Life Post-Miracle

This entry is not about science.  My heart is writing this time.  As amazing as the chemistry behind Kalydeco is…it just can’t describe the perspective on life that this experience has given me.   I’m sure that everyone can relate to feeling desperate in their own way.  I mean, maybe there has been a time that you sat down to pray to God and said, “If you just give me this one thing, I will never ask for anything ever again.”  Something so important to you that you would gladly give everything else you possess, just to keep that one thing.   Let my child be alive and healthy. 

When your baby suffers from cystic fibrosis, you never have to think when you blow out those birthday candles, or when you see a shooting star, or when you sit down to pray.  The wish is always the same.  Please just let my baby breathe and live and grow.  Please just ease his suffering and allow him to have the life he deserves.  Please don’t make me attend my child’s funeral.  Please let there be a cure for cystic fibrosis. 

Everyone’s experience with cystic fibrosis is unique.  We found out when Brady was 3 weeks old via a positive newborn screen and subsequent genetic panel, which identified his mutations.  There are chunks of time from Brady’s infancy that I seriously don’t remember…or I’ve somehow shoved that pain down into the furthest depths of my mind.  The script I had written for my life got thrown in the trash and I am the type of person that likes to be in charge.  Feeling so out of control was mind altering for me.  I’m not trying to claim that it was in any way harder for me than any other person who receives the same news…I just want to express that it nearly made me crazy.  I had an extremely hard time accepting the diagnosis in the beginning and I became very isolated for about 9 months.  I did not want to talk about it at all.  I don’t think I left the house much.  It was a very dark place for me mentally.  Especially since every day that went by I fell deeper and deeper in love with Brady.  I think the FEAR aspect of cystic fibrosis is what really altered my personality the most.  I hope my friends would back me up when I say that I’m typically pretty gutsy.  But this…this had me paralyzed with fear.  In the midst of this time of fear and depression, I read about VX-770 for the first time.  I tried my best to examine the data Vertex presented objectively, and to manage my expectations, but you can imagine that I grasped onto this concept of “fixing” Brady’s CF with both hands.  Before I had even truly come to terms with Brady’s CF diagnosis, I had a glimmer of hope offering me a sort of “way out” of what felt like a horrible nightmare.    Right then I wrote the new script for my life: Be as aggressive as we possibly can with treatment to preserve Brady’s lung function until this drug becomes available, and then give him the chance to live a long healthy life.  That has been my singular focus.  I know it is more common these days, but when Brady was born it wasn’t typical protocol to put infants on Pulmozyme at 6 mo., but we requested to do it and his Dr. agreed.  We requested Hypertonic Saline at 20 months, also in the absence of lung problems, to further assist his mucociliary clearance and PREVENT lung issues.  The infant trial was going on at that point, and there was no clinical data for use under age 6.  We had to do the first treatment in the office under Brady’s Dr.’s supervision to make sure he tolerated it well, and then continued our treatment schedule at home. 

AND NOW he has KALYDECO!!  Every day I hear more great personal stories about this medicine changing lives.  Once again, not a day goes by that we don’t pay special attention to how fortunate we are to have Kalydeco.  

I am 34 years old and THIS is my first tattoo!  The Kalydeco molecule, the words "Honor the Gift," and Blue Lightening!  A day will never pass that I don't think about this gift!

I remember attending a parent education event put on by my son’s clinic when he was about 2 years old and having an argument with the VEST representative.  He told me that Brady would need the VEST for the rest of his life and I disagreed with him.  Of course, I went on to explain to him how this new investigational drug was going to take away the need for his VEST one day.  This was just one of many, “oh you poor desperate crazy mommy” looks I received before VX-770 started getting some press. 

With every treatment that we do, for a split second I think, “one down.”  I have always envisioned a finish line.  Because I am such a visual person, I began saving the little vials that hold breathing treatments.  Each little vial represents a chunk of time that Brady dedicated to caring for his lungs.  Here is one of many vases I have filled with these little babies.  I think it is an interesting conversation piece.  My husband thinks that if I collect one more garbage bag full of these, I might be a HOARDER. 

I don't normally keep it in the middle of the room like this, I just wanted to show the size of the vase!  I use it to raise extra money at my CFF events by having people guess how many vials are inside!

The reason I wanted to tell you all my quirks is to show how surreal these last few weeks have been for me.  Having this dream come true is the wildest thing I’ve ever experienced.  This has been the focus of my life since I heard the words “cystic fibrosis.”  That wish to end all others arrived at my doorstep. Brady is breathing easy. Something has shifted in me.  I see the day coming that my collection of vials might be complete...

