Sunday, October 14, 2012

NACFC Update: Exciting new methods of Fighting Pseudomonas infection in Cystic Fibrosis!

CFTR modulator data has taken center stage in my Conference blogs so far, but I'm equally excited to summarize some other really interesting talks about new methods to treat Pseudomonas infection in cystic fibrosis.  As we know, chronic infection in the CF lung leads to loss in lung function and bronchiectasis (irreversible widening and loss of elasticity in the airways) over time.  Even if you have an effective antibiotic to treat Pseudomonas, very little medicine is able to penetrate the “biofilm” inside CF lungs to reach the infecting bug.  Think of the  biofilm as an impenetrable layer of super-slime.   When a pathogen enters the CF lung, it finds a nice cozy home in the already thick, sticky CF mucus.  Tissues become inflamed and as cells die, long strands of DNA are left behind, that further bind mucus together.  This makes the environment even more hospitable for bacteria and so the vicious cycle of inflammation, infection, and impaired mucociliary clearance in the CF lungs has begun.   Chronically infected areas of the lungs begin to form these “biofilms” that can eventually cover the entire inside surface of the airways.  Searching for new ways to penetrate the biofilm have yielded some exciting new lines of potential treatments for CF infections.

Before I get into this new research, I want to tell a short story about a job I had in college and I promise it will all make sense in a minute.  One summer I worked with an Entomologist (scientist who studies insects) at WSU.  We worked with local organic farmers to help them eliminate problematic bugs from their crops without using pesticides.  For example, if a farmer had a problem with a particular beetle eating their potato crop, they would hire us.  Our solution was to introduce a different insect to their fields, which didn’t eat potatoes, but absolutely loved eating those problematic beetles.  After the beetles were eaten up, the introduced insects would move on, because their food source would be depleted.  By contrast, if a pesticide had been used to deal with the problem, ALL the bugs in the field would have been killed, even the beneficial ones.  Plus, there would have been a bunch of chemical toxins introduced to the soil and crops.  This natural method of pest control made a lot of sense to me.  Now back to Pseudomonas…

Abstract 270: Rational Design of a Pseudomonas Aeruginosa Bacteriophage Therapeutic and its Efficacy in a Murine Lung Infection Model.   Presented by David Harper Ph.D
Just as there are countless viruses that can specifically infect humans, there are also millions of viruses in our environment that only infect bacteria—bacteriophages.  Bacteriophages are already present in our bodies by the trillions and are completely harmless to us.  They can only survive if they are able to infect a “host bacteria.”  Bacteriophages kill their host immediately upon infection.  Bacteriophages are also host specific, which means there are certain varieties that only infect Pseudomonas aeruginosa (Pa).  I certainly like the idea of tiny Pseudomonas assassins (trigger 007 theme music)!  This line of research explores whether using a bacteriophage cocktail specific for Pa might be an effective way to treat chronic Pa infection in the CF lung.  The investigator used 3 Pa specific bacteriophages in his “killing cocktail” and administered the treatment to mice infected with Pa.  What he found was really amazing.  Unlike antibiotics, bacteriophages easily penetrated the biofilm.  They proceeded to infect and kill the Pseudomonas, and even disrupted and disseminated biofilms.  Because bacteriophages have no interest in infecting anything besides their specific target, there was no collateral damage to the airway tissues.   In the mice, it was shown to be an extremely effective at killing Pseudomonas previously THRIVING in the biofilm.  For a bacteriophage, visiting a biofilm is sort of like going to an “all you can eat buffet.”  They love it!  There are bacteriophages specific to both mucoid and non-mucoid strains of Pseudomonas, so I guess what I’m saying is—You’d better keep both eyes open Pseudo…there might be a new bug getting introduced into the potato field!  I think the guy who came up with this idea is a freaking genius and I sincerely hope we can see something like this translate to human infections in the near future.  There are plenty of negative issues surrounding chronic antibiotic use, including: bacterial resistance, unpleasant side effects, ineffectiveness because of inability to penetrate biofilm, and more indiscriminate killing of bacteria (they kill the good guys along with the bad guys).  This bacteriophage treatment technique could bring something totally new to our tool kit for treating CF, and might even help solve one of the biggest issues facing the world of medicine right now—antibiotic resistance.  I haven't been able to stop thinking about this research since I watched the presentation...or my summer killing problematic bugs in potato fields! 
Studies are planned in humans, but no timeline was given yet.  This research was performed by Blake, K.L; Henry, M.; Debarbieux, L.; McConville, M.L.; Prosser, I.M.; Parracho, H.M.; Enright, M.C.; Harper, D.R.  AmpliPhi Biosciences, Bedford, UK and Institut Pasteur, Paris, France. 

