Dodging Bullets

In the interest of full-disclosure, I feel I need to give an update.  Something interesting happened since my last blog post—Brady got sick.  Let me preface this entry by saying that Brady has only had a few minor colds in his lifetime, and a case of Roseola as an infant, but has never had a serious respiratory exacerbation before.   Then, about a month ago, he got hit with a bad virus.  First, vomiting and diarrhea for a full 6 days.  Stomach bugs are no fun, regardless of the circumstances, but I was expecting the illness to run its course pretty quickly.  It didn’t.  This led me to an important question:

The Crisis

What the hell do you do when a patient is unable (for whatever reason) to take their Kalydeco orally?

During the course of the 6 day stomach bug, Brady missed several doses of Kalydeco.  Other doses were thrown-up after just a few minutes, and none of the doses were taken with an appropriate amount of fat (so very little drug was probably absorbed).  Brady was monitored closely by his pediatrician for dehydration and given Zofran to help with nausea.  As the days passed and the missed doses piled up, I began to see some of the symptoms of cystic fibrosis reappear in him.  When he began taking Kalydeco, the sinus inflammation/polyps shrunk within just a couple of days, and he was finally able to breathe through his nose.  After several missed doses of Kalydeco, I could hear the inflammation returning to his sinuses just as quickly as it had left.  Of course, I had to lick the poor kid’s forehead a few times to test for the characteristic “CF saltiness,” and to my horror, it also seemed to be returning.  All I could think about was getting him back on track with his Kalydeco dosing. 

Anecdotally, I have heard several older patients/adults describe their experience in “coming off” Kalydeco as extremely unpleasant.  Some say they can feel their chest tightening and feel that old “heaviness” with just a single missed dose.  The data shows that sweat chloride levels also suffer from a rebound effect when the Kalydeco is removed—shooting to all-time highs before returning to the normal baseline level. 

As Brady’s nausea began to fade, the cough started.  It appeared this virus wasn’t done with him yet.  The cough took ahold quickly and was the worst sound I have ever heard come out of him.  It was an uncontrollable, tight, barky sounding, unproductive cough.  Bronchospasms would wake him in the night and send him into coughing fits that sometimes ended with vomiting.  During Vest treatments, he would cough until he cried and begged to turn the machine off.  It scared me so bad.  After 3 days of CONSTANT coughing, he began a course of Augmentin and a 6 day burst of Prednisone to reduce the inflammation in his lungs.  The steroids helped tremendously with the bronchospasms, but he was still coughing a lot, and the sound had turned deep and phlegmy.   We decided to add Hypertonic Saline back into the treatment schedule, 2X a day, to help clear out the gunk.  The next few weeks brought gradual improvement, but were slow going.  He is finally almost back to 100% and we have dropped Hypertonic Saline again. 

By now you might be asking: “What’s the big deal”?  I mean, ALL KIDS GET SICK.  What is so extraordinary that I had to write a whole entry about this?  For me, this was a frightening experience on a number of levels.  First of all, watching Brady’s CF symptoms reappear was awful.  It illustrated for me what an extremely powerful drug Kalydeco really is.  Kalydeco has a short half-life and is metabolized quickly by the body, which is why timely dosing (every 12 hrs.) with appropriate fat (we shoot for 20 grams) is important to maintain levels in the bloodstream.    When levels in the blood drop and CFTR function turns off again, it doesn’t take long for ol’ shitty CF to come knocking.  It really throws the body for a loop.  I asked our CF Clinic Pharmacist if there was any way to administer Kalydeco via injection or IV for cases where a patient is unable to take the med orally and was told, “Not at this time.”  I don’t even know if that is possible, since Kalydeco is a fat soluble compound.

