Hiking Off-label

I’ve been visualizing this for years.  From the moment I first heard about VX-770(4 years ago), there have been lots of naysayers.  Predicting it won’t work like they say, it will fail in clinical trials, it is too good to be true.  I’ve tried to remain positive and focus on the possibility that the vision might be true.  As the years passed and the trial data came out, my vision took on color and detail.  I started envisioning the day that Brady wouldn’t have to wake up to an hour of treatments.  The day when my heart might not skip a beat because I hear someone in the store cough.  The day when I have the luxury to worry about regular things, like how popular he is in school, or how good he is at sports…because I don’t have to worry about his simple ability to breathe.  I’ve always believed that if Brady could get this drug before he has sustained significant permanent lung damage, that he might truly be spared a lifetime of breathing and airway clearance treatments.  A second chance. 

It is difficult to describe where my head has been since last Tuesday’s big announcement of FDA approval of Kalydeco.  The initial phase I will call BREAKDOWN: A huge wave of emotion.  Unbelievable.  I cried for hours that day.  I mean, I sobbed in a pile on the ground.  I cried in the bath tub.  I cried at the coffee shop.  I think I scared some kids because I cried at the park.  A weird cry too.  I mean, I know I had a huge smile on my face as the tears streamed uncontrollably.  I emailed Brady’s Dr. that morning and heard back from him within the hour.  This is exactly what he said in regard to getting Kalydeco for Brady off-label,

“Pure speculation, based on prior drugs through the years (though obviously this is a unique and groundbreaking drug, so precedents may not be perfectly applicable:

1. Likely will be a several week delay until the supply is actually available. Don't know if this will initially be available through typical retail pharmacies, or restricted initially to CF pharmacy and/or a few select outlets.

2. Since off label use is always a huge question with any new drug, especially an expensive one, I would imagine the process for kids like Brady will be a "one foot in front of the other" process. We would write a script, submit it to pharmacy, expect rejection initially by third party payor based on age, then write letter(s) documenting the appropriateness of off-label use. I would anticipate that the process would take several months, but that enough pressure will build nationally that third party payors will relent, especially when age is the only off-label parameter, and age isn't that far off (for example, not an infant). But of course I am totally speculating, as I don't even know the cost of the drug yet (do you?).

3. Meanwhile, I would anticipate CFF producing a position paper supporting off label use, at least for age parameter. This should come out fast and should help a lot (again, I am purely speculating---I have no insider information that such a paper is pending or even being contemplated at present, but I would be shocked if it isn't already in rough draft form).”

I think the important thing to remember is that there is NO PRECEDENT for this.  We have tried and succeeded at getting many other drugs for Brady off-label in the past, like Pulmozyme for Brady at age 6 mo.(for which it is NOT approved).  We understand that Kalydeco is different because it is a new type of drug and one of the most expensive ever marketed in the United States. BUT… How many CF parents out there would walk across hot coals right now to get a similar drug to their child?  I’m so determined to get this drug to Brady because every day that he lives without it is a day he might colonize some nasty bug, do further damage to his pancreas and liver, or catch a virus that could lead to permanent lung damage.  I’m sure I don’t have to explain to other CF parents how every single time we go to clinic we are nervous about what the culture is going to say...what the chest x-ray might reveal…what his bloodwork might indicate… We have been extremely lucky that he still has clean cultures for now, and has very good lung health.  Let me preface this next part by saying this: I realize Brady is not going to die if he doesn’t get the drug right away.  I realize that even if we had to sit around and just wait for him to turn 6 years old(a year and a half from now), he would be fine, excellent even!  With the exception of his sinuses, he has enjoyed a tremendously healthy childhood so far.  I’m sure that some people look at my reaction to the FDA approval and feel like I’m jumping the gun by trying to get the drug for Brady right now.  I want to explain why I’m so utterly convinced it will be safe for him and is just as crucially important for him now as anyone with G551D. 

1)      We, and Brady’s Dr., believe the 150 mg./twice daily dosage is safe and appropriate for him.  All trial participants, whether they were skinny 6 yr. old girls or grown adult men received the same dose.  Also, the full prescribing information for Kalydeco(available on Vertex’s website), describes that participants beginning the drug should monitor the drug’s effect on their bloodwork every 3 months for the first year and annually after that.  We have already discussed this with Brady’s Dr. who will be monitoring Brady’s bloodwork even more often than that!  If the dosage would happen to be too high, which we don’t believe is true, we will be watching him like a hawk and closely monitoring how his organs are handling and metabolizing the drug.  The prescribing info says to space doses more widely, or even drop down to once a day dosing for cases of elevating liver enzymes to more than 5x over normal levels.  People seem to assume we are being reckless by trying to put him on this drug when it hasn’t been trialed in children his age.  Some parents also don’t believe in putting their infant on Pulmozyme even before lung problems develop (which we did, OFF LABEL).  I guess we will just have to agree to disagree.  We also give Brady tons of nutritional supplements and he sees a naturopath in addition to his CF specialist.   Doing what everyone else is doing has never really been our biggest concern.  We have always been extremely aggressive with Brady’s preventative care because we want to keep him as healthy as possible.  We would never be pushing for this if I believed it wasn’t going to be safe for him. 

2)      We believe living with non-functional CFTR is a way bigger risk than the taking the drug “off-label.”  I think we can all agree that living with cystic fibrosis is dangerous.  Patients lose an average of 1-2% lung function for every year that they are alive.  There is constant risk of developing cystic fibrosis related diabetes, liver problems, bacterial colonization, or permanent damage from a nasty virus.  I’ve been a little bit surprised by some people who act like TIME is a luxury that we enjoy here in the CF Community.  People have died waiting for this drug and others will die waiting for the combo.  Every day waiting is too damn long.  I mean, let’s say that we decide to just wait and this is the year that Brady colonizes pseudo and ends up in the hospital for his first tune-up.  Is it the end of the world?  No.  I know he is still young and going to be fine.  Does that mean I don’t want to prevent it from happening and try to get him on this drug while his lungs are as pristine as possible?  HELL YES!  The whole key to being able to actually REPLACE lots of your current treatments with Kalydeco is to get the drug while your lungs are still very healthy.  As we are seeing with the adults who have been taking the drug for a little over two years now, some have dropped many of their treatments…others haven’t/can’t.  I want to give Brady the chance to live the rest of his life without those treatments and if we intervene NOW, we feel pretty good about his chances!  His chances will probably still be very good when he turns 6, but we have absolutely no way of telling what the next 18 months might bring.  CF can surprise you when you least expect it.

