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Seriously, how close are we to a cure? CFF State of the Science Update 2015

Monday, April 13, 2015

Several weeks ago, I attended the Cystic Fibrosis Foundation's Volunteer Leadership Conference in Virginia. 

One of my very favorite parts of VLC is the State of the Science because it is when the CF Foundation provides their annual science update.  I wanted to share what I learned there (feel free to watch the entire conference here:  

There was a lot packed in to a small amount of time.  But I narrowed down the most important parts of this update to four main points of interest:

1.) Kalydeco Update
2.) An update on the Combo Drug (hopefully to be out this year)
3.) VX-661
4.) 2nd Generation Modulators
5.) Stem Cell Biology/Gene editing
6.) Personalized/Precision Medicine

The "State of Science" at VLC was presented by (from L to R) the Cystic Fibrosis Foundation's CEO Bob Beall, Preston Campbell, the CFF's Executive Vice President for Medical Affairs, Michael Boyle, Director of Adult CF Programs/Associate Professor of Medicine at John Hopkins Hospital and Bill Skatch, the CFF's Vice President for Research Affairs.

This picture demonstrates the five ways the CFTR mutated genes work incorrectly.  At the bottom, it shows how many people have that particular gene.

Bennett's F508del gene is a Class II (87% of those with CF have at least one gene in this group). Bennett's 621+1G>T gene is a Class I (12% of those with CF who have at least one mutation in this class).

There are two ways that scientists are working to help fix the underlying reason for Cystic Fibrosis. These two ways or types of medicines are called "potentiators" and "correctors."  This explanation is super important to understand in order to follow the rest of the Scientific Update.

For those types of CF mutations where the protein is already sitting up at the surface, ready to turn on or ready to work but doesn't work correctly, "potentiators" are considered most helpful.  "Potentiators" are what we call medicines that can open that channel up or potentiate the channel because the channels are already there, they just need help with opening that gate up.   Kalydeco is a potentiator drug.

The more challenging problem in CF, but the one that scientists are making the most progress on, are those genes that benefit from medicines called "correctors."  "Correctors" are those medications that seem to benefit those with CF mutations in Class II - where the protein has not even made it up to the surface yet.  In order to fix this mutation, the protein needs to be moved up to the surface.  The reason it's called a "corrector" is because it corrects the folding so the cell allows it to get to the surface and work.  Lumacaftor is the first corrector drug.  It is believed to benefit those with F508del/F508del mutations.

KALYDECO UPATE: Kalydeco (also known as Ivacaftor) looks like it benefits those with CF mutated genes in Classes III, IV and V.  Another 20 mutations are just about to start being tested in clinicial trials for benefits of Kalydeco.  Kalydeco alone may benefit about 15% of those with CF.

COMBO UPDATE: There is excitement in the CF community because in a few months, the FDA will decide approval on the combination of Ivacaftor (Kalydeco) and Lumacaftor for those with two F508del mutations. Data shows that patients clearly benefit from the Combo drug (although, this drug is not strong enough to fix the condition for those with one delF508 mutation).  If approved, those with the most common CF genetic mutation would take a pill twice a day.  The FDA has set the date for May 12th to meet about the Ivacaftor/Lumacaftor combo.

VX-661 UPDATE: For those, like Bennett, who are not expected to benefit from Kalydeco or Lumacaftor, there is another set of CFTR Corrector, VX-661, that is hugely promising.

I learned during this talk that VX-661 is a drug that the CFF accelerated because of its potential.  Apparently VX-661 wasn't supposed to be in clinics until 2017 or 2018 but the CFF saw potential for this drug and decided to put in 25 million dollars towards getting this to patients faster.

Currently in clinical trials, VX-661 looks like Lumacaftor but works better, has less drug interactions and has a better safety profile overall.

This is a drug Bennett should benefit from. So, I'm very hopeful! They did not give us an idea of when it would be on the market but I do know they are in Phase III clinical trials so happening quickly!

Studies show that the benefit from VX-661 is even better Lumacaftor and may work with those with just one F508del mutation.  So, it could benefit up to 87% of those with Cystic Fibrosis.

Here are the current upcoming studies for those with one F508del mutations.  There is a study for those with two F508del mutations, a study for those with F508del and a Class I mutation (stop codons), a study for those with F508del with a Class V mutation and a study for those with F508del and Class IV mutation.