Also, this was the first bad respiratory bug that Brady has ever had.  I know many of my readers can probably relate when I say that listening to your little CFer cough causes both emotional and physical pain.  I mean, I feel an actual stab of pain in MY chest when HE coughs.  When your kid has CF, it becomes impossible not to analyze every cough, throat clearing, snort, or sneeze that comes out of them.  Unfortunately, a cough is rarely just a cough with CF, and can signify infection with some funky organism or worse.  I began to fear that Brady might end up in the hospital with this virus—something I didn’t think I would have to face once Kalydeco was onboard.  The reality is that Kalydeco may be able to lower Brady’s sweat chloride scores to a normal range, but he still has cystic fibrosis and is just a few missed doses away from his old problems.  Very humbling.  Missing those several doses probably put a big exclamation point on the respiratory symptoms caused by the virus, but the point is…HE GOT BETTER.  He didn’t end up hospitalized and I don’t believe he has an underlying infection.  The pediatrician told me he had been seeing a lot of this bad bug in his office, with the majority of kids presenting with symptoms similar to Brady’s. 

The Lesson

I think Brady just had a bad virus, and his symptoms were punctuated by missing Kalydeco for several days.  Because Brady is a complicated case (has CF, but also has Kalydeco normalizing his CFTR function), his Pediatrician consulted with his CF specialist several times.  Everyone (Brock and I, CF Doc, and Pediatrician) agreed that it was best to err on the side of caution and treat Brady a little more aggressively.  For me, this was a scary little glimpse into pulmonary exacerbations.  Of course, there is no way to know this for sure, but I feel like this virus could have led Brady to his first admission if he hadn’t been able to re-start Kalydeco just as the cough initiated.  It feels like we dodged a bullet.  It also broke my heart to get a little better taste of what many of my CF friends/families regularly endure (and I realize it was a mild, tiny taste).  The strength of this community is unparalleled. 

The Motivation

Brady recovered from the virus just in time for our recent trip to Boise, where I had been invited to speak at a CF education event.  As we packed our bags, I recalled all the lives that CF was currently interrupting.  I wondered how many trips had been cancelled, how many school functions had been missed, and how many sleepless nights CF families had spent because of CF.  I renewed my vow to work even harder and try to do more, because we have the luxury being healthy enough to do it.  I hope I chose the right words at the education event and made an impact on some of the families there.  The clinic team in Boise is really impressive.  One of the providers there, Dr. Perry Brown, is not only administering quality care to his patients, but working on a personal fundraiser to raise money for the CFF.  We all know how busy these Docs are, so I think it says a lot that he is committed to the community on this level.  We are lucky to have Docs like him and I encourage you to throw him a few bucks to help him reach his goal:   http://www.crowdrise.com/500milesforcysticfibrosis/fundraiser/perrybrown. 

I am currently in D.C. for a CFF strategic planning committee meeting on adherence and I fly home in the early a.m.  It has been rewarding work, but I am missing my boys.  I will be avoiding all moving sidewalks in the airport tomorrow…as a precaution.  Cheers to Vertex on their recent announcement of VX-661 combo data!  http://investors.vrtx.com/releasedetail.cfm?ReleaseID=757597 

The Light at the End of the Tunnel

It is time for an update. 

We have been super busy since returning home from Spain, but I know everyone is curious to know how Brady is doing after a year of treatment with Kalydeco, so here it goes.  He had CF clinic on Feb. 28^th.  Brady practiced PFT’s at this visit, but is still struggling with his technique (he is only 5, after all), so his numbers weren’t really meaningful.  His lungs sounded great though, and he has absolutely zero baseline cough.  Brady hasn’t gained a ton of weight, like many patients do on Kalydeco, but I am not worried.  He is extremely tall for his age, and has a slim build like my husband.  His energy level on Kalydeco is absolutely through the roof—I mean, he is like a different child (a child on crack cocaine!!).  We decided that we will perform another sweat test, mostly out of curiosity (his last sweat test was 17 mmol/L!  Amazing!).  The lab has been really booked up, but we hope to get in this week or next for the test, and I should have those results to report in my next entry. 