3)      Brady takes now, or at least initially started, almost every single one of his medicines OFF-LABEL!  Any newish drug (let’s say out in the last 10 years) is not going to have been tested for its benefit and FDA approved for, let’s say, a 3 year old with cystic fibrosis!  Brady began Pulmozyme at 6 months of age off-label (it has only been trialed in ages 1+).  He began Hypertonic saline off-label (the ISIS trial was going on when he started) at age 20 months.  He has been taking ursodiol for CF related liver complications off-label since 4 months old.  He has never been diagnosed with asthma, but takes Singulair off label.  He takes Prevacid to help his enzymes work better.  Not an FDA approved use people--Off-label!  While I understand that this is a problem we will likely be facing with our insurance coverage, I just want to illustrate that the fact that it is off-label means crap to me!   Honestly, the only meds of his that are on the FDA label for treatment of a young child with CF are the enzymes and the vitamins!  This leads me to my last point.

4)      We like to hike off the main trail.  Brock, Brady and I decided to take a hike this morning.  We are sort of on vacation right now in Arizona.  We are staying near the White Tank Mountain Regional Preserve and there are miles of hiking trails through the Sonoran Desert.  We parked at the trail head, but then almost immediately “went rogue” and ventured off the trail system to blaze a path of our own.  This is the way we always do it.  As we stumbled along the rough rocky terrain I couldn’t help but notice both the pros and cons of venturing off the main trail. 

Cons: You are a lot more likely to see a rattlesnake, twist your ankle, step on or simply get too close to a cactus, fall down, and scratch up your legs.  If anything does go wrong, you are further from help. 

Pros: You are a lot more likely to see a lizard, jack rabbit, or ground squirrel (which is why we are there as far as Brady is concerned).  You are more likely to find the rare cactus listed in your cactus field guide that you have been searching for.  The main trail doesn’t lead up to the little ridge with the best vista of the valley…thousands of saguaros and the mountains in the distance, so you have to go “off-label” to get there.  I guess what I’m trying to say is that today, we went for a hike and caught a lizard with our “lizard catcher”(Tupperware).  We hiked up to the best view in the whole area, and we all three came home with a few cactus spines in our butts…but it was worth it.  Brady has been prancing around all day singing this song from one of his Sesame Street videos, “You can do it, you’re not too small.  Don’t give up, even if you fall.  You can do it, you can answer the call, but you’ll never ever know if you don’t try at all.”

Beautiful Mess

And BOOM!  It happened today! The FDA approved Kalydeco (VX-770) for use in patients with the G551D mutation of cystic fibrosis, who are at least 6 years old!!  The approval today is almost 3 months ahead of their April 18^th target review date.  This morning started out like any other--give Brady Prevacid and start treatments.  Treatments finished, we had moved onto breakfast plus a handful of pills.  He was eating his eggs and waffles when I saw the post on Facebook that the FDA had approved Kalydeco.   I read it and re-read it, and re-read it before I started making weird noises.  I lose my ability to form words when I’m that excited.  I could hear that Brock was on the phone upstairs in his “office.”  He is working from our rental house in Arizona right now.  I ran to the top of the stairs and started making more sounds.  He hung up the phone a few seconds later.  “What’s wrong?!!  WHAT IS WRONG?!” In his voice, I could tell he was scared Brady was hurt or something, but I was still unable to talk.   I ran back downstairs and hoped he would follow me.  Finally I spit out: “READ IT BROCK!  WHAT DOES THAT SAY?  DOES THAT SAY WHAT I THINK IT DOES?”  My heart was beating out of my chest.  My whole body, especially my hands, were shaking uncontrollably as we realized what was happening (my hands are still shaking now).  The next hour or so was filled with messaging on facebook, calling our families, and having wild emotional breakdowns.  “Mommy is sad.”  “No, Mommy is happy!”  It has been a confusing morning for Brady.  After the initial freak out, I realized I needed to take care of some business.  I made phone calls to Brady’s clinic, Vertex Pharmaceuticals, and my attorney.  I emailed the CEO of the CFF and listened to the Investor Conference call held by Vertex today.

See, this news is like a dream come true for us, but there is one little detail that poses a problem.   Brady is only 4 ½ years old and the drug is approved for children age 6 and up.  I learned that Kalydeco is going to have a $294K annual price tag per patient.  Since clinical trials have only been performed in kids age 6+, the insurance company would consider it “off-label” use and will almost certainly reject the claim.  We understand that there is a clinical trial planned for “mid-year 2012” for children aged 2-5 with G551D OR OTHER GATING MUTATION!  They wouldn’t spill any further detail on the specifics of that trial…which is going to give me a nervous breakdown.  Another source of mine believes the trial will begin dosing phases in 1-2 mo.  And trial phases a few months after that.  The trial is scheduled for 6 month duration and is a double blind placebo control.  Approval for this age group is estimated for early 2013.  This news hit me like a gut punch.  Because Brady is only 4 ½, we have a couple of options. 