A second exciting presentation regarding the fight against Pseudomonas infection was:

Abstract 268: ALX-109 Potentiates the Effect of Tobramycin at Killing Pseudomonas Aeruginosa Biofilms on Human Airway Cells.  Presented by Sophie Moreau-Marquis, Ph.D. 

For reasons unknown to researchers, the iron concentration in the CF lung has been found to be 400x higher than in the non-CF lung.  Iron has been shown to promote the growth of Pseudomonas biofilms on airway cells.  This research looked at the possibility of chelating excess iron in the lungs to allow antibiotics to more effectively battle Pa infection.  Chelation is a process where one chemical combines with another, to render a new stable model that is not reactive (it sequesters, or holds the iron captive so it can’t react with other molecules).  ALX-109 or Alaxia, is an iron-binding glycoprotein, that has recently been granted “orphan drug” status by both the FDA and EMA. 

In the study, ALX-109 was combined with Tobramycin and tested on Pa strains isolated from the sputum of CF patients. The Tobi + ALX-109 combination significantly disrupted biofilms.

It was concluded that an inhalation therapy combining Tobramycin with ALX-109 may be beneficial to CF patients infected with mucoid clinical isolates of Pseudomonas.  This research was conducted by Moreau-Marquis, S.; Stanton, B.A. Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH.  Phase 1 clinical trials are planned.

I love the idea of getting some new powerful weapons to fight CF infections and I encourage anyone interested in participating in clinical trials to sign up for email alerts from the CFF here!

We finally made it home from Orlando this afternoon.  What a long trip from Orlando to Northern Idaho!

Saturday, October 13, 2012

NACFC Update--Caring For Patients on Kalydeco: Emerging Topics in CF Management.

Brock and I started off today's session by filming an interview for the CF Foundation about the positive impact of Kalydeco on Brady and our entire family.  We also filmed "My Dream for CF" videos.  After that we headed to the third and final Plenary Session of this event entitled: Adherence...Where's the App for That?  I will go into the details of this session later, but will say this--new therapies and medicines are of absolutely zero use if they do not get utilized by the patient.  As a parent of a young CFer, I understand that there are challenges in maintaining the rigorous CF treatment schedule.   This session focused on ways to help patients overcome those barriers to become more compliant with their treatments, which ultimately leads to better health outcomes and fewer hospitalizations.  There are all sorts of cool new apps and web based technologies coming along to make staying adherent EASIER on the patient.  The future of tracking your PFTs may become as easy as simply blowing into your smartphone, which will then automatically send the data to your care center's database.  How awesome is that? 

We attended talks all morning, which I will also summarize at some point, but right now I want to focus on the most interesting information I got today, which came from a "Luncheon Roundtable" session.  There are dozens of highly specialized topics to choose from in these sessions, which are discussed in an informal manner by the 10 or so attendees that fit around your table.  There was no question which discussion I wanted to be a part of--Caring For Patients on Kalydeco: Emerging Topics in CF Management.  Each table has a "moderator" or expert who leads the discussion.  Our moderator was Dr. Frank Accurso M.D. University of Colorado, Denver.  We didn't have a ticket to attend this talk, but eventually got seated and entered the discussion already in progress.  We had a nice variety of guests at our table, consisting of nurses, a Pulmonologist, a GI doc, and a pharmacist.  When we were finally seated, we were asked to introduce ourselves and describe why we were there and what we hoped to learn.  When I announced that we were parents of a 5 year old that had been on Kalydeco for over 8 months who showed a drop from 105 mmol/L to 17 mmol/L on Kalydeco and a CT scan showing "no visible damage," and our goal was to learn how to proceed with his care...well, we suddenly became the focus of interest for everyone else at the table.  I'm not sure what they were discussing before we arrived because as soon as WE got there, we were bombarded with questions.  First of all, every one of them was surprised that Brady had Kalydeco and wanted to know first and foremost how we had obtained it.  I described that we had been discussing Kalydeco with Brady's Pulmonologist since infancy and had prepared a strong case for his medical necessity of the drug.  We didn't do anything special, or secret...we simply obtained a prescription from Brady's Dr., submitted it to CF Services Pharmacy, submitted the required "prior authorization form," and provided a load of Brady's medical information at the request of our insurance company.   It was approved and shipped to our house just like any other medication that Brady takes (except you have to sign for this super expensive one!).