The big question on everyone’s mind is still—“What do we do now?”  Does he still need breathing treatments and airway clearance?  What about other oral meds like Prevacid, Ursodiol, and Singulair?  We decided to keep doing his only remaining breathing treatment—daily Pulmozyme, and once a day Vest treatment.  We agreed that everyone would feel more comfortable experimenting with coming off Pulmozyme after we are past cold and flu season.  I anticipate that we may move to Pulmozyme every other day at our next quarterly visit, and then maybe stop altogether if that goes well.  Honestly, I am really hesitant.  I know that he has a clean CT scan showing no bronchiectasis.  I know he has no cough and healthy lungs…but it is just so scary.  Doing treatments is how we “take care” of our kids with CF and I’ve got a real mental block about removing breathing treatments altogether.  I just want to do the right thing for him, so we are being very cautious.  After all, the goal is not to get him off all his meds—rather, to have him achieve his best possible health, and we feel really good about his health right now. 

We also decided to hold steady with his oral meds, but agreed that it is a topic to be revisited.  At last year’s NACFC, I saw evidence that patients taking Kalydeco were able to restore normal pH in their digestive system—meaning that Prevacid should no longer be needed.  Brady still takes pancreatic enzymes, but his overall digestive function has never been better.  No stomach aches and perfectly normal looking poops (this might be too much info for those outside the CF world, but my CF peeps can appreciate this for the miracle it is!). 

As a baby and toddler, Brady occasionally had elevated liver enzymes, which is why he takes Ursodiol.  We monitor his liver function regularly with blood work, and he has maintained normal function for close to 2 years now.  Kalydeco is metabolized by the liver, and some patients report elevated liver enzymes on the drug.  For those with severe liver damage, adding a drug like Kalydeco can really stress the organ, elevating those numbers.  On the other hand, patients with a minimally damaged liver might actually be able to improve their liver function, as Kalydeco thins the thick mucus clogging the organ’s ducts.  Brady’s liver enzymes have remained in the normal range and even improved slightly since beginning Kalydeco, so we see the potential to remove the drug in the future.  I know that there are studies ongoing right now to examine how Kalydeco affects organs beyond the lungs, so I would really love to see the results of that work before we remove Ursodiol.  I expect to see some data at the NACFC next fall.   

Additionally, we are all thrilled that Brady’s serious sinus issues still appear to be completely GONE.  We haven’t seen his ENT in almost a year, and he hasn’t needed antibiotics or steroids since he began taking Kalydeco.  This is a stark contrast to the constant cycles of Prednisone, and 3X daily steroid rinses he used to need to “manage” his sinus symptoms (and none of this worked anyway.  He was well on his way to needing his second surgical sinus clean-out at age 4).  I will never forget how amazing it was to watch Brady regain his sense of smell and begin breathing through his nose after only 3 days on Kalydeco.  Today, Brady continues to breathe freely through his nose.  He hasn’t snored in over a year, and still enjoys smelling anything and everything around him. 

Basically, it was a fantastic clinic visit!  We couldn’t be happier about Brady’s health.  Kalydeco is everything we hoped it could be AND MORE! 

Brady in his new "blue lightening" super hero cape!

 

As for me, I am staying plenty busy.  I am on the Great Strides Committee in Spokane, WA and like many of you, I am working hard to build my team and fundraise for the walk.  I’m also planning a wine event to benefit the CFF this spring.  I just returned home from my second CFF Adherence Action Team meeting in Washington D.C.  It really is such an honor to work with the amazing people on my team.   Next month, we will wrap up our work with one final meeting in D.C., and our recommendations will be presented to the Board of the CFF.  As a community, we are so extremely lucky to have The Foundation.  Working on this strategic planning committee has illustrated for me how much the CFF cares about every aspect of fighting this disease, far beyond simply funding drug trials.  

As a side note, I was a little embarrassed going into the meeting this time.  On my way to D.C., I performed a running face plant on a moving walkway in the Salt Lake City airport trying to catch my next flight.  I went down hard—breaking my fall with my left cheek, leaving me with an impressive “shiner.”  I also scraped up my left knee pretty bad.  Nothing boosts your confidence more than showing up to a room full of people you admire with a black eye! 