That covers about 90%+ with Cystic Fibrosis.  I am so very excited!  I have looked in to getting Bennett in one of these studies but, from what I found, these studies are happening in children and adults over the age of 12.  

2ND GENERATION MODULATORS UPDATE:  I'm not just excited for VX-661 for Bennett.  I'm also very excited about 2nd Generation Modulators.

This is a part of the Update that literally went so fast I neither understood it nor valued it.  In fact, I have had to spend several hours rewatching video from VLC over and over again so I could type what Dr. Skatch shared during this few minutes on stage.  This is amazing stuff but it's complicated.  So, as not to mess it up, I'm just going to write what he said had you listened to him speak.

Here is 2nd Modulators explained by Dr. Bill Skatch (pretty much verbatim):

"It's very clear that alot of effort has been put in to CFTR.  And the patients that have these mutations are going to have tremendous benefit.  But some of these things are going to take time and certain mutations are not going to benefit from these correctors. So to reach that 100%, there are several paths we are taking.  One path is to look at other types of treatments or channels.

To explain, you have nice cilia beating and mucus is moving along in the lungs of a healthy patient. But in a CF patient, where there is a defect, that water layer shrinks so cilia can't beat and mucus piles up up.

One of the strategies is to think: are there other ways we can improve that water layer?  Can we restore moisture to the lung that doesn't require CFTR modulator compounds?

So, the CFF is working on several projects that are designed specifically to target for other proteins, not just CFTR.  One of those proteins is a sodium channel.  

As you know, chloride moves through CFTR.  But sodium moves through another channel, that you can consider to be a partner of CFTR.  And it turns out, one of the reasons that water layer shrinks down and collapse is because the sodium channel absorbs too much sodium.

So we are working several companies to develop molecules that will specifically target the sodium channel (it's called ENaC).  If we can shut down that channel, there is good evidence, in the laboratory, that the water layer can be restored. We believe that that will help cilia beat better and help move that mucus up.

The nice thing about this is: it doesn't matter what your CFTR mutation is.  This type of therapy has the potential to work in all CF patients - because all CF patients share that problem with same dehydrated mucus and this very thin layer of water.

So the CFF is working with several companies such as Parion that have very exciting new molecules that can specifically attack the sodium channel."

"The corrector molecules were once a crazy idea - to take a broken protein, that doesn't move through the cell, to repair its folding, get it to the surface and then turn it on.  That seemed really impossible 15 years ago.  But now, in the test tube/laboratory, this 2nd corrector molecule is showing that is as good as Kalydeco.

What's happening now is there is a very large effort, in terms of 2nd generation screening.  There are multiple companies looking at new and better chemical compounds.  Millions of compounds were screened last year.  We are looking at very diverse compounds.  We are thinking, the more we look, the better chance we have to finding the best molecule.

We also got much smarter, in terms of how we are screening.  We are using human airway cells to try to screen how these molecules work.  We are targeting these molecules to specific parts the CFTR protein, because we now have an idea of how the protein is broken.

Our goal is develop modulators - correctors - that will be as good as Ivacaftor in the F508del patient population.

What does this look like?  We are thinking, as we move in to the future, we are probably going to need, for many of the folding mutations, two correctors plus a potentiator - a three drug combination.

That will hopefully to get us where we need to be.  This will hopefully open the door for a large number of CF patients."

"If everything goes perfectly (15% of potentiators + 50% F508del homozygotes + 40% F508del Heterozygotes), that covers about 95% of those CF patients.  But it leaves 5% of CF patients that don't make CFTR that can be potentiated.  

This 5% is very complicated - nonsense, stop-codon, splicing variants, deletion variants, etc.  These are going to require a completely different type of therapy. One way to go after these is to develop therapies, therapies that are applicable to all patients (such as the 2nd generation modulator idea). Another way is we can target these mutations very specifically.

If we look ahead, what do we want to do?  The goal is to take the therapies we have and make them better until we have a cure for all patients."

"We know what the problem is.  The problem is in the gene, the DNA.  It's a mutation, small deletion, which is altered.  That mutation is translated into RNA. And the RNA in the cell is a template from the DNA.

So, if you have a mutation in your DNA, that mutation is then translated in to the next step of the biological problem, which is RNA.