On a side note, I think there is a big misconception out there that no one can get Kalydeco unless they are G551D and over 6 years old.  That simply is not true.  The only thing you need to obtain Kalydeco is a prescription and a way to pay for it (either by being INCREDIBLY independently wealthy or having insurance coverage).  Of course, getting insurance coverage for "off-label" cases has proven to be the tricky part, but many patients/parents don't even try because they have been told that it is "impossible."  Everyone told us that also, but I hope our experience illustrates that the "impossible to get" concept is BULLSHIT.  Vertex pharmaceuticals has ABSOLUTELY NOTHING to do with who is able to take Kalydeco.  They can't provide any financial assistance to patients attempting an off-label Rx, because they don't want to get sued, but drug makers do not provide medicines to patients directly (except on compassionate grounds in the case of Kalydeco), pharmacies do.  I mean, do you think that every time a new prescription is submitted, that the pharmacy calls Vertex to ask if it is OK??  Hell no.  That is not how it works.  All the pharmacy cares about is how you are going to pay for it.  If you have insurance coverage, you are golden.

After describing all the incredible changes we've seen in Brady, everyone turned their focus back to the topic of--How do you move forward with treating CF patients on Kalydeco?  Should the regular schedule of medicines and therapies be maintained, or is it OK to drop some?  Are there some patients that may eventually be able to stop ALL of their regular CF therapies?  I wish I could say that there were clear answers to these questions, but the consensus at the table was that NO ONE KNOWS!  Everyone agreed that the treatment of these new Kalydeco patients must be addressed on a case-by-case basis, with the most important factor being how much permanent lung damage/scar tissue/bronchiectasis each patient had obtained before the initiation of Kalydeco treatment.  The idea is that the Kalydeco has the ability to halt further progression of the disease in certain patients (like those with G551D or other gating mutations).  If a patient starts Kalydeco BEFORE much damage has occurred, there is an opportunity to drop some of the regular CF therapies.  On the other hand, patients in the end stage of disease with considerable scar tissue may need to remain on all of their maintenance meds in addition to Kalydeco.  Think of it like this--if someone smokes for 30 years and then stops, they will certainly experience an improvement in their lung function, but the lungs have suffered some permanent damage and will never reach the same level of function as someone who has never smoked in their life.  It is a similar situation with CFers on Kalydeco.  With that  being said, the discussion then moved back to Brady's case and the question then turned to, Which medication to you remove first and why?  Is it more important to stay on Hypertonic Saline or Pulmozyme?  What about airway clearance?    We described our rationale for choosing to slowly wean Brady off of Hypertonic Saline first (which Brady began at 20 months old, and used to do twice a day).   Hypertonic Saline is designed to temporarily rehydrate the airway surface liquid (ASL) on the lining of the lungs, allowing for better clearance of particles and pathogens.  Kalydeco has also been shown to rehydrate the ASL, but through the mechanism of restoring proper chloride transport out of epithelial cells by activating CFTR function.  We decided that because Pulmozyme works by a different mechanism of action (cuts up long strands of DNA left behind when cells die in the lung.  Those strands can contribute to the formation of biofilms by binding mucus together).   Some people at the table agreed with us, others thought that Pulmozyme should be the first of those two meds to go because of its high cost.

We also discussed whether patients might be able to clear infections from their lungs and no longer require antibiotic therapy.  Most agreed that they would need to see more convincing evidence than a "clean" throat or sputum culture to be really sure that the infection had been cleared (there is lots of evidence that throat cultures do NOT give an accurate picture of what is growing in the lung).  Bugs residing deep in the lower airways are often not reflected in throat or sputum culture, but can be picked up by techniques like broncheoalveolar lavage (BAL).  BAL is an invasive technique where a liquid is squirted inside the lung and then collected and cultured.  You can imagine that BAL is more difficult to perform, but yields a much deeper understanding of the bacterial environment inside the lung, than swabbing the back of the throat.  Again, no one knew any single correct path forward.