Looks "tough" right?

 

When our Adherence meeting adjourned at 5:00 p.m., I had a choice to make: go back to my hotel room to ice my face and knee, or take a cab to the CFF Volunteer Leadership Conference in Reston, VA—a 30 min. ride from my hotel.  I hadn’t registered for the Conference because I knew I would be busy with the Adherence meeting.  I went to my room for about 5 minutes, but it was absolutely killing me to sit there feeling sorry for myself, knowing that my CF family was so close by…so I grabbed a taxi and arrived at the Conference around 6:00 p.m. (fashionably late, just in time for dinner!).  Almost immediately, I knew I had made the right choice.   I managed to track down Dr. Beall fairly quickly, and landed myself a seat next to him that evening.  This is the second time I have invited myself to a CFF dinner reception, and I figure I am probably getting a reputation as a notorious party crasher!  That evening, the CFF honored the volunteers who work so hard to fund our search for a cure.  I was surrounded by my heroes that night—and I had to fight back tears every second of the reception (sometimes unsuccessfully).  Dr. Beall told me that he had talked about Brady in his speech earlier that day and I nearly choked on my salad when the “My Dream for CF” video that I had filmed for The Foundation in 2011 came up on the big screen at dinner.  I may have been a party crasher—but I felt like I belonged there that night.  After dinner, I got the chance to meet and greet so many more of my heroes.  Most of the time, I was introduced as, “the mother of the rock-smeller,” or “the tattoo lady.”  I had banged up my knee pretty badly with my flying leap at the airport, so I had on some ugly gray tights.  Several people requested (in their least creepy tone) that I please take off my tights so they could see my Kalydeco tattoo.  


The day I got my tattoo, which reads, "Honor the Gift" and features a small blue lightening bolt and the molecular structure of the Ivacaftor/Kalydeco molecule.  What's not to love?

After 3 or so glasses of wine…I gave in and let the ol’ scabby knee and unpedicured foot out to display the seemingly famous tattoo!  It is so funny to me that my left foot is my most recognizable feature!  I tried to personally thank as many people as I could that night and shared the details of Brady’s experience with anyone interested in listening.  My heart swelled with pride and gratitude that evening and I have never been more inspired, energized, and determined to keep working. 

My hope for everyone I met that night, and for everyone reading this, is that you can see the light shining at the of the tunnel.  I know fighting CF can feel endless, dark, and scary.  I know that every minute waiting for a miracle, is a minute too long.  CF is an unpredictable bitch of a disease and I wish so badly that the combo could be available immediately.  Sharing Brady’s story and progress is important to me because the hope for the future is real and that light at the end of the tunnel is shining brighter with each passing day.  It is exhilarating to see the Vertex combo moving into phase 3 with a newly granted “breakthrough” status that could allow it to come to market even faster than Kalydeco—which was one of the fastest FDA approvals ever!  Follow the link to read about what this brand new breakthrough status means:  http://www.pharmatimes.com/Article/13-01-09/US_FDA_announces_first_Breakthrough_Therapy_Designations.aspx

Keep moving.  The tunnel may be shorter than you think.  Can you see the light? 

Pleasure and Pain

I've been thinking about how to write this entry for weeks and I still don't have the answer, so I'm just going to start...  Right now I am in Spain with Brady, my husband, and my mother.  We have been here since Christmas eve.

A little back story--In 1998, I participated in an international exchange program to The Netherlands.  I became great friends with my roommate there--a Spanish girl named Neus.  I ended up spending Christmas with Neus and her family in Valencia in '98 and then stayed with them in Spain for the summer following our school year.  The time I spent here as a young woman will always be cherished as one of the most amazing experiences of my life.  Neus has come to visit me in The States many times since then and we have maintained our friendship through the years.  I never dreamed it would take me 14 years to make it back...