My life is divided up into three sections now: Before CF, Pre-Kalydeco, and Post-Kalydeco. 

Still, each morning when I sit down to Facebook with my coffee, I see another mother describing her child waking up gasping for air, or entering the hospital, or struggling to grow.  Then I post my Kalydeco update on Brady.  There is a part of me that says, “Can you imagine how your post sounds to that mother?  She must wish I would just shut the hell up.”  Sometimes Brock threatens to take my computer away from me because I’m so often sitting in front of it crying.  Sometimes happy, more often sad.  Since Brady is in the 4% of patients with the coveted G551D mutation, there are 96% still on the sidelines just watching this miracle take place.  A day does not pass that I’m not incredibly grateful for this gift we have been given.  I'm obligated to share.  I seriously feel it is my DUTY to bring as much attention as we can to this “success story,” particularly since it was fueled 100% by the Cystic Fibrosis Foundation and those who support them.  We feel more motivated than ever to fundraise for the CFF.  For the 3^rd year, my husband and I are hosting a golf tournament at the Coeur d’ Alene Resort on May 11^th.  http://onparforacure.weebly.com/

Brady loves to be the star of the golf tournament!

We also lead a team of walkers, Brady’s Buddies, in Great Strides in Spokane, WA on June 2^nd.  http://www.cff.org/Great_Strides/dsp_DonationPage.cfm?walkid=7873&idUser=286719

With this gift comes the responsibility to make sure that the other 96% feel hopeful.  Every parent should be hopeful because those new drugs are just around the corner.   I know there are many patients and parents that have been disappointed by promising clinical trials in the past and they are hesitant to believe this can be true.  My hope is that you open your heart up again because this time it is REAL. 

To summarize my feelings right now, I would say everything is coming up roses…

-I cherish every moment with Brady and every breath that he takes.

-I live every day in gratitude.

-I will work to honor the gift of my own health and teach Brady how important it is to nurture his health as he grows up.

-Nothing can bring me down—I just don’t get upset over life’s small issues anymore.  Everything seems sunny when bathed in the sweet light of a miracle. 

-I never dreamed I could feel this free and light-hearted again.

-I will work to repay the Cystic Fibrosis Foundation for this gift until the fear of CF has been lifted FOR ALL!

What a rollercoaster ride this has been.  I don't remember applying for this job, but I am certainly honored to have it.  Sharing Brady's story is truly my privilege.  To reference a great blog by a fellow CF mama, I’m not sure why Brady was selected as one of those first passengers on the helicopter ride to safety.  http://bennettgamel.blogspot.com/2012_01_01_archive.html

But I do know that I will not let that pilot forget that others are waiting.  Ideally, we will circle back, through those rising flood waters with a cruise ship…with capacity for everyone, rather than another small helicopter.  That way, there will be plenty of champagne ready for us to all celebrate a victory over CF together!! 

Thank you to everyone who works so hard to support the CFF.  I see how many people are working to raise money for Great Strides and other events right now!  I know you have your own personal reasons for supporting the CFF, but it is still important to say thank you.  Thank you for doing what you do, because for Brady-- the outcome is real and it is miraculous.  Those millions of dollars given to the CFF for research have manifested themselves into an extremely expensive bottle of pills in my kitchen.  Those pills are changing our lives.  Thank you.  Good luck to everyone fundraising this year!  The ball is rolling!  We just have to keep pushing forward!  I hope that you look at my posts and go ahead and curse me a little if you like ;)  I can handle it, but then get out there and do your best to support the CFF because you see that same healthy future for yourself or your child!  Brady is living breathing PROOF that they are on the right track, and I'm telling you it is possible to turn those dollars and that determination into something spectacular.  We repeat the sweat test on Brady tomorrow morning.  Baseline number was 105, what will his new number be??  Updates to come on Brady's new health stats compared to his baseline stats!  We are having another blood draw this Friday so we can discuss the results with Brady's CF Doc at our March 8th appt.  We also plan to discuss tapering Brady off of some of breathing treatments at this appointment.  Sooooooooo exciting!!

Genetic Origami

There is so much excitement in the community right now!  I know that everyone is on pins and needles waiting for Vertex to release the official data for the VX/770, VX/809 combo trial this summer.  While people are so tuned in, I want to take the opportunity to summarize a little more data from the NACFC about the process of “fixing” DF508. 

