Wednesday, 25 June 2014

Vertex results from TRAFFIC/TRANSPORT

Yesterday Vertex announced preliminary results from the Phase 3 trial of Lumacaftor in combination with Ivacaftor in patients aged 12 and over with two copies of the F508del mutation. The trial involved 1,100 patients at almost 200 sites across the world.

For me, the most interesting points were:
  • Mean absolute change in % predicted FEV1 was approx. 3% and mean relative change in % predicted FEV1 was approx. 5% (on the basis of pooled data). That means if a patient’s baseline FEV1 was 60%, on average they would have seen an increase to 63%. While this is less dramatic than the effect seen in G551Ds on Ivacaftor monotherapy, it was statistically significant and, for many people with CF, each % point maintained is important;
  • Statistically significant increase in Body Mass Index (BMI)
  • Delayed time to first pulmonary exacerbation;
  • 30-39% reduction in pulmonary exacerbations (depending on the dose);
  • 39-61% reduction in exacerbations requiring hospitalisation;
  • 45-56% reduction in exacerbations requiring intravenous antibiotics;
  • Some people on the trial had baseline FEV1 below 40%. While the eligibility criteria was 40%, some dipped below this threshold in the period between screening and first drug. These patients seem to have responded just as well as those with higher baseline FEV1;
  • Approx. 90% of people on the trial decided to rollover into the open label extension including those who had been taking placebo during the trial period. This says something about how the drug made patients feel in themselves; and
  • The Quality of Life questionnaire (which is validated by regulators) failed to show any improvement in quality of life. This seems at odds with the data above and, to me, suggests the instrument is not tuned into the things that really matter to patients. Perhaps there is a need to develop a new way of measuring quality of life. It would be a long process to get a new instrument validated but it could pay dividends and it something that could be done in partnership with patients and families.

Vertex now plans to submit the data by the end of 2014 to regulators in the US and EU in order to get a marketing authorisation. If approval is given, they will then embark on the process of securing reimbursement. All this will take time and there are risks at every stage.

While this combination therapy does not appear to be transformational for those with two copies of F508del in the way Ivacaftor has been shown to be in many G551Ds, it is exciting and provides a solid stepping stone for further development by Vertex and others. It is probably more of a bridge to the future than a home run in itself. It should reassure researchers that this problem is one that can be solved.

It is surprising that the effect on exacerbations was so dramatic given the modest effect on FEV1.

Here’s why I think reducing exacerbations is more important than increasing FEV1:

FEV1 is hard to measure in a reliable way even in adults. It is dependent on technique and it can be affected by lots of factors unrelated to underlying lung function. It becomes less reliable as lung function deteriorates which is, arguably, when we most need a reliable measure.

If you ask someone with CF how they feel, they are unlikely to talk about FEV1. FEV1 is not something patients feel or necessarily perceive.

It is well established that more exacerbations lead to worse health outcomes. The mechanism is clear and cruel - most people with CF die of lung failure, every exacerbation can cause incremental lung damage that is irreversible so moving us a little step closer to lung failure. If we think of it like a staircase down to lung failure, we obviously want the distance between each step to be as long as possible and we want each step to be as shallow as possible. Weight gain directly helps here too. Just breathing and keeping permanently resident bugs at bay takes a lot of energy for us. The more energy we have in reserve the better able we are to fight off infections before they flare-up into exacerbations (or the better we are able to minimise the severity of the exacerbations that do hit us). Therefore, weight gain can help extend the distance between steps and minimise the depth of the steps by creating resilience. 

Obviously exacerbations are disruptive to life so there is a clear and immediate quality of life impact for patients and families.

Personally, I wish I had known when I was younger that exacerbations tend to cause irreversible lung damage and knock you down a step. When I was a teenager and relatively healthy, I hated doing all my treatments particularly nebulisers and airway clearance. I sometimes used to think, “I’m fine and busy with my life. I won’t bother doing all my treatments. I'll wait until I get sick and then go to the hospital to get fixed". I didn’t think I was losing anything but I really was.


Traditionally FEV1 is seen as the gold standard test for measuring the effects of new therapies. There may well be a case to review that now. The therapeutic pipeline for people with CF is stronger than ever before and these results will help underpin further development.