Database Syst Rev 2007, Issue 2


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