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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The Beginning of the End?

by on February 3, 2010
in CFTR, quality of life, Vertex

It’s been a weird day.  I had planned to write about meditation and why having a “lung disease” doesn’t mean you can’t meditate.  This was something I used to actually believe, since beginning meditators are often instructed to “follow the breath.”  I tried this…I really did!  It only made me completely anxious and sure that I was suffocating!

I was going to wax prolific on how it is actually easy to use other objects to “anchor” the mind, and how wonderful it is to start each day with a relaxing (usually) and centering meditation practice, without even thinking about the breath.

Then, as I always (sadly) do before I started to write, I checked my email.  There I saw the following press release , and I literally lost my breath.

Vertex Announces Results from Phase 2a Trial of VX-809 Targeting the Defective Protein
Responsible for Cystic Fibrosis

-VX-809 was well-tolerated at all dose levels when dosed once daily for 28 days-
-Statistically significant changes observed in measurement of sweat chloride suggest increased CFTR
-Data support planned combination trial of VX-809 and VX-770 in second half of 2010 for CF patients with
the F508del mutation-
CAMBRIDGE, Mass., Feb 03, 2010 (BUSINESS WIRE) — Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today
announced results from a preliminary analysis of data from a 28-day Phase 2a clinical trial of VX-809 in patients with cystic
fibrosis (CF) who are homozygous for the F508del mutation. VX-809, an oral investigational Cystic Fibrosis Transmembrane
Conductance Regulator protein (CFTR) corrector, was well-tolerated across all four dose groups studied. In the trial, VX-809
showed a statistically significant decline in sweat chloride at both the 100 mg and 200 mg once-daily doses, suggesting that the
activity of the CFTR protein was increased in patients during dosing. Additionally, VX-809 demonstrated a dose response in
change in sweat chloride across the four dose groups. On the basis of these results, Vertex plans to initiate a combination trial
of VX-809 and VX-770, an investigational CFTR potentiator, in the second half of 2010. VX-809 and VX-770 were developed
with support from Cystic Fibrosis Foundation Therapeutics, Inc., the nonprofit affiliate of the Cystic Fibrosis Foundation.
“This Phase 2a trial evaluated the potential effect of an oral compound to improve trafficking of the defective CFTR protein,
and its results represent an encouraging step forward in the development of new therapies to treat the underlying cause of CF
in patients with the most common CFTR mutation, known as F508del,” said J.P. Clancy, M.D., Director of the Pediatric
Pulmonary Center at the University of Alabama at Birmingham and Principal Investigator for the VX-809 Phase 2a trial. “In the
trial, VX-809 was well-tolerated across the dose groups, and statistically significant changes in sweat chloride, an important
biomarker of CFTR activity, were observed at certain dose levels. There is high interest in the CF community in new
approaches to CF therapy, and we look forward to the future exploration of VX-809 and VX-770 as part of a novel combination
regimen aimed at treating the majority of CF patients.”


Ok, first if you need a review of what this all means, read an earlier post here.  The big news here is that Vertex 809 somehow “corrects” the trafficking problem of the dF508 defective protein…at least enough to cause a change in sweat chloride concentration.  This is huge! We know that another Vertex drug, Vx 770, potentiates  (enhances) the effectiveness of the chloride channels present at the apical membrane in the G551D mutation, and is now being tested on people with the dF508 (most common) mutations as we speak (read, write, whatever we are doing).  So, if Vx 809 gets the protein up there, and Vx 770 opens it….

Is this the beginning of the end of CF as we know it?

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Sick and Happy Takes on New Meaning

by on March 17, 2009
in general

I am going to be the first ever to blog about the negative effects of happiness in CF.  The following is an excerpt from an article from Stanford Medicine, published yesterday (the emphasis is mine).  In brief, the article reports the discovery of an exaggerated white blood cell response to inflammatory signals leading to lung destruction in CF lungs:

So what are the live neutrophils doing in patients’ lungs? The new findings surprised Tirouvanziam’s team. After collecting fresh neutrophils from cystic fibrosis patients’ sputum and analyzing them with fluorescence-activated cell sorting, the team discovered that signals from the patients’ lung tissue were reprogramming live neutrophils with conflicting messages. The first set of signals switches on what Tirouvanziam calls “an ancient happiness pathway” — a chain of commands that tell the neutrophils that nutrients are plentiful, and that it’s a good time to translate the cell’s library of genes into new protein. The second pathway is a cellular alarm system associated with inflammation and stress.

“They’re receiving a lot of signals at same time, and we think the happiness signals are messing them up completely,” Tirouvanziam said.

His team now suspects the inappropriate activation of the “happiness signal” — the molecular target of rapamycin, or mTOR, cell signaling pathway — may trigger neutrophils to release large quantities of human neutrophil elastase, the enzyme that destroys the elastic fiber of lung tissue. In healthy individuals, neutrophils never release destructive human neutrophil elastase into nearby tissue.

So maybe Sick and Happy should now be called Sick because I’m Too Happy????

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Living a Medical Miracle: CF Today and Tomorrow

by on August 3, 2008
in general

I thought it would be appropriate to launch my new blog the day I returned home from probably the most exciting CF conference I have attended.  While many of you may have read some of my articles on wellness and exercise before, the purpose of this blog is somewhat more selfish…it gives me something to do while inhaling hypertonic saline.  In fact, I almost called it “The Saline Chronicles,” but I wasn’t sure how to to search engine optimization with such a domain name.  “Sick and Happy” is more appropriate, because my goal with all this writing is 1) to create help, both with words and with audio and visual assistance, for PWCF to begin and maintain lifestyle practices which will improve quality of life  (after all, isn’t that what we are here for?), and 2) wax prolific on my new favorite subject: how to use the rapidly growing and amazingly popular field of positive psychology to live better in our bodies, such as they are.

Tiffany Christensen, author of “Sick Girl Speaks!” gave an amazing presentation at the start of this weekend’s conference in Redwood City, California.  As she chronicled in a deeply moving and occasionally hilarious one woman show, having CF can be an incredible tool to use when “finding the permanent me.”  Tiffany embodies positive psychology.  It is people like her that I want to learn from, and write about in these posts.  

But before I do that, I first want to describe why this conference was exciting. The bottom line is that there are some amazing new drugs making their way through clinical trials right now. The two I am most intrigued by come from Vertex Pharmaceuticals, and are showing incredible promise.  I never really have believed that there would be definitive treatment for CF in my lifetime, but now I really am starting to wonder.

This makes it even MORE important to do everything in our power now to keep as healthy as we can, using as many techniques as we can.  This blog is another channel through which I hope to communicate  that your future is more in your control than you may think! As my former Pathology mentor, Klaus Bensch used to say, “A scar is a scar is a scar!”  He was of course not referring to CF lungs, but a general principle throughout the body.  It is impossible to revert scar tissue to functional lung tissue.  Therefore, it is even more essential now than ever before to do everything you can to slow down the inflammation↔tissue damage↔infection cycle now.  When a treatment that corrects the basic defect arrives, the more functional lung tissue that you have, the better off you will be for the rest of your life.

So I intend, through this blog, to  use my background as a person with CF, as a physician who understands the pathophysiology of CF more than I probably should, as a fitness fanatic and personal trainer, as an executive wellness coach, and, mostly, as an “old survivor” at almost 48 years old to talk about how to keep on top of your game until that great day comes when you’ll take a pill to move your CFTR to the cell membrane, and another pill to make it work better!

To learn more about me and my coaching services, check out www.newdaywellness.org.  Until tomorrow, smile, a New Day is coming!

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