1) Wait for the trial to begin.  Hope he can be enrolled in it and be in the 50% that receives the actual drug and not the placebo OR

2) attempt to get the drug “off-label,” which will entail a legal battle with the insurance company, but may potentially lead to Brady getting the real drug sooner.  After a few short hours of thinking on this I decide that I really only have one option.  There isn’t a chance in hell that I’m going to be able to sit around and wait.  If Brady hasn’t gotten the drug in the meantime, we will attempt to enroll him in the clinical trial.  But right now we’re going to do our best to get it for him and FIGHT FIGHT FIGHT!  Brady’s CF specialist is ready and prepared for the appeal process with the insurance company.  We are working on getting weight information on some of the 6-11 yr. old trial participants, so we can prove that a 150 mg. dose is appropriate for Brady (he weighs almost 50 lbs, which I’m sure is similar to some of the trial participants who were 6 years old.)  I have a huge knot in my stomach.  My hands are still super sweaty.  The idea of having a legal battle over a drug this important and this expensive makes me want to puke.  I know I’ve said this before, but I think if the drug is out there and others can start taking it and halting the progression of their disease and I’m told to sit around and wait for 6 months or a year for Brady to get it…then my head really might explode.  Vertex has scheduled another conference call this Thursday, where they said they will outline their plans for 2012, so I hope they bring more details to the table. 

Typically, I try to include some useful information in this blog, so I wanted to share some of, what I considered, to be the highlights from the Vertex Conference call I listened to earlier today. 

-Price is set at $294K annually per patient

-Vertex has a patient assistance program up and running: http://www.vertexgps.com

-They estimate that there are 1200 patients nationwide with G551D, 200 of those are under 6.  Expanding to other gating mutations would double that population.    

-The trial for 2-5 yr. olds will include all gating mutations and is scheduled for “mid-year.”

-They expect a positive European ruling in the next few months.  They applied for all gating mutations.  They aren’t sure if it will be approved for all gating, or simply for G551D, as in the U.S. 

-Price will be re-evaluated if Kalydeco becomes a part of the treatment regimen for all CFers in the future.

Please understand that I’m so tuned in to certain pieces of information, so I’m sure I’m missing some big points.  Feel free to listen for yourself at http://investors.vrtx.com/events.cfm

I’m going to write more when I can think straight, and when I get more info...  I really wanted to do a little writing today to commemorate what a mess I am.  How crazy it feels to receive a miracle.  I want to be clear about one thing.  How to get the medicine to Brady is such a good problem to have.  Kalydeco exists and is now being marketed for sale!  Jesus.  That is wonderful news!  I don’t want any portion of this blog to sound like a complaint, because I’ve never felt more fortunate.  I swear I’ve been floating somewhere above my body all day, looking down and watching this beautiful mess unfold.   What lies ahead is so scary.  We don’t have any idea what is going to happen next or how we are going to make sure Brady gets this medicine that he needs.  One thing is for sure.  If a big fight has to go down…I volunteer to get in the ring.  Seriously, put me in coach.  I don’t mind getting bruised up.  Those who know me personally realize I actually get a kick out of a good fight and backing down is not a part of my vocabulary.  And for my sweet Brady…well I think I’d do just about anything.  As a fighter, I know that I’m going to need a solid team in my corner to have a shot at winning.  I’m going to watch Rocky now for inspirado.  I hope to see you all back in my corner real soon.  I’ll end with a toast (since I’m already drinking)—Cheers to ANYTHING BEING POSSIBLE in 2012! 

Mutation Matters

I want to use this blog to revisit a topic that was featured in so many different talks at the NACFC this year--Individualized medicine.  As more and more is learned about the genetics of cystic fibrosis, researchers are learning that each person's case of CF is truly unique.  This "genetic signature" is the product of your CF genotype plus a slew of other modifying genes.  At the Vertex Pharmaceuticals booth, they were giving out all sorts of awesome info on CFTR science and classes of mutations.  Inside one of these books, they discuss this information as a "Call to Action" to our physicians to review their knowledge of CFTR science, and embrace the new idea of using genetic mutations as a guide individualized treatment for each CF patient.  Then it dawned on me...this is new for everyone, patients and doctors alike.  With these big chages on the horizon, I think it is more important than ever for CF patients and families to be involved with their care team and stay in the loop about new research information.  I also realized that I blogged in some detail about the misfolding problems associated with the DF508 mutation, and that it might be a good idea to pull back a little and really break this mutation business down.  Let's talk about mutation classes and CFTR function.

I learned that there are have found close to 1900 different CF causing mutations.  There are many individuals that have one common mutation and another extremely rare one.  Many older patients may not have any genotype information, as it wasn't part of the diagnosis protocol 20 years ago.  Many other patients might have that genotype info sitting in their chart somewhere, but it never really useful information before. Now is the time to figure it out. 

The CFF and Vertex both divide CF causing mutations into 6 classes.  Mutations within each class have a similar CFTR dysfunction.  When assessing CFTR function, researcher basically examine two aspects:

1) How much CFTR reaches the cell surface
2) How much Chloride transport activity the existing CFTR exhibits. 

Researchers believe the key to controlling this disease is to increase the amount of functional CFTR for each patient using small-molecule drugs (like VX-770).  They believe if they can activate 20-30% function, that they will see a significant drop in clinical symptoms of CF.  They really hit the jackpot with VX-770, which activates about 50% CFTR function in G551D patients.  In essence, when Brady is able to take this drug, he will achieve about the same level of functional CFTR that I have as a symptomless carrier--50%. 

I want to make one important point before moving along to the mutation classes.  In new information being published about CF mutations, as well as in the CFTR2 project, you are going to start seeing genotype-phenotype correlations.  In other words, they are attempting to make correlations between CF mutation and clincal presentation of things like pancreatic sufficiency, liver disease, CFRD, etc... These correlations were made by performing a statistical analysis on National Registry (and European) data and is NOT MEANT IN ANY WAY TO BE USED AS A TOOL TO PREDICT INDIVIDUAL OUTCOMES!  Basically, if you are in the group that has little to no functional CFTR, you will see associations with more CF complications.  If you are in the groups with some functional CFTR, there will be fewer associated complications.  I encourage everyone to visit http://www.cff.org and watch the archived Plenary Session 2, entitled CFTR2, from year's Conference.  They describe exactly how these correlations are made and how they might be used.  For some variables like pancreatic sufficiency, they are able to use genotype to make a fairly accurate prediction about whether or not a patient will need enzymes based on their genotype.  For other variables, especially lung function, the correlation is very weak (their own words!).  In fact, I sat through a talk at the Conference all about how siblings or even twins with the exact same genotype and environment can have drastically different cases of CF.  In other words, DO NOT FREAK OUT ABOUT THE CLINICAL ASSOCIATIONS.  Think of it as a snapshot of what has happened in the past--not a tool for predicting the future.  Modifier genes (that might affect the body's inflammation response, cell death, etc...) and countless other non-genetic factors(age of onset of chronic infection, level of care, nutritional support, exposure to secondhand smoke) all play a role in determing clinical variability.  Honestly, I don't pay much attention to the clinical associations.  I'm much more interested in the TREATMENT ASSOCIATIONS!

