Wednesday, 25 June 2014

What the Vertex Phase III Results Mean

Following yesterday's announcement from Vertex Pharmaceuticals of the results of the Phase III clinical trial of the ivacaftor and lumacaftor combination therapy, our Director of Care & Research Dr Janet Allen explains the key results.

Vertex announced the Phase III
combination clinical trial results for people with cystic fibrosis carrying two copies of F508del (which accounts for around 50% of the UK cystic fibrosis population). Now the dust has settled from the flurry of excitement, I’ve had a chance to look through some of the details in the text beyond the headline data on FEV1 lung function. What I find striking is the effect of the combination treatment on pulmonary exacerbations, which is remarkable, especially alongside such modest effects on FEV1. This finding on pulmonary exacerbations translates through to significant reductions in hospitalisations (39-61%) and IV antibiotics (45-56%). As we all know, pulmonary exacerbations contribute to continuing decline in lung function for people with cystic fibrosis. Together with the need for hospitalisations and IV antibiotics, this has a demoralising effect on individuals and their quality of life. The data here implies that these events could be halved by the combination treatment.  We have just come off the phone with Vertex where we discussed this exciting data and the team commented that many of its expert panel have also remarked on the beneficial effect on pulmonary exacerbations and how disproportionate it is to the effect on FEV1. Clearly more analysis needs to be completed and we need to have a better understanding of this effect but it is remarkable and shows that FEV1 is not necessarily the gold standard marker for measuring the effect of a drug in cystic fibrosis.

The other point that should not be missed is that this is a landmark scientific achievement. The F508del mutation in CFTR causes this protein to be fold incorrectly, which is a really difficult problem to fix. Many other conditions are caused by misfolded proteins and many programmes have tried unsuccessfully to restore the folding pathways in people. Here, a small molecule has been discovered that affects the complex folding of the protein, CFTR. This is an amazing achievement and shows the real value of linking high quality science and drug discovery with the determination to make a difference. 

The Trust is looking for people who took part in the trial to share their experiences – please email James Barrow, Head of Public Affairs, at


  1. This is amazing news, however I have only one mutation of F508del and the other Q220X can this help those with only one mutation?

  2. that is great news, My daughter only has only one mutation of f508del i was wondering too if any hope for only mutation ? =)

  3. My 11 year old son has one F508del and the other one unidentified. I also want to know if the heterozygous state could benefit from the treatment.

  4. Hi Dr Allen,

    Thanks for your analysis.

    I have my own theory on the drug results, which I'd love to hear your thoughts on.

    I look at the P3 results for 809/ivacaftor and, like you, note two things.
    1. FEV1 increases are very modest, even compared to some studies of the therapies hypertonic saline and DNase
    2. Reduction in IV antibiotics is pretty stellar, at 45-56%.

    What might this tell us? Could it be that focusing on improved mucus clearance thanks to enhanced chloride transport by rescued CFTR... is not the main benefit of 809/ivacaftor?

    I was reminded of Sharktank's paper on the lactoperoxidase system in CF -- -- and wondered the following:

    Mucus clearance can be aided by improved CFTR function, but also by therapies such as DNase etc. But the damaged lactoperoxidase system in CF has not yet been addressed by a to-market therapy (though I believe Meveol is aimed at OSCN therapy). So could it be that restoring some CFTR function is at last getting some hypothiocyanate into position, boosting the body's inate ability to fight infection, even without clearing mucus more efficiently?

    Even a modest boost to the lactoperoxidase system could explain that big reduction in IV usage and hospital admisssions. Whereas a small increase in chloride transport might be having a rather modest effect on mucus clearance, explaining the smallness of the FEV1 hike.

    Do you know whether Vertex has measured before/after levels of OSCN in the lungs of patients on 809/ivacaftor? Is the improved transport of thiocyanate a credible theory for improved infection fighting in the trial patients?

    Look forward to hearing your thoughts!

    Best wishes.

  5. Could Dr Allen comment on the following questions please:

    1) Is there a scientific reason why the benefit would not be observed in CF-sufferers with only one version of the f508del mutation or it is simply that the study was limited to those sufferers with 2 copies?

    2) Is there a reason why benefits would not be seen in sufferers below age 12 or is this just the limit of the study due to the people involved in the trials?

    Your comments / feedback would be appreciated.

    Thank you

  6. Anonymous... without wishing to step on Dr Allen's toes, the answers to your two questions are, I believe:
    1) In terms of people with one f508del mutation and one of another type, there IS an observable response to 809/kalydeco, but it is very modest. This graph shows you how someone with two f508del mutations (homozygous) stacks up against someone with just the one (heterozygous):

    As you can see, the difference is striking. And when the benefit of 809/kalydeco is already modest for homozygotes (3%-ish absolute FEV hike), it is unlikely that any clinically significant efficacy could be proven for heterozygotes on this therapy.

    The biology here is fairly simple: with two copies of f508del-CFTR you have twice the number of faulty proteins to act upon than a heterozygote has.

    Having said that, they are looking at a few key mutations that might respond well to the combo. So keep a look out for those trials upcoming.

    For most f508del heterozygotes, Vertex has said they believe they will need a third drug ("second generation corrector") to be added into the mix in order to see a clinical effect.

    2) Benefits absolutely will be seen in people with CF <12 yrs old! There are kids taking Kalydeco under the age of six (off-label, because the label stipulates it's for age six and up) who are doing brilliantly on it.

    This is a feature of drug trial standard practise. Nail the safety and pharmokinetics of the older population first, and then move on to the somewhat trickier assessment of younger patients. There are many factors involved, including it being harder to run the necessary checkups on young kids. And try getting FEV1 results from a 2-yr-old!

    Kalydeco is, I believe, now being trialled for 2-5yr olds, so we'd all hope to see a similar pattern for 809/kalydeco.

    Hope this has helped... and hope Dr Allen swoops in with corrections if any of the above is wrong!

  7. Dear Tom, thank you for the explanation and comments.

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