This year, new data was presented that Kalydeco changes the pH in both the GI tract and the airways, restoring the body's natural ability to kill bacteria and pathogens.  CF patients typically have a more acidic environment in their airways and gut because of the body's impaired ability to secrete biocarbonate (a base that neutralizes acid).  The more acidic the environment, the less natural "killing power" your body has.  Patients taking Kalydeco were able to restore normal pH in their airways and gut, which leads us to believe that complete eradication of infection is at least possible

At this point, Dr. Accurso announced that he had to leave for a different meeting, and he brought in a new moderator for our discussion.  I desperately asked him to answer some questions about the "trials of 1" initiating in Denver, before he left, but his response was that I could email him with those questions...which I will certainly do.  I'm so sorry I can't provide more details about this. I promise I will try to get those answers!  Again, I wish I could write more this evening, but I only have a few minutes left to get ready for the "CF Prom" tonight!  One last important little tidbit that I forgot to mention earlier is that I asked Dr. Accurso why we saw Brady's sweat chloride first drop from 105 mmol/L down to 48 mmol/L, and then saw a further decrease down to 17 mmol/L.  He asked me if Brady had eaten pizza or some other super salty food before his 48mmol/L result.  I questioned why that would matter and he revealed to me that salt intake can affect sweat chloride results.  The take home point is super excessive sodium intake can artificially increase the sweat chloride score and should be avoided just prior to the test (like the day before).  I'm not suggesting that you eliminate salt intake--rather, adjust to more "normal" dietary sodium rather than the stardard high salt intake typically recommended for CFers to get a true measurement.  That was news to me!

Our flight leaves tomorrow morning at 7:30 a.m.!  I miss Brady so bad!! 

Friday, October 12, 2012

Plenary 1

It will probably take me several months of blog entries to detail everything I want to say about this year's NACFC, but I have to start somewhere.  This entry will summarize what was discussed in yesterday's Plenary Session.

Plenary Session 1: Reversing the Basic Defect: A Vision for the Future
Speakers Steven M. Rowe, M.D., MSPH and William Skatch, M.D.

In my mind, the overarching theme of this talk was: OK, we've fixed G551D, we think that Kalydeco will be expanded to all Class 3 and 4 mutations, and some others with residual CFTR.  Here is how we are going to go about figuring out a similar treatment for every last CF patient.

First, Dr. Rowe presented some really interesting information from the GOAL study, which is an extended study on Kalydeco in patients to examine secondary endpoints not included in the previous trials.  They are interested in understanding some of the unexpected/unexplained effects that have been seen in patients on this therapy.   Exactly how has CFTR modulation affected the patient's mucociliary clearance (the ability of those little hair-like projections inside the lung to sweep particles and bacteria out)?  How does Kalydeco affect intestinal and/or lung pH and sweat rate?  His focus was on the mucociliary clearance (MCC) endpoint.

He showed how the typical CF lung has severely impaired MCC because those little hairs are bogged down by thick mucus and basically just stop moving all together. This is part of the vicious cycle of infection and inflammation that takes place in the CF lung.  When the cilia stop moving, the body's natural ability to rid the lung of harmful pathogens becomes severely impaired.  They were able to show that CFTR modulation with a drug like Kalydeco could restore mucociliary clearance and movement of cilia in patients.  Boom.  This is the first ever data to show a marked improvement in MCC in CF patients. 

He also announced that the Kalydeco trial for 2-5 yr. olds "officially" had been cleared to begin enrolling patients as of yesterday (10/11).  If you are interested in this trial and you haven't already spoken to your CF care center, do it now.