Ok.  Here we go.  This can be extremely confusing because some people call the classes by numbers.  Other times you might here jargon related to the CFTR dysfunction like, "gating," "deletion," "non-sense," etc...

Class 1 (Nonsense, Stop, X-mutations, premature splice mutations)

Mutation Effect:  Protein synthesis defect causing failure to synthesize full length protein

Cell Surface Expression: Little to no functional CFTR

Channel Function: Little to no function

Example Mutations:  W1282X, G542X, R553X, R1162X, 2184delA, 3659delC, 621 + 1G-T,  711 + 1 G-T, 1717 – 1 G-A, 1898 + 1 G-A

Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…

Class 2 (Misfolding/Trafficking, Deletion)

Mutation Effect: Protein processing defect often resulting from improper folding and trafficking to cell membrane.

Cell surface expression: Little to no functional CFTR

Channel Function: Little to no Chloride channel activity

Example Mutations: F508del, N1303K, 1507del, R560T

Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…


Class 3 (Gating, Missense)

Mutation Effect: Defect in regulation impairs opening of channel.

Cell Surface Expression: Normal quantity of dysfunctional CFTR at cell surface.

Channel Function: Little to none

Example Mutations: G551D, G551S, S1255P, G178R, G970R, G1244E, G1349D

Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…

Class 4 (Channel, Conductance)

Mutation Effect: Insufficient amounts of Chloride move through the channel

Cell Surface Expression: Normal quantity of dysfunctional CFTR

Channel function: Some

Example Mutations: R117H, R334W, R347P

Clinical Associations: fewer CF related complications

Class 5 (Splicing)

Mutation Effect: Splicing error causes variable synthesis of protein, CFTR is produced in smaller than normal quantities.

Cell Surface Expression: Some (variable) functional CFTR at the cell surface

Channel Function: Some

Example Mutations: 3120 + 1 G-A, 3849 + 10 kb C-T, 2789 + 5 G-A, A455E

Clinical associations: fewer CF related complications

Class 6 (Stability, Protein truncation)

Mutation Effect: CFTR degrades too fast.  Not enough functional protein present. Protein truncation causes increased cell-surface turnover.

Cell Surface Expression: Unstable

Channel Function: Some

Example Mutations: 4326delTC, N287Y, 4279insA

Clinical Associations: fewer CF related complications

Learn More
Until CFTR2 goes online sometime next year, I think the best resource out there is the website associated with Vertex called http://www.CFTRscience.com
You can go to this site and watch animated videos showing the unique dysfunction that different classes of mutations exhibit.  You can page through amazing slide presentations with all sorts of great graphics.  You can go to the "educational resources" tab and request that they send you all the booklets that they gave your Dr. at the Conference this year.  I have been geeking out hard on this website and I hope everyone takes the time to pay them a visit.  This is basically the tool that they are using to educate/refresh the memory of CF physicians about CFTR, so let's see what they are learning!  Of course, you can always go to http://www.cff.org and do a general search for mutation classes.  This will bring up a short 2 page article about Targeting CF Mutations and is a lot less technical.  In closing, I think this information is crucial for patients to embrace because it is a huge change for Doctors to approach CF care this way.  Genotype information is going to be crucial to find and enroll in the huge number of mutation specific clincal trials coming our way.  My hope is that everyone gets to obsess over their mutation specific therapy as it comes down the pipeline, as I've been able to do with VX-770 for Brady.  I will never forget the day that I first read about VX-770 (Brady was an infant).  I had to go to Brady's medical information file and dig out a letter that listed his specific mutations (they were nothing but a jumble of letters and numbers to me before). 
All of a sudden, it became significant.  Extremely significant.  I believe now, more than ever that they are on track to developing drugs to control CF like VX-770, for other classes of mutations.  MUTATION MATTERS!

Troubleshooting:

What if my insurance doesn't want to cover genetic testing?
--The CFF is planning a patient assistance program to help cover genetic panel costs.  This program is set to begin next year, alongside CFTR2

What if I had the test, but they only identified 1 of my mutations?
--Of course, it is best to know both mutations, but knowing only 1 is much better than knowing none.  In the case of VX-770, only a single patient in that trial was homozygous for G551D.  In other words, they were treating only one of each patient's mutations and still had great success with treatment.  Also, as more mutations are discovered, those genetic panels will include more and more mutations...increasing the chances that they will be able to find that elusive second one.

I know both my mutations, but didn't see them listed in the example mutations
--With close to 1900 CF mutations, this represents just a small fraction of them.  Please ask your Dr. to help you determine which class and the specific type of CFTR dysfunctions that are associated with your mutations.   