First of all, 50% of the CF population is homozygous (2 copies) for DF508, and 90% have a single copy.   Researchers believe that approximately 30% of CFTR function is needed to get the type of clinical benefits seen with Kalydeco (big drops in sweat chloride paired with large gains in FEV1).  This can be achieved by treating only 1 mutation, so this DF508 research affects almost everyone with CF.  As I outlined in the blog entry “Mutation Matters,” http://luckycfmom.blogspot.com/2011/11/mutation-matters.html
cystic fibrosis mutations are placed into different classes, depending on HOW the CFTR protein is dysfunctional in the cell.  Researchers are looking at two major concepts when classifying:

        I.            How much CFTR matures properly and reaches the cell membrane

      II.            How much of that CFTR on the membrane actually opens and functions properly to transport Chloride.

  For patients with G551D, the protein matures and reaches the appropriate place in the cell, but simply does not open enough for effective Chloride transport.  Kalydeco makes that channel open, and restores Chloride function similar to what carriers of the CF gene exhibit—around 50%.  Sweat chloride levels dropped 47-48mmol on average.  Brady’s baseline sweat test was 105.  If his score drops the average amount (we will find out next Wednesday!), he will go to a 58, which is considered the inconclusive gray area for diagnosis of CF.    

The dysfunction in the DF508 mutation is much more complex and this is the detail I’m really trying to get to in this entry.  For reference, we need a model of the CFTR protein. 

Think of it as a piece of origami.  Every single fold must be made correctly, and in the right order, or it will get crumpled up and thrown in the trash.  DF508’s first problem is that it gets misfolded in nucleotide binding domain 1 (NBD1).  Technically, a base pair is missing from the genetic sequence, which is why it is sometimes called a “deletion” mutation.  Anyway, correctors like VX-809 work to chemically fill that deletion and restore the folding mechanism.  I am hopeful because the amount of protein that they could restore through combination treatment was dose dependent (more VX-770, more CFTR), and also, that they never reached a ceiling or peak on clinical improvement in the short amount of time that patients were on the combo (only 1 week), so they are truly unsure what pumped up dosages might achieve.  VX-809 degrades the action of VX-770, so when the two drugs are combined, they found that they needed to increase the normal dosage of VX-770 to get the best effects.  I am curious and hopeful that a higher dosage combination might be able to reach that critical threshold of benefit and proceed to phase 3 clinical trials.  In vitro (lab), they were able to achieve a 35% restoration with the combo, so it has a real chance.  The ongoing clinical trial will determine if this same restoration can be reached when actually administered to live people.  If this combo were to succeed and reach the market, it is estimated for 2016. 

If you have been following the Vertex clinical trials, that last paragraph may not have been newsworthy.  There is truly no way of knowing how that combo will perform when dosages are optimized until the data is released.   I have been seeing a lot of questions and confusion about “second generation” correctors.   This projected next step in treatment is the result of an increasing body of knowledge researchers are accumulating about DF508.  It was recently discovered that DF508 has a second major obstacle to cell maturation (messing up the origami swan).  The CFTR protein has 2 major parts (nucleotide binding domains or NBD) that must interact with one another for perfect protein assembly.  The second major problem facing the DF508 mutation, is instability at the CL4 interface.  This interface is the place where NBD1 and NBD2 come together. 

This interface problem can also be improved with a different type of corrector compound, designed to stabilize this site.  They found that when two different corrector compounds with different actions(one to fix misfolding, one to stabilize interface) were combined, they worked synergistically-- in other words--the combined result is greater than the sum of the two individually.  This means you might get 20% restored with one corrector alone, and 20% out of the other corrector alone, but when combined…20% + 20% = 70% or more CFTR restoration! 

VX-770 will absolutely be a part of this combination, because even when DF508 proteins fold and assemble properly—they also exhibit a gating defect if they manage to make it to the cell membrane.  This is where VX-770 comes in.  VX-770 works to open ANY CFTR that makes it to the cell membrane, thereby overcoming the gating defect.  DF508 is also suspected to suffer increased cell turnover/premature cell death (defect similar to class 6 mutations) at the cell surface, further reducing the ability to transport Chloride.   So let’s review all the different issues that must be overcome to restore function of the DF508 mutation:

1)      Initial NBD1 misfolding due to deletion of base pair in genetic sequence—needs corrector compound like VX-809 or something similar to restore proper folding.