RNA is used to make protein.  So the defect of the the RNA is then translated in to the protein defect. And the protein, if it's CFTR, is what causes symptoms.  So, this paradigm is very basic in biology.

For the past 50 years, the CFF has been working on the symptoms - better therapies for the the mucus, better therapies for the infection, better therapies for nutrition.  This has had a tremendous burden on the patient in terms of the amount of effort and time.  But it was had tremendous affect on  lifestyle and lifespan and making life better.

We are now entering in a very early stage, of moving backward along a path to get to the more basic defect.

When we talk about correctors and modulators, we are talking about protein-based therapy. Those molecules work on patients that have specific types of protein abnormalities.  But some mutations don't allow the protein to be made.  In some patients, they don't make the so modulator therapy will never work.  Those patients need different types of therapies.  One of those therapies is to move back on more layer is the RNA.

That RNA molecule may be manipulated in a couple of ways.  One, in a project we are working with Shire, is to simply take normal RNA and put it back to patients.  If we can take normal RNA in to cells, then those cells will make normal protein and that normal CFTR will function in any patient.

So there is a lot of challenges for this.  But we are very encouraged by the results of Shire.  Shire is moving very quickly. We hope to have RNA therapy coming in to patients within a year to two, maybe by the end of this year, but hopefully in 2016.  We just committed 15 million dollars to that."

STEM CELL BIOLOGY/GENE EDITING:: "The CFF is also working on ways of addressing stop codon mutations, specifically.  The CFF recently put in 6.7 million dollars into a company called PTC to try to develop a molecule that will help the ribosome read through to those stop codons to make the protein.

It was unfortunate that that molecule did not work as well as had hoped.  But have not given up. We are going back and starting several collaborations with new companies to look for better and more effective molecules that will work on these stop codons and nonsense mutations, specifically, to allow the protein to be made, which then can be potentially augmented by potentiators and potentially correctors, if the protein doesn't fold correctly.

How about the one time cure? If we could go back to the DNA...if we could prepare the DNA in the cells that need to make CFTR, then those cells would make normal CFTR and all of this process would be completely normal.

Five years ago, this was an absolutely impossible dream. But what has happened in the last five years is there is some very exciting technology, where you can go into the cell and highly specifically target regions of the protein, regions of the gene, that are defective and repair those defects.  This is called gene editing.

There are a couple of ways to go back about this.  There are a lot of technical difficulties to make this work.  But this is tremendously powerful and really provides, for the first time, the ability to go into the cell and remove the CFTR defect.  Instead of treating the disease, this is essentially removing the disease.

One way this might work is to take cells out of the lungs of patients, identify which cells are the critical cells needed to restore the airway, go in to those cells and edit the CFTR gene so that now it makes that normal protein and put those cells back in to the lungs of patients - have those cells grow, reproduce and populate the airways, then it would be possible to basically eliminate the need for correctors, potentiators or any other kind of therapy

Just last week, we brought 30 investigators who are experts in stem cell biology to the CFF.  We had a fantastic discussion about what cells we need to target, how to the cells behave, how do we grow them so they can actually graft in lungs etc.

I will say there are many obstacles but it was a very encouraging discussion. There are a group of scientists out there that are really excited to work on this problem.

In December, we invited a group of scientists to the Foundation to talk about gene editing.  We are bringing those people into the CF field.

This is where we would like to go.  This is a long project. There are many obstacles. So, we see this as a long term goal but as a way to totally transforming the disease.

As we look forward, we are looking personalized medicine or precision medicine.

One of the key roles is the maximize the function of CFTR.  This means we take the patients particular mutation, their genotype, and we target therapies that will maximally allow that genotype to function.

We want to combine the best types symptomatic therapies with the best type of genetic therapies (protein-restoration therapies).

Many patients today are going to continue to need symptomatic therapies.  We are going to continue to work on better therapies.

We hope as we bring these new types of therapies to younger patients in children and restore CFTR function, then those individuals will never need any type of symptomatic therapies.  This is our overall goal."

This was a fantastic update.  Here's the bottom line: My heart is overwhelmed with hope.  For most of those with CF, we are SO close!!  And no one is going to be left behind.

One Response to “Seriously, how close are we to a cure? CFF State of the Science Update 2015”

    Besides CFTR correctors, we also have important advance in mucolytic front.


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