Neus and I in 1998

From the time Brady was an infant, I had the hope of VX-770.  We knew that if we could keep Brady's lungs healthy until the drug reached the market, he might be able to enjoy a long, healthy, relatively normal life.  As many of you know, it is a strange position to be in--knowing there is something right around the corner that will turn your world upside-down.  We were super aggressive with preventative treatments and especially careful about exposure to germs/bacteria.  The idea was that ONE DAY, we wouldn't have to live that way.  ONE DAY we would be free.  ONE DAY we would take a fabulous family vacation to celebrate Kalydeco, Brady's health, and our new lives.

On February 10, 2012 Brady took his first dose of Kalydeco.  The drug took effect almost immediately and we watched with wonder and awe as our son's health improved before our eyes.   His one year anniversary on "Blue Lightening" is just around the corner.  Over the last 11+ months, we have slowly and cautiously removed many of Brady's breathing and lung clearance treatments.   The physical effects of the drug have exceeded my expectations--which were extremely high.  As the months passed and our dreams became reality, we started planning our celebratory vacation to Spain, and now we are here.  We decided, with Brady's Dr., to leave his VEST machine at home and bring only the Acapella for airway clearance.  The industrial size Mobilaire 50 psi compressor that powered through so many treatments was also left to collect dust in Idaho, and instead we brought our tiny Omron Microaire Nebulizer for the single vial of Pulmozyme that Brady inhales daily now.  In terms of CF--we fit everything we needed to care for Brady for over a month in a single small backpack (with room to spare!).  The backpack may have been small, but it held over $30K of Kalydeco inside (Brock didn't put it down for a single second!).  You know that feeling you get when you leave home and you are just SURE you have forgotten something??  I still can't believe that we were able to travel so light, and that we haven't missed a thing!

See, this trip feels sort of like our "victory lap."  Brady IS doing amazing and we ARE enjoying our new lives.  But everything is not quite what I had expected.  I was so focused on how Brady's health would change, that I simply didn't put much thought into the psychological mine field that would continue to ravage my brain post-Kalydeco.  It just doesn't feel good or right to circle the track with our precious bottle of medicine in hand while Dalton's mother suffers the heartache of losing her child to the same disease--while Missy battles to improve her health enough to undergo a lung transplant--and while new babies are born and diagnosed with CF every day.  Damn it.  I know it is important to share Brady's story because it gives families HOPE.  I know it is important because families worked for decades to support the CFF and their work and donations gave rise to the research that resulted in Kalydeco.  I know it is important because it is an event worthy of celebration...but I am keenly aware that the war is not over and that the majority of patients and families are still waiting for their miracle.   I am constantly torn between feeling so lucky and happy about Brady's health and feeling like an insensitive prick to the others who are still battling. 

So, I'm going to do what I feel like I have to do--keep sharing, and keep working.  I received an email from the Director of Clinical Research Resources at the CFF a few days ago.  The CFF is forming 5 strategic planning committees composed of board members, Foundation staff, patients and family members, CF Care Center staff, industry participants, and outside experts to help realize certain goals over the course of the next 5 years. Anyway, they invited me to be on one of their teams--the "Adherence Action Team," and I will be flying to Bethesda for 3 face-to-face meetings this spring and working with the team via phone conferencing, email, and team website also! I am honored to represent patient families in this effort.  Of course, Great Strides time is also coming up again and it is more important than ever to keep those donations rolling in to finance medical research for CF patients.  I know that the wait for the combo is going to be too long, but I am extremely hopeful that many more patients and families will be taking their victory lap soon.  I'm so excited to read about more "Kalydeco miracles" as patients in the UK begin treatment with Kalydeco (and coming soon to Scotland--CONGRATULATIONS!).  

I am going to conclude this entry with some of our vacation pics.  I know it isn't fair, but downplaying the miracle of Kalydeco wouldn't be right either.  It is time for our family to make up for some of the freedom that CF took away from us.  It is time to celebrate! 