More hope than you can shake a stick at

Ok.  I've been reading a lot of questions about hope for other mutations, like F508 to see a great control drug similar to VX-770.  I know people are scared that the VX-809/VX-770 combo might not work and that it will send us back to the drawing board, tacking years and years onto the waiting time for a real change for that population.  I completely understand that concern and I feel like I need to try harder to make it clear how much hope you should have that this WILL HAPPEN.
Drug Discovery: High through-put screening
VX-770 was discovered through a process called high throughput screening, which is a technology powered with robots and supercomputers to scan a huge number of compounds very quickly.  They look for molecules that perform specific actions (like opening the gate for chloride ions in the example of VX-770) Before high throughput screening, researchers might be able to screen, let's say 100 compounds a year with old school techniques.  I'll go back to the burned out light bulb analogy I used before.  If you had to check every light bulb on the planet to discover a single burned out bulb, you would never find it in your lifetime...or in a million lifetimes.   High throughput screening changed the face of medical research.  It enables millions of compounds to be screened, in a relatively short amount of time.  Now, instead of going one light bulb at a time, they can check entire cities or even States at once.  It improves your chances exponentially.  Researchers will typically get their hands on a collection of compounds that someone sort of "owns."  Nearly all of the compounds being screened have never been used for any type of therapeutic purpose.  Remember, we are talking about millions or billions of potential compounds.  If a molecule is found that makes a little blip on their graph, they isolate it and take it to the lab.  This is where they tweak it chemically to see if they can turn that little blip into a big blip(bigger positive effect).  Then they can start testing it in the lab on epithelial cells to see how it affects the function of things like the cilia (those little hair like projections that sweep particles like bacteria off the surface of the cell.)  After lots of tweaking, the clinical trials process begins.  This is exactly what they did with VX-770.  

Other mutations:
One thing that blew me away at the Conference was how many other correctors already exist and are being tested.  We aren't just talking about the Vertex compounds here.  They have already discovered many (probably tens or hundreds) of compounds that make those initial small blips.  In some of the talks, I would see a slide present 10 correctors I had never ever heard of and how they are working(or not) to fix those two F808 misfolding problems I mentioned in an earlier blog.  They are also in the process of screening already existing drugs to see how they act on mutations. They have found some compounds that exibit corrector action for F508.  This is directly from something presented at the conference:

"We constructed a novel high throughput cell based assay to test the ability of small molecules to restore F508 CFTR trafficking to the plasma membrane.  In a screen of known drugs we identified the non-steroidal anti-inflammatory (NSAID) drug Ibuprofen.  Ibuprofen has previously been reported in small-scale clinical trials to improve the symptoms of CF and prolong lung function in CF.  However, this is the first report of ibuprofen being a corrector for CFTR.  Ibuprofen increased the cell signal up to 27% of wild-type signal." **Disclaimer-Talk to your damn Dr. before you run out and start an ibu regimen!  This is a trial!

Also remarkable is that they are finding a wide variance in how people with F508 respond to corrector compounds.  They will have a population of double F508 having a wide range of responses...some very good, indicating that there might be other genetic markers at work, making it more therapeutic for that subgroup.  So what I'm trying to say is that even if the VX-809/VX-770 combo isn't the magic bullet, it might be for another small subpopulation of F508 that have other genetic markers that enable it to work better in them.  What I'm saying is that if VX-809 doesn't work, there may be another compound already approved like ibuprofen that might be able to be combined with a potentiator and shave years off the clinical trial process.  I'm saying any one of those little blips might be tweaked just right and shoot the efficacy through the roof.  I'm screaming that the combo of two corrector compounds working synergistically on the two misfolding sites for F508 has been shown in the lab to restore up to 60-70% function in some cases(that is above and beyond how well VX-770 works for G551D)!!  I'm reminding you that with big time companies like Pfizer getting involved, they are bringing with them the databases of compounds that they own to be scanned for previously undiscovered treasures.  I believe with all my being that there is more hope about fixing this than you can shake a stick at!  I read one question the other day that prompted this blog and it was something like, "Someone tell me if there is any hope for F508 and I need a simple answer."  All I could think was, well do you want an answer or not, because it is not simple any way you slice it.  I realize that trying to understand the research can be daunting, but it is impossible if you don't even try.  I guess I just think it is worth it because the place (in my head) where I live now is where I wish you all could be. I'm not trying to sugar coat this or string anyone along.  This is something I believe with all my heart. You know, when VX-770 was in early development, everyone thought I was crazy for believing it could work.  I don't think I need to tell you who got the last laugh.   I cannot wait until next year's Conference in Orlando to see where they have taken this...I have no doubt that there will some failures, but more importantly...there will be some successes!  I think they are so far ahead of where many of the families seem to think. 

Just for fun, I'm posting a picture of a model of the CFTR protein.  It looks complicated, doesn't it?  My recommendation to you is that you join me in hope.  Please join me in believing.  I realize not everyone loves chemistry as much as I do, but isn't it worth sitting though a few lousy science classes if it gives you a ticket to that place in your head where you believe everything is alright??  And I hope I've made it clear that I'm happy to help/translate with this kind of info or help find someone else who can if I don't get it either.  It isn't simple...but WOW is it worth it!

Honor the gift

Let me preface this entry by saying that today I am feeling so tired, so I hope this makes sense.  In other words, the day after day of being super excited and not sleeping or eating normally is catching up to this old lady.  I am a pretty emotional person also, and the last few days have been quite overwhelming.  About 10 o'clock this morning, I hit a wall and thought I was going to just pass out in the hallway...Fortunately, the very next presentation I saw was about VX-770 and apparently that particular subject works like crack for me.  I see a big crash coming soon and as amazing as the last few days have been, I miss Brady, my husband, and my juicer.  I don't have a lot of time to write before the closing events this evening so I'll jump right in.

Plenary session: Pulmonary Exacerbations
1st of all, the drug development pipeline has been updated and changed format on the www.cff.org website.  It contains more information than ever before and I encourage you to explore the new, more interactive format.  The pulmonary exacerbations talk first went into the difficulty of defining what exactly constitutes an exacerbation.  They would like to establish a standardized method of identification and treatment among care centers.  Currently, the protocol of treatment almost always includes a round of either oral or IV antibiotics.  Seems logical, but data showed that in many cases, bacterial growth rebounded right back to pre-flare-up growth levels within a short time after treatment, even when FEV1 had increased, which begs the question: Is this the right course of action?  They also addressed questions about how bacteria move or migrate throughout the airways.  Do infections "slough" off one area of the lung and migrate to another?  How do they spread and disperse?  Also, which bugs (of the many they may see in culture) are the real trouble makers in terms of destruction of lung function?  This talk presented a ton of questions, but not many answers.  It was actually pretty surprising to me that so little is known about what causes pulmonary exacerbations and how to treat them.  The speaker presented question after question about exacerbations and ended up with a slide that read exactly "We know a little more than Jack."  As in, we know slightly more than jack shit about this and we need more studies.  They have lots of ideas for learning more about this basic concept of risk factors that promote exacerbations and the most effective ways to treat them.  They hope to learn from COPD exacerbation model and continued research projects are underway. 

