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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Up until very recently, therapy for CF has been directed at correcting the consequences of the defective CFTR protein (thinning mucus, improving clearance, treating infection, calming inflammation, improving nutrition, etc).  Yes, when the gene was discovered in 1989, there was a flurry of research in the area of gene therapy…finding a safe mechanism to insert a copy of the “normal” CFTR gene into the targeted cells, and getting it to work.  This proved to be quite an undertaking, and while there is still much being done in this field, the exciting research making news today is from companies like Vertex Pharmaceuticals. With the Vertex drugs and others like them, this is the first time that a therapy—a small-molecule, not gene therapy—is actually directed at trying to correct the defective protein.

In a recent article in Xconomy, Dr. Bonnie Ramsey (who should really be in the CF-caregiver Hall of Fame) responded in part to a question about the Vertex drug VX-770, “Whether it turns out that Vertex is 100 percent successful or not, this is such a giant step forward, it’s like a man walking on the moon.”  Walking on the moon…. I remember that day.  It was huge.  It is my mission with this article to try to explain as best as I can what she is talking about.

To understand why VX-770 and its partner in crime VX-809 make such as giant leap forward for mankind, we first must have two small refresher courses.

CF Mutations 101

There are more than 1,600 known mutations of the gene that causes CF.   We now know that each of these mutations fits into one of five “classes.”  Each member in a class of mutations causes a disturbance in the sequence from gene (DNA) to CFTR (protein) to functioning CFTR protein at the membrane of the cell (electrolyte transport into and out of cell) in characteristic ways.

In a Class 1 mutation, there is no synthesis of CFTR protein at all.  Zilch.  This can be the result of a “nonsense” mutation, where a STOP message is read on the mRNA (transcribed from the gene) somewhere along the line, and synthesis of the protein is aborted.  Or, a Class 1 type of mutation can lead to a misread of the gene because of a “frameshift”.  Think of a frameshift as what happens when you forget to answer ONE question on a multiple choice exam where you have to fill in the answers by coloring in ovals on a separate sheet…all the answers after the one you forgot are wrong…chaos ensues).  No CFTR protein…pretty severe CF.

A Class II mutation is one where the gene codes for a protein that is constructed by the cell machinery, but because of the error from an amino acid deletion in the gene, the processing of the resultant protein is messed up. As a result, the protein is defective in folding, stability, and channel gating (the opening for chloride ions is not regulated properly).  Because it is unstable, not much of it makes it up to where it is needed at the cell membrane.  Our friend, delta F508 is a Class II mutation.

Class III mutations allow for the gene to code for a CFTR protein which makes it up to the membrane, but as a result of this “milder” mutation, the CFTR channel is not regulated or activated properly.  G551D is an example.

Class IV mutations are similar to Class III in that a protein is made and gets up to the surface of the cell, but it has “altered conductance.”  The ion channel just doesn’t work as well as it should.  R117H is an example.

Finally, Class V mutations are those where there is simply reduced synthesis of the CFTR protein.

Clinical Trials 101

You often read or hear about newly developed drugs being tested on humans in “clinical trials.”  These trials occur in a series of steps, or phases, that are designed to answer different questions.

Phase I trials are when researchers test a new drug in a small group of people for the first time.  These studies evaluate overall safety of the drug, look to find effective dose ranges, and document any side effects.

Phase II trials are designed to evaluate effectiveness of the drug and are generally performed with a much larger group of people.  Safety continues to be monitored closely.

Phase III trials are done with very large groups of people to confirm effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug to be approved for use.

Now, back to regular programming:

When gene therapy was not proving to be wildly successful, some companies started to ask if the defective protein could be fixed.  Fortunately, a technique known as “high-throughput screening” was being developed just as the need to find ways to tweak the CFTR protein was becoming glaringly apparent.  Very simply, high-throughput screening uses automation (robotics and high-speed data processing and control software) to rapidly test hundreds of candidate “small molecules” to find the ones that show a specific biologic activity.  In the case of CF, they were looking for molecules that could assist with translation of the RNA “message” to form a CFTR protein normally, or molecules that could assist CFTR in getting up to the membrane, or molecules that could open the dang thing up and let the chloride ions flow as they should.

One company, PTC Therapeutics, found a compound called PTC124, which could to “read through” the STOP sign on the Class I nonsense CF mutations.  PTC124 (now called Ataluren) only works for Class 1 (nonsense) mutations, of course, but clinical studies so far are looking very promising.  Phase I and II studies have confirmed that Ataluren is safe, orally tolerated, and showed encouraging efficacy.  A much larger and long-term phase III trial is scheduled for this summer.

In the case of CFTR protein modulation, Vertex Pharmaceuticals looks for small molecule correctors and potentiators.  Simply put, a corrector gets the CFTR protein to the membrane in larger numbers.  This would be helpful in the Class II CF mutations such as delta F508.  A potentiator works on the protein already at the membrane, increasing its effectiveness.  This kind of drug could potentially be beneficial in several of the mutation classes.

VX-770, an investigational CFTR potentiator, is intended to increase chloride ion transport through the defective CFTR protein.  Vertex chose to specifically look at people with the Class III G551D mutation in the early phase trials of VX-770, because in this mutation, the protein is already where it needs to be on the membrane.  It just needs to be tweaked to open properly.  They figured that although only 4% of people with CF carry this mutation, the odds of showing effectiveness would be best in this small group of patients.

And, indeed, they were right!  Not only did Phase II trials show a marked (10%) improvement in lung function after only two weeks of treatment, they also showed that both nasal potential difference (PD) and sweat chloride levels moved distinctly toward normalized values (this is exciting because no treatment ever has shown to change the sweat chloride levels).  Importantly, when people stopped taking the drug, lung function values, sweat chloride values and nasal PD values returned to their baseline values.

Based on these positive results, Vertex is now initiating larger, Phase III trials.  These are designed to look at larger numbers of children and adults with the G551D mutation over a longer period of time.  In addition, a Phase II study of VX-770 in patients with CF aged 12 years and older who are homozygous for delta F508 is planned to start in the third quarter of 2009.   The hope is that VX-770 will measurably increase the effectiveness of the small amount of CFTR protein that actually makes it to the membrane in Delta F508 CF. If so, then all we need is a corrector to get more of the protein to the membrane, and throw in a dash of VX-770 to create a “Vertex-cocktail” of sorts.

Vertex is hoping that VX-809 is just that corrector (and so am I).  This molecule is designed to increase the amount of deltaF508 CFTR protein on the surface of cells lining the airway.  It is one phase behind VX-770.  So far, Phase I studies have not shown any safety or tolerability issues.  A Phase II study of this drug is now underway.  Where can I sign up?

In summary, I think the message is this:  There is serious cause for hope that one day soon, we will take yet another daily pill (or two…) that is going to improve our lives beyond anything that has yet been discovered.  Is it going to “cure” CF?  Not likely.   A scarred pancreas is not suddenly going to produce enzymes or insulin.  Damaged lung tissue is still damaged.  I am not suddenly going to have a normal FEV1.  But if I knew that a daily pill might slow or even halt the downward slide of lung function that has up until now seemed inevitable…I’d be pretty psyched!  I might even volunteer to write an article about it.  I only have one suggestion for Vertex Pharmaceuticals.  Will you please give these things proper names?

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