He also discussed how Kalydeco might be effectively used in other CF populations and how they plan on moving forward with testing this concept.  They are using two approaches: 1) The Genotypical Approach and 2) The Clinical Approach.  This means that they are using genotype information (which mutations the patient has) to identify some candidates (for example, the upcoming trial for R117h, which is a class 4 Conductance Mutation).  Other candidates might be found because they clinically present with symptoms suggesting some residual surface CFTR function--such as those who are pancreatic sufficient or have lower sweat chloride scores (in the 80 mmol/L) range.  He went on to describe the small study that will be taking place in Denver which is the new "trial of 1" design format.  In this format, there is no placebo and the efficacy of the treatment is based on the patient's response.  I am hopeful that this type of study design will open up a lot of doors for future trials in rare mutations, who might otherwise be excluded from large scale studies.  This is good news for heterozygotes because it is so incredibly difficult to predict how those patients will react, and right now they are being excluded from taking part in CFTR modulator studies.  We've got to change that!

Class 1 Mutations:
Next, he summarized the results of the Ataluren trial.  I wrote about this briefly yesterday.  Basically, Ataluren didn't produce statistically significant study enpoints, and also exhibited an antibiotic interaction with Tobi and other aminoglycosides--which completely nullified any treatment effect.  He mentioned a new compound called NB124 that seems like a promising candidate for promoting translational read-through of the protein to produce a full length functional CFTR.  He also discussed combining this compound with a potentiator to enhance its effect.  Getting NB124 to market is going to take some time.

Class 2--F508 and others
They are super focused on addressing the F508 mutation since 50% of the CF pop. is homozygous and 40% of the CF pop. has at least 1 copy.  F508 exhibits several defects in the cell which cause its ultimate dysfunction: 1) Improper protein folding and assembly, 2) Gating defect if any CFTR does manage to reach the surface, and 3) Instability at the cell surface (increased cell death/turnover).  I wrote a detailed blog about this after last year's NACFC, and this year they understand in even greater detail the various issues with F508.  Multiple corrections must be made for this protein to successfully form, move to the cell surface, and then WORK once it gets there.  The VX-770, VX-809 combo is able to rescue approximately 30% CFTR function, enough to produce meaningful clinical changes in patients.

Class 5 and 6 mutations
I didn't catch any concrete details on how to address these two classes, which are not as well understood as some of the others.  He concluded that "further studies" will be needed for all heterozygotes, which encompasses ALMOST everyone in these two groups.

Lastly, Dr. Rowe was excited to announce how many new companies had started CFTR modulator programs like: Pfizer, Genzyme, and N30.  Vertex DEFINITELY needs some competition! Now it is a race to the finish line!

Dr. Bill Skatch spoke next.  He is a member of the "CFTR Folding Consortia" as well as the "CFTR Structure Consortia."  In other words, he walks, talks, and dreams CFTR!!  His talk was very technical, but featured some of the coolest graphics I've ever seen to describe the steps needed to produce functional CFTR in the body.  His talk went much deeper into the details of F508 dysfunction.  He explained that CFTR is like a "molecular jigsaw puzzle."  There are twisted pieces, globular pieces, and straight pieces.  They must all be the correct shape and come together in a step-by-step fashion.  It is such a complex process that it takes the human body 7-8 minutes to make a single CFTR molecule!  There are other proteins called "chaperones" that help regulate folding and speed.  They are learning that these chaperones are an important part of this process.  He described that the final protein must exhibit exactly the right amount of stability, and flexibility at the cell surface to keep from "unraveling" and degrading to become useless in Chloride transport.  He described in great technical detail how they can test this stability by measuring how much energy (in the form of heat) it takes to cause the protein to unravel and degrade.  They need to make CFTR stable enough to remain functional and intact at human body temperature (F508 mutants are unstable at body temp).  He explained the "ceiling" affect that single corrector combinations inevitably hit because one corrector can't take each of these aforementioned problems into account.  Then he described how combining several correctors to account for the multiple dysfunctions was the path to restoring 70-80% functional CFTR for F508.  They know what they are doing. I am headed out the door to a dinner reception!  I may post more later depending on how much wine I drink...Please excuse any errors or typos.  I am trying to be fast!

Thursday, October 11, 2012


It is hard to believe that so much activity and information can possibly be packed into a single day...This morning Brock and I kicked off the NACFC with a breakfast meeting with Dr. Beall.  I get incredibly nervous when I know I will be meeting with Bob, but after that first hug and bout of tears, it only takes minutes before his demeanor puts me at ease.  We took the opportunity to share all the details of our Kalydeco experience with him and gave him the book we made filled with the "true Kalydeco stories" from other patients.  Hearing those success stories is extremely rewarding for Bob and if you contributed to the book, Thank you.  He truly loved it.  I feel like a big hog, because all the "thanks" has been given to me, even though all I did was assemble the stories.  When I get back home, I will post some pics of the final product.  It was such a privilege to put together so many beautiful stories. 

