One article I published focused on the science behind genetic inheritance of recessive genes, specifically that of the defect gene resulting in Cystic Fibrosis. In this article I will take a look at the most recent research into the area discussing a medicine currently awaiting approval for funding.

The Research

Scientists, as ever, are busy conducting research. Teams all around the world are testing new gene therapies targeting the defective CFTR gene. Recently a newly authorised drug ivacaftor, marketed as KALYDECO, targets one of the CFTR mutations responsible for CF.

The drug, described as a potentiator, activates a disabled CFTR protein used to manage chloride exchange within the cell. Ivacaftor is directed against one specific strain of CF called G551D, as well as being partially effective in other strains.

65 Roses for Cystic Fibrosis PhotoCredit: Tanya Dawn (Flickr)

65 Roses for Cystic Fibrosis PhotoCredit: Tanya Dawn (Flickr)

CF mutations are categorised into classes ranging from class I to class V. G551D is a class III mutation. Speaking at a conference for parents of CF patients  Dr. Edward McKone, senior clinical lecturer for UCD Conway Institute of Biomolecular and Biomedical Research and Consultant in Respiratory Medicine for St. Vincent’s University Hospital, summarises the mutations using the analogy of a revolving door.

“Imagine the CFTR protein as a revolving door. In class I the assembly process is almost entirely flawed and as a result the door is never completed and so there is no [gene] expression. In class II, the F508del most common in Ireland, the process is still flawed but it’s not recognised until after the door is made and released. However the cell then recognises that the finished door is in fact flawed and so it is destroyed.”

“Again in class III we have a flawed door, this time though, it survives and is installed but it doesn’t work, it’s jammed shut. For class IV the door is installed but wedged just slightly ajar, so some chloride channels can be exchanged but not nearly enough. Finally in class V you have slightly better expression of the gene again. Class IV and V see about 10-12% effectiveness which is not great but compared to 2% for class I to III it is much improved.”

The newly authorised and currently available ivacaftor treatment increases the functionality of the CFTR protein, providing CF patients with G551D class III mutation a much improved quality of life. Gene therapy treatments such as ivacaftor and others currently in the process of being trialled represent a major shift in treating CF.

KALYDECO is effective against the G551D strain of CF which accounts for approximately 10% of the CF population. What then for the more dangerous and far more common strain F508del? A new drug gene therapy has undergone clinical trials and only recently has been approved by the European Medicines Agency (EMA). 

Dr. Ed McKone Classes of CF

Dr. Ed McKone Classes of CF

The Process

The newly approved drug, marketed as ORKAMBI, is a combination therapy using the proven ivacaftor treatment along with the experimental lumacaftor drug treatment. The EMA approved the drug on a European wide basis but that doesn’t mean it’s available yet.

The pharmaceutical company need to need to negotiate on a nation by nation basis for the supply of the new treatment. In the case of Ireland that means working with the Health Service Executive (HSE) Corporate Pharmaceutical Unit (CPU).

In an interview with Katie Murphy, Research and Development Officer for Cystic Fibrosis Ireland, herself a CF patient benefiting from KALYDECO describes the process. “The HSE-CPU work very closely with the National Centre for Pharmacoeconomics (NCPE). They are approached by the pharmaceutical company with a dossier detailing the trial results of the drug treatment.”

The NCPE then undergo a ‘rapid review’ process of no more than four weeks at which point they have to make a recommendation either in favour of the drug treatment or make a formal request for further examination.

“The NCPE are looking to see if a drug is providing value for money essentially. They have a formula, dependent on a wide range of criteria but usually if a drug costs less than € 45,000 per patient per year and the evidence suggests beneficial effectiveness as compared with current treatments they approve the treatment at the rapid review stages.”

In cases where the drug has a high budgetary impact it is recommended for a Health Technology Assessment (HTA). “The NCPE are quite good at including patient organisations in this process to assess the benefits of patient impact of a drug treatment” Ms Murphy says. The HTA process is outlined in the flow chart below.

Katie Murphy CF Research Ireland Process

Katie Murphy CF Research Ireland Process

The Future

The CF gene targeting lumacaftor/ivacaftor treatment has only just been approved by the EMA and so the pharmaceutical company will be gearing up to begin the negotiating process with the NCPE and HSE-CPU before being subject to the HTA process.

That’s a lot of acronyms and the process still leaves a long time before the treatment might be available. The NCPE operates on a 90 day ‘stop-clock’ process meaning time is paused outside of working hours.

The good news is that this is the single biggest step in moving towards the goal of CF patients worldwide; so that one day the only acronym you will need to know is that CF stands for Cure Found.

I have included a list of the Acronyms used in this piece to help clear things up.

Acronym Meaning Function
CF Cystic Fibrosis Inherited Lung Disease
CFTR Cystic Fibrosis Transmembrane conductance Regulator Defective Gene and Protein Responsible for CF
EMA European Medicines Agency European Medical Oversight
NCPE National Centre for Pharmacoeconomics Irish National Medical Review Board
HSE Health Service Executive Ireland Health Service Administration
CPU Corporate Pharmaceutical Unit

(Branch of the HSE)

Interface between HSE and Pharmaceutical Companies
HTA Health Technology Assessment New Treatment Review Process

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