Plaza de Espana--Sevilla

Seafood Paella

Soccer game at Camp Nou--Barcelona vs. Espanyol

Brady at the Beach--Benicassim

Brady and Neus--She was a volunteer organizer for a kid's race in Valencia, so Brady ran!

Checking out the shark tunnel at Oceanografic--the largest aquarium in Europe!

Almost a Cure

I've had to explain what cystic fibrosis is to a lot of friends, family, and strangers over the years.  Since Brady started taking Kalydeco, I've found myself struggling with my spiel (a great problem to have!).  Let's examine the facts:

1) Brady still has cystic fibrosis.  He still has the genetic mutations he was born with (G551D, DF508). 

2) He still takes pancreatic enzymes, special vitamins, and several other prescription meds as a result of being born with CF.  His pancreas has suffered "permanent" damage that Kalydeco hasn't corrected.

3) According to the gold standard diagnostic test for CF--the sweat test, Brady no longer diagnoses positive for cystic fibrosis (last test was 17 mmol/L, 17!!!  Well within the normal range). 

4) Kalydeco has corrected the basic defect of cystic fibrosis in Brady's body (dysfunctional CFTR has now become functional).  Functional CFTR leads to thinner mucus, improved mucociliary clearance, and restoration of proper pH in the lungs and digestive tract in the body (CFers typically have an overly acidic environment in their lungs and digestive tract, promoting infection and impairing digestion.  Kalydeco restores the body's correct pH, giving the body innate bacterial killing power.).

5) In CT scan, Brady's lungs currently show "No visible damage" and appear to be functioning completely normally.

6) Today, Brady has absolutely no lung or sinus symptoms of CF :)

7) Kalydeco is anticipated to add decades and immeasurable quality to Brady's life.

8) If Brady stops taking Kalydeco, the symptoms of cystic fibrosis will return almost immediately.

So what does that all mean?  It means my explanation of Brady's condition just got a lot more complicated...I have caught myself using the following phrase recently because I don't know what else to say:

 

"It is almost like a cure for him." 

 

I hesitate to include that word at all--cure--because I am really not sure what that means, and because that word holds so much power.  I know that unless you are a part of the CF world, or perhaps have seen a news piece about Kalydeco, most people won't understand why Kalydeco is such a big deal for us.  They won't understand that it has changed everything we do and think about every minute of the day.  I mean, it isn't a real cure, because Brady still has CF and has to take that magic blue pill twice a day or he is back to old-fashioned CF...BUT, as long as he is taking Kalydeco, his body doesn't realize it has CF.  Almost a cure is good enough for me. 

 

With all this in mind, my husband, Brady's Dr., and I have some decisions to make about how to move forward with treatment.  Brady is currently still doing once daily Pulmozyme and 15 minutes twice daily on the Vest.  We have been very slow and deliberate in removing treatments from his regimen because his safety is ALWAYS our #1 priority.  We don't want to remove any treatment that could potentially still be beneficial to him. Theoretically, and from everything we have clinically observed in Brady--he shouldn't really need ANY lung treatments or lung clearance anymore.  Not even the experts at the NACFC seemed to have a real answer for us on the best path forward with treatment...the ball is in our court.  

 

The Scenario:

 

We are planning a big family trip to Spain over the holidays and I have had a goal in my mind of being able to make that trip without Brady's Vest machine. We have been training Brady on the Acapella device as a more travel friendly option for airway clearance, and would still be able to do manual chest PT in the event that he caught a bad virus and was in need of a good beating ;)  We are taking a portable nebulizer and will be continuing his Pulmozyme treatments as usual.  I am anxious to discuss this again with Brady's Dr. at his next appt. (end of Nov.), and see what he thinks!  Feel free to comment your two cents on the topic!  Take the Vest...or not?

 

The full-length Plenary Sessions from this year's NACFC are now available online and I encourage everyone to watch!   https://wiww.nacfconference.org/plen.archive.html

 

 





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! http://www.cff.org/research/ClinicalResearch/Find/ClinicalTrialAlerts/

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

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!! 

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!