Next, I attended a talk about Key Advancements along the CF Drug Development Pipeline.  They described what went wrong with Denufosol(an inhaled treatment that attempted to correct for CFTR dysfunction by activating an alternate channel (calcium channel) to transport chloride ions.  In short, the trials were poorly designed and seemed to use some pretty creative statistical analysis to get as far as they did in trials.  This talk felt sort of like an apology.  Next up, they commented on where we are with Bronchitol.  Bronchitol has already been approved for use in Europe, and is thought to have a similar line of function as Hypertonic Saline.  Rather than inhaled salt, Bronchitol is a large molecule sugar alcohol that comes in the form of an inhaled powder(Similar to Advair, which saves a ton of time with a single inhalation vs. 30 or so min on neb with Hypersal).  They plan to get this drug approved in the US soon, but they weren't sure when.  They also couldn't comment on its efficacy above and beyond what is seen with Hypersal.  In my mind, if it works as well as Hypersal but can be taken in a fraction of the time, it would improve quality of life enough to make it worth it.  I'm sure we will be hearing more about this soon here in the US.  This is where I hit that wall I mentioned earlier.  Fortunately, next up was the data about VX-770.  There was no new data, but rather a review of the trials that led to the FDA application.  You would think that I would be getting used to seeing these stats by now, but something about those graphs on those huge projector screnes of dramatically dropping sweat chloride scores alongside similarly dramatic spikes in lung function put me in tears...again.  It is nearly impossible to wrap your mind around a concept like this when you have been dealing with CF for any length of time.  The more tired I get, the harder it is for me to control my emotions and act professional.  I've been screaming on the inside the entire time I've been here and as I sat in that darkened room of completely subdued scientists and physicians...it was all I could do to keep myself seated and quiet.  I wanted to stand up and give an old school fist pump and woot with each new graph displayed.  I also wanted to kick the lady next to me because she didn't even seem to be paying attention.  It just never ever gets old.  My hands still shake and sweat, my breathing goes all funky, and I'm pretty sure my eyes bug out when VX-770 is the topic of conversation.  I know getting VX-770 to where it is today has taken decades of collaboration between Vertex and the CFF, but it is truly is amazing that it was discovered at all.  Dr. Beall told me yesterday that when they first began screening for compounds to treat the basic defect of CF, VX-770 was in one of the first few thousand compounds they screened.  In the millions of compounds that they have screened since, nothing has come close to being as pharmacologically perfect.  Imagine setting out to find a single burned out light bulb in all of Orange County and then finding it on the very first block you search.  Finding that compound was more than lucky, it was a miracle.  The last talk in this workshop was given by a researcher from Pfizer, one of the largest pharmaceutical companies in the world, who has now thrown themselves into the arena of CF small molecule research.  Vertex now has company in searching for new and better functioning corrector compounds.  Pfizer has its own databases of compounds that haven't previously been screened by anyone and they hope to find some gems there.   They want to find the "next generation" of correctors that work specifically on the two misfolding sites I described on F508 yesterday.  They believe that a two drug combo of correctors working synergistically will provide the best results and are setting out the find those burned out lightbulbs.  Let's all hope they get as lucky as Vertex did, so they can begin the process of clinical trials...like NOW NOW NOW!

Next up was a special luncheon attended by CF patients, families, and certain caregivers.  The face of healthcare is changing.  Patients and providers can both do more to improve the quality of care, especially for chronically ill patients like those with CF.  I didn't see this coming, but this talk hit me like a ton of bricks.  "Tiffany Christensen is the CEO of Sick Girl Speaks, Inc. She was born with cystic fibrosis and has received two life-saving double lung transplants. Today she is a national public speaker, the author of “Sick Girl Speaks!” and “We are the Change: Transforming the Healthcare Experience through Partnership.” http://www.sickgirlspeaks.com
Yes, you read that right.  She has undergone not one, but two double lung transplant procedures.  It is amazing to me that she has spent most of her life very ill and close to death.  There was so much life in that tiny lady that her body seemed too petite to possibly contain all the energy and positivity that she exuded.  I'm planning an entire blog entry centered on the tools she taught about communication between patient and provider.  I don't have the time to go into detail now as the closing event for the Conference begins in less than an hour, but I do want to say this.  She described her drive to do something meaningful with her life as a way to "honor the gift."  As soon as she said the words, tears sprung into my eyes and the words haven't escaped my mind for a second today.  Honor the gift.  She knows how lucky she is to have been given the gift of a second...and a third chance at life.  She now works to train medical students, medical staff, and patients on how to improve communication in healthcare, especially in regard to end of life issues.  Brady doesn't need a transplant, but VX-770 certainly feels like a gift to me.  I'm not sure exactly how, but I will be spending the rest of my life trying to "honor the gift" I've been given through continued work and advocacy for the CF community.  I'm so humbled I can barely stand how lucky I am.  I have so much more to say, but I have am out of time for now.  I fly out at 7:45 a.m. tomorrow morning.

Coffee with Bob and day 2 of NACFC

Today started off with the second Plenary Session, entitled CFTR2.  The CFTR2 project has a goal to identify and classify as many CFTR mutations as possible (they have close to 1900 different mutations identified now), and put that information into a database that can be easily accessed by both patients/families as well as researchers.  Beyond simply identifying mutations, CFTR2 will attempt to offer more clinical information on what is known about each of those mutations.  For example, some are associated with pancreatic sufficiency, or less severe lung disease.  It will be a place to go to find out all about each particular mutation.  This might not seem like much, but the CFF has worked hard over the years to gather extensive amounts of patient information through their patient registry program to be able to provide this type of clinical data correlated to mutation.  As we are learning--mutation matters, so this will be a wonderful resource that should be up and running sometime next year. 

