by on June 24, 2014
in CFTR, cystic fibrosis

Just as we all remember where we were and what we were doing when JFK died, I remember where I was in 1989 when I learned that the gene coding for CF had been identified.  It was a BIG day. Everyone in the CF world was convinced that a cure was just around the corner. I was a medical student and soon to be resident at Stanford, and couldn’t wait to be a subject in gene therapy studies.

Of course, that didn’t exactly pan out as expected.  Inserting a corrected version of this newly identified gene was much more complicated than anyone could guess, and gene therapy as a cure for CF is still a long way off.  But, 25 years later, as a result of sequencing the gene and determining the structure and function of the protein it coded for, we are having another BIG, BIG day.

Everyone in the above-mentioned CF world has been anticipating the day that Vertex Pharmaceuticals would announce the results of their two phase 3 combination trials of Kalydeco (ivacaftor) with VX809 (lumicaftor).  These were huge studies, not just in the sense of numbers of patients (1000 total), but also in the significance of the results.  Kalydeco had already proven to be a huge success for a small number of people with a rare CF mutation, G551d.  “Blue Lightening” as some fondly refer to it, at the cost of over 300K per year, has proven to be a literal life saver for people with this mutation.  You can argue for days about the price–and many , many people have deep concerns about this–but you can’t argue that Kalydeco has been a game changer.  By correcting the defective gene product itself, Vertex has proven that the long awaited CF “cure” is quite possibly just around the corner.

I put cure in quotes because taking a Vertex drug is NOT going to undo what has been done.  Scarred lungs will remain scarred. Treatments to contain chronic infections will continue to be necessary.  Pancreatic enzymes will still need to be replaced.  CF-related diabetes will continue to need management with insulin.  By “cure,” what I mean is “contained,” or managed chronically, just as diabetes or high blood pressure are managed.

But these combination studies, named TRAFFIC AND TRANSPORT, were going for the BIG money (pun intended), deltaf508 homozygotes, the most common genotype to cause CF.  Yours truly is a double delta f508, and I was a subject in the study.  Now that the results are published, I can talk about my experience.

I still don’t know if I got the drugs during the first six months, as I was blinded.  But when I rolled over to the open label portion of the study, when i knew for a fact that I was taking both drugs, I immediately got sick and ended up with pneumonia.  Then, two months later, the same thing happened.  And then, the same thing happened again.  In sum, three rounds of  pneumonia in four months.

Coincidence?  Maybe.  Prior to rolling over to open label, it had been 19 months since I had needed IV’s for pneumonia.  So I don’t know for sure…but I had to stop the trial, and I’m not about to take those two drugs together again until I have a LOT more information.

But my story is not what Vertex is reporting today, so I’ll stop there.  Vertex says that they have achieved their primary endpoint of absolute improvement of FEV1 of about 3%.  In addition, secondary endpoints of weight gain and decreased pulmonary exacerbations were statistically significantly achieved.  This is big! Wall street is going crazy.  Facebook is exploding.  Champaign corks are popping!

A lot of people are going to make a lot of money.

A 3% change in FEV1 is not a ton. As a comparison, Pulmozyme studies showed an improvement of about 6% in FEV1.  Kalydeco improved FEV1 in G551d folks by about 10%. According to Dr. Bonnie Ramsey, one of the lead investigators in these trials, patients probably wouldn’t even notice a 3% improvement. So why is 3% a game changer?  And why is this a BIG, BIG day?

Today is a BIG, BIG day and I will always remember where I was (sitting on the toilet, of course) when I read the press release, because today we know for sure that it can be done!  It can be done for the most common form of the disease, not just in the lucky (?) few with G551d. It’s as if we’ve been running a marathon for 25 years, slogging along, runners (patients) dying left and right, trying to cure or control this damn disease, and suddenly today, the finish line is in sight.

The delta f508 mutation leads to a misfolded protein (CFTR) which mostly gets chewed up and spit out by the cell’s quality control mechanisms before it can ever get to where it needs to go, the cell membrane. Here, even the very few CFTR that make it to the target site don’t function correctly to allow chloride ions to traverse the membrane.  That’s why we need at least two drugs…one to help with the folding and one to help with the functioning.

But there are two areas within the  CFTR protein that are misfolded.  Lumicaftor (809) corrects one of them.  Then Ivacaftor (Kalydeco) corrects the functioning (partially) of the protein at the membrane.

So 3% is not huge, but better correctors are just around the corner, including second generation correctors that fix the second misfolding site in the dd508 mutated gene product.  People, the end is near, and the race is on!  Vertex is madly working on other correctors, as are big pharmaceuticals like Pfizer and Genzyme.  Competition is really, really good.  There will now be a sprint to the finish line because everyone wants to be the big winner in CF.  The game has changed.  The slog is now a sprint. Everybody wants to be the company that does for delta f508 what Kalydeco has done for G551d, or better!

The race is on, and now we are going to watch capitalism work, for better or worse.  CF patients and investors in the correct company will win.  People who actually have to pay the astronomical prices for these medicines will lose.


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4 Responses to “A BIG, BIG DAY”
  1. Robin says:

    Julie, nice job in explaining. Hoping it all turns out as wished for……….

  2. Megan says:

    Great post – thank you for sharing. I’m also a double delta f508, so will be reading as much as I can in the coming months. I wasn’t on the trial, but I feel the exact same way you do – we have this in our sights! Finally, we can move the ball on this thing.

    Best of luck to you and us all!

  3. Julie Desch says:

    just around the corner…

  4. Caitlin says:

    Thanks so much for sharing Julie. I was in TRANSPORT and TRAFFIC as well and am now on open label. I did not develop pneumonia but have had more frequent hospitalizations/exacerbations since 2011 than ever before. My FEV1 has also dropped. I’ll never know if I would be in the same position (or worse off) had I not been in the study. It might also be due to my age that the drop in FEV1 is to be expected. I DO know these results were not what I was hoping for. Thanks again for sharing.

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