* The most exciting and fantastic news that I have to report from today is the positive buzz regarding the VX-809/VX-770 combo!   Tweaking dosages of both compounds has enabled them to reach the statistically significant improvements they were looking for.  They were able to rescue approximately 30% CFTR function, which is sort of the magic number to see big clinical improvements ((Kalydeco rescues approximately 50%, for perspective).  HELL YA!!  I'm super encouraged that this combination will be progressing to phase 3 trials, and could be coming along sooner rather than later.  Even if it isn't the "magic bullet" that Kalydeco is for gating mutations, this combo could go a long way toward improving/stabilizing lung function and increasing quality of life. Isn't that what it is all about? 

* The recently listed trial on taking place in Denver for heterozygotes IS the individualized "trial of 1" or "trial in a box" design that Peter Mueller of Vertex proposed earlier this year!  It is a small initial trial, but this is really exciting news for heterozygotes, patients with rare CF mutations, or anyone who wants to see individualized genetic modifier treatments reach patients FASTER.  This will enable patients with any suspected surface CFTR activity to trial Kalydeco and decide whether the therapy should be continued based on their own body's response.  Again, HELL YA!!  

* The overall feel I got today regarding Ataluren, is that this drug hasn't lived up to expectations.  There was some discussion about the possibility of combining a drug to increase translational read-through of the CFTR protein (like Ataluren), with a potentiator like Kalydeco to boost results... But, it was mentioned several times that they already have discovered compounds that work BETTER than Ataluren ever did at improving protein read-through.  The biggest problem with Ataluren is that it binds to the same site on the cell's ribosome as some inhaled antibiotics like Tobi and other aminoglycosides.  Basically, Tobi and Ataluren need to work on exactly the same spot in the cell...if Tobi is there, Ataluren can't bind and do its job.  Inhaling Tobi almost completely nullifies the therapeutic effect. Damn.  The Ataluren presentation was very vague and I still don't have any answers about what their steps are moving forward (I even mustered the balls to stand up to the mic and ask the presenter a question about their plans for further trials or to combine with another compound and wasn't given a conclusive answer.).   Again, I'm not certain about the future of Ataluren, but my overall feeling is pretty negative about this drug reaching the market to treat Class 1 mutations on its own.  The primary trial endpoints were not met, and the antibiotic interaction problem may be too large to overcome.  Again, the information given was quite vague, and I just want to reiterate that this blog is my interpretation of what was presented.  It was never directly stated that Ataluren won't move forward.  In their words, "we are working with regulatory bodies in the U.S. and Europe to determine the best path forward."  What does THAT mean?? 

* Lastly, I want to mention that the first Plenary session today was amazing.  There was a SHORT celebration of the success of Kalydeco, followed by details of their plans to move forward to treat the rest of the CF pop.  They are impatient and understand the urgency to keep progressing.  They now understand, in dizzying detail, the dysfunction of F508 and have a road map for correcting it.  As mentioned earlier, there is positive buzz about the VX-809/VX-770 combo, but the "second generation" of combos already being tested in the lab have the potential to rescue 70-80% CFTR function--far exceeding the effect of Kalydeco for gating mutations.  To achieve these results, the second generation drugs must address the multiple dysfunctions that this mutation presents: 1) folding, 2) stabilization, and 3) gating.  I said it last year and I'll say it again: THEY HAVE IT FIGURED OUT.  IT IS A MATTER OF TIME AND MONEY.  I'm more optimistic than ever after a full day of lecture.  I have so much more to say, but it is after midnight and I have another full day tomorrow.  I plan to write summaries of the individual talks I attended today, which focused mainly on F508 correction and early CF lung disease.  Brock and I also attended a fancy dinner this evening, where my Kalydeco tattoo was finally uncovered to be appreciated and photographed by many : )  The speakers at this dinner gave moving presentations that didn't leave a dry eye in the house.  I am experiencing emotional overload.  I may have finally exhausted myself to the point of sleep.