Next, everyone went their respective ways to attend morning sessions.  I decided to attend a talk about  Gene Modifiers of CF Lung Disease.  Studies have shown variability in lung function between siblings and twins, indicating that other forces may be at work in determining the clinical outcomes.  Specifically, two sites on the chromosome were discovered to have significance in determining severity of lung disease.  It was a very technical talk, but I will try to boil it down.  One of the sites they found to be significant regulates cell death and the other site helps regulate the body's inflammation response.  They hope to be able to learn how to manipulate functions at these crucial sites, so that therapies might be developed to correct for alleles associated with more severe lung disease.  Understanding these types of modifying genes could help explain why two children from the same family can have drastically different "cases" of CF.  As we know, inflammation plays a huge role in CF.  Getting control over those inflammation genes would sure be nice...

I also attended a talk entitled: Antimicrobials in the CF Airways--How disease alters innate immunity.  This was an interesting session that showed how loss of CFTR function impacts the normal defense mechanisms in the respiratory tract.  Healthy individuals possess an "antimicrobial shield" that keeps the lungs from becoming infected.  That shield is missing or impaired in individuals with CF.  CFTR plays an important role in regulating airway surface liquid (necessary for mucociliary clearance).  Impaired bicarbonate secretion alters the pH of that airway surface liquid.  Lower pH reduces the "killing power" of the antimicrobials so that the body is unable to defend against something such as pseudomonas, which is an infection fairly exclusive to the CF pop.  They are using pig and ferret animal models to study the primary effects of loss of CFTR and will continue that line of research.

Genetic Suseptibility for CF-related Diabetes Identified by Genome-wide Association.  While there are similarities, CFRD is unlike type 1 or type 2 diabetes.  Diabetes develops frequently in people with CF, occuring in 25-50% of adolescents and adults with CF.  CF related diabetes develops over time as the capacity of pancreatic beta cells to secrete insulin declines over time.  They used a continuum to explain how CFers can exhibit transient and significant drops in insulin sensitivity when ill or having a pulmonary exacerbation.  In other words, it isn't a clear case of diabetic or not...it is more like diabetic while taking steroids or during a flare-up, and then a swing back toward more normal function when well.  These swings between good function and bad function go on over time until the patient is chronically on the bad side, when interventions typically begin.  The mechanisms of the development of CFRD are not well known, but several genetic markers have been located as risk factors in the development of type 2 diabetes(totally unrelated to CFTR or what genotype of CF you have).  CF patients who also had these markers, were more likely to develop CFRD.  With that information in mind, individuals with CF who have a family history of type 2 diabetes were found to be 3X more likely to develop CFRD than those who don't.

After lunch I attended my coffee meeting with Dr. Beall and the VP of Commications for the CFF, Marybeth McMahon.  This time, I had my act together.  They were both very interested in how issues are perceived within the community and what they can do to better address or educate about those issues.  They wanted news from the inside.  I spoke frankly about the impatience and worry over the success of the combination Vertex trials and the bittersweet nature of a breakthrough like VX-770 for people who won't benefit from this right away.  They are acutely aware that time is of the essence and were genuinely interested in what they could do (besides hurry up with that damn cure!) to address the concerns of those still waiting.  For me, this topic has caused me many sleepless nights.  There is a certain amount of guilt that I just can't shake about having the child that will benefit first.  But at the same time, I know that VX-770 will likely be a part of the treatment regimen for many mutations of CF (as they will require both corrector and potentiator compounds), so it is absolutely a good thing for everyone that it is approved.  I think there is also a misconception that the F508 mutation has been put in the backseat while G551D has taken all the focus.  As I will explain, the dysfunctions of the F508 mutation are numerous and complex.  The G551D mutation is functionally, one of the easiest to correct for and VX-770 was discovered while screening millions of compounds with robots and supercomputers.  It was not, by any means, an intentional snubbing of fixing the most common mutation...rather, a place to start.  The "potentiating" action of VX-770 is a single piece of a larger puzzle for F508.  I think it is an appropriate time to revisit the new information I learned yesterday about fixing F508.  They now know that there are 2 distinct and separate problems that occur in F508 that cause misfolding of the protein.  Misfolded proteins do not mature and travel to the cell membrane.  If they only correct for one misfolding problem, they seem to top out at about 15% retrieval of CFTR function for F508 patients, which isn't enough to have clinical benefits.  The good news is that they've shown that when both of these misfolding problems are corrected for in the lab, the two correctors work synergistically (the action of the 2 correctors together is greater than the sum of the two individually), producing the clinically significant outcomes we all want.  Blah blah blah...So what does that mean for VX-809 and VX-661?  I'm afraid they still aren't sure.  From what I've learned since I've been here, I have a gut feeling that the VX-809/VX-770 combo alone won't be enough.  A third compound (or different corrector) will need to be factored in to correct for the second misfolding site.  This is just my opinion.  

Highlights and tidbits:  During our coffee today, Bob said "When VX-770 is approved in April...."  He sounded pretty damn sure that next April is when it is all going to happen.  I asked about the pediatric trial and he says it will not be placebo controlled, and of fairly short duration (3 months).  This trial is about safety and appropriate dose for kids, not proof that it works.  I asked him when it will begin enrollment and he promised to find out something more concrete than "sometime in 2012" and report back to me within the next 2 days.  Then he invited me the dinner reception this evening for Conference Speakers and Fellows as his personal guest.  That's right...it's a date.  Naturally I accepted.  He also went on and on about the book and how much he loved it.  He even brought it to registration this morning to show his friends.  He is very proud of it :)   After coffee, I went to film "my dream for CF."  I was so nervous.  I hope I did alright.  Of course, it rained here today so my hair was all funky. I'm sure that I'm leaving things out, but I will write more either tonight or tomorrow.  Right now, I've got to get ready to meet my new boyfriend Bob for our date!   Once again, sorry for the screw-ups, I'm trying to get this updates done FAST!
 

Prelude to a kiss

I am exactly where I belong.  Today was one of the most amazing days of my life.  My flight landed at 9:30 p.m. last night, but I was so pumped that I was up and ready by 6:30 a.m. this morning.  I made my way to the Conference and sat through some interesting sessions today.  Here is a brief summary of the sessions I attended:

Workshop: Novel Strategies for CF Therapy--The speakers in this workshop discussed topics including results of a clinical trial to test the anti-inflammatory properties of N-Acetyl cysteine (bioadvantex fizzy tabs).  Clinical test showed a "protective" effect of orally ingested NAC against pulmonary exacerbations.  They are interested enough in this data to proceed with further trials.  The stats weren't mind blowing, but interesting. 

Gene Therapy: I made a point to attend these workshops because I feel that it is an area of research that I know the least about.   The first speaker addressed the gene therapy trials and success they have seen utilizing lipid-mediated gene therapy in mice.  I realize the concept of gene therapy has been around for a long time.  It seems like they have finally found a vector (method of delivery) with the lipid model that facilitates sustained gene expression that is well tolerated by the patient.  Mice treated with nebulized therapy showed gene for extended periods, as well as changes in mRNA. The "lipid model" has already been tested in humans and the next presenter addressed safety and gene expression in humans with CF for his talk.  They found that very low, repeated (monthly) doses of gene therapy gave the fewest side effects with the greatest translated gene expression.  A larger study is planned to initiate soon, but funding was cited as a major obstacle to moving forward.  I've been so focused on Vertex for obvious reasons, but it was great to hear about this potential "cure" continuing to progress. 

CFTR: Fixing DF508
It is complicated business to correct the function of DF508.  Today I learned that researchers have discovered 2 separate dysfunctions that cause misfolding of the CFTR protein for this mutation.  Estimates show that approximately 20-30% CFTR function must be restored to get significant clinical benefits.  So far, they seem to be hitting a ceiling with how much they can restore with ANY single corrector, including VX-809 (which they estimated restored 15% CFTR).  I heard, for the first time ever, that they think it will take a combination of TWO separate correctors plus the VX-770(or another potentiator compound) to hit their goal of restoring function for this mutation.  This DOESN'T MEAN that the correctors in trials aren't working...It means that it might take VX-809 + VX-661 + VX-770 for example, to correct for this mutation.  After a full day of lecture, I am just as optimistic as ever about the advances being made to treat DF508.  As I said before, it is much more complicated, but they are on it like "white on rice."  The detail that they are able to describe the function of the CFTR protein is just dizzying.  It is no longer a mystery, but simply a quest for the right combination of compounds.  It was stressed many times that no assumptions should be made until further trial data is released. I hope I can report more about this tomorrow. 

The Changing Face of the Infants with CF
This series of presentations highlighted the changes that have come about as a result of newborn screening and early intervention.  The session entitled "CF Lung Disease-No Time to Waste" was a little scary.  It basically showed statistical evidence(though CT scan) that lung disease begins to progress shortly after birth...even in the absence of symptoms.  20% of screened infants even showed early signs of bronchiecstasis in the absence of symptoms.  This early damage to the small airways can be undetectable.  What I took away from this workshop is: DO NOT WAIT UNTIL SYMPTOMS PRESENT TO TREAT THE CF LUNGS!  Be proactive rather than reactive.  By the time it is noticed through symptoms, significant damage is already done.  If you are on the fence about starting treatments like Pulmozyme or HS Saline...don't wait.  Just do it. 

Here is where things start to get really exciting!  After the classes today, all 4000 attendees came together for the 1st Plenary Session of the Conference.  I arrived early and found the giant ballroom mostly empty...except for Dr. Bob Beall, and several other major players that I have only seen in educational webcasts.  So I did what any good stalker would do.  I planted myself about 3 rows behind him and stared and smiled weirdly at him for about 10 minutes.  Finally, my excitement got the best of me and I launched myself at Dr. Preston Campbell.  He quickly decided I should speak with Dr. Beall.  He led me over and introduced me to him.  I know that I squealed, covered my face with my hands, and jumped up and down before I threw my arms around him.  This is not normal behavior for me.  I hugged him hard, thanked him, and I think both Campbell and Beall cried a little bit too.  Since people were pouring into the room, we didn't have much time.  Somehow, within a span of about 15 minutes, I landed a reserved seat in the FRONT ROW DIRECTLY IN FRONT OF THE SPEAKER!  I was seated right next to the Foundation big wigs and major donors.  It was amazing and surreal to watch the next few hours unfold.  The Plenary Session today was about the progress of the last 25 yrs in CF research.  It was like music to my ears.  I was lucky enough to meet some families in the CF community including Lindsay Shipp and her mother Barb.  Lindsay has participated in the VX-770 trials...and is also an amazing singer/performer.  She sang for us at the VIP dinner that I snuck into(thanks to Raven and Britt!).  I'm so thankful for people like Lindsay, who have done so much to pave the way.  Not to mention that she was just a beautiful little firecracker that lit up the room.  The VIP dinner was attended by only 117 of the 4000 attendees, so there were some important people there.  I heard that Bob was talking about me at his table, so we decided it would be a good time to give him the book of pictures and letters from all of us.  THIS IS WHEN I KISSED HIM!  3 times I think.  We took pictures and he was very appreciative.  I thought it couldn't get much better until later in the night, right before I left he told me, "In all my years, this is the most thoughtful, nicest gift anyone has ever given me."  I just about lost it.  For those of you that contributed, please know that he loved it for real.   I decided I'd better get out of there so I could cry it out in private.   All happy tears.  Surreal, overwhelming happy tears.  My coffee meeting with Bob was changed to 2:00 tomorrow afternoon and I learned that I will get the opportunity to film a "my dream for CF video" for the Foundation also.  The absolute only way that today could have gotten any better is if my shoes were more comfortable.  Please excuse any typos or errors.  It is very late and I'm exhausted.  More tomorrow.  Can you feel me smiling?