2)      Instability at the CL4 interface—would require an additional corrector molecule with a different mechanism of action to help restore stability at this assembly site.

3)      Proteins that do successfully mature and reach the cell surface, also exhibit a gating defect similar to class 3 mutations.  VX-770 will be needed to ensure the CFTR channels that make it to the surface actually open and restore Chloride transport.

4)      Increased cell turnover at surface means that it is even more important to include a potentiator like VX-770 to keep the channels open as much as possible to achieve best results. 

In conclusion, I want to say that by including information about the “second generation” correctors, I am in no way implying that the first generation correctors won’t succeed to market and make a huge impact on the CF community.  There is a real chance for a first generation treatment to be successful.  BUT, no matter what, the second generation combinations of 2 correctors plus potentiator have shown in the lab to be incredibly effective and those are projected for a 2020 market date.  Restoring even a modest amount of CFTR can slow the progression of CF, so a first generation could at the very least, buy some time.  At the very best, it may work as well as VX-770 works for G551D.  I can’t wait to see.  And I know I have said this before, but I truly believe they have solved the puzzle for DF508, that now it is a matter of time and money to see these molecules through to the market.  I know many people have wondered why the G551D mutation was targeted first, rather than DF508, which would affect a much larger group of people.   The fact is that G551D has one simple dysfunction to correct--open the gate.  In addition, VX-770 was one of the first molecules discovered to have activity with the CFTR protein.  With DF508, restoring Chloride transport is much more challenging and complex.  You have to first build the gate before you have any hope of opening it.   Here is a very simple white board explanation of the action of VX-770 and VX-809 that I made about a year ago.

One final note for Class 1 or stop mutations.  I sense the frustration with the lack of data on the final Ataluren trial.  10% of CFers have a mutation in this class and are curious to see whether this is a viable option or not.  I don’t have any inside data on the effectiveness of Ataluren alone, but one presenter at the NACFC talked at length about the lab data that VX-770 might be combined with a drug to promote translational read-through of the protein (what Ataluren is supposed to do) to increase Chloride transport activity.   I guess I wanted to include this data because even if Ataluren alone doesn’t prove to be the magic bullet for nonsense mutations, that doesn’t necessarily mean back to the drawing board.  VX-770 may be able to be combined with a drug like Ataluren to increase the CFTR rescue for this mutation class.  Because VX-770 is already FDA approved, it would shave years off the clinical trial process, so that is great news.   

For Reference:
You can check out a lot of this information for yourself in the first Plenary session at the NACFC last fall: http://www.cff.org/research/NACFC/2011NACFC/

Additional information was taken from my notes from:

 

"Combination of Correctors & Potentiators for ΔF508"

Track : Symposium Session III Date: Saturday, November 05, 2011 NACFC
Speaker Steven Rowe from University of Alabama at Birmingham and John Boyle from John's Hopkins

Abstract 4. The CFTR Folding Pathway: Steps Altered by ΔF508 & Implications for the Discovery & Development of CF Therapeutics

Track : Workshop Session I Date: Thursday, November 03, 2011 NACFC
SPEAKER :

Juan Luis Mendoza from UT Southwestern Medical Center at Dallas

 

Abstract 6. Methods to Establish Mechanism of Corrector Action

Track : Workshop Session II Date: Friday, November 04, 2011 NACFC

SPEAKER : was supposed to be Philip Thomas, Ph.D., UT Southwestern Medical Ctr., but was replaced by his colleage and formerly mentioned Juan Luis Mendoza. 

 

Quick Kalydeco Update:

Brady is now 2 weeks deep in his Kalydeco treatment.  He seems like he feels fantastic.  Tons of energy, and sleeping better at night.  We have reduced his steroid sinus rinses from 3X/day down to once a day and he is maintaining clear sinuses.  He has gained a little over 1 lb. since he started the pill.  I have only slightly decreased his enzyme dosage(I've been giving him about 2.5 rather than 3 Zenpep per meal).  We go in to repeat the sweat test next Wednesday.  We will repeat bloodwork and see his CF doc again on March 8th (1 month from beginning treatment).  So far I say two thumbs WAY UP for Kalydeco!

Dr. Thomas began working on the molecular pathology of cystic fibrosis as a postdocatoral fellow at Johns Hopkins University. In 1993, he moved to UT Southwestern where he is now a professor of Physiology. His group is focused on elucidating the molecular basis of CFTR function and dysfunction with the goal of developing improved, targeted therapies. Current efforts include studies of the folding of CFTR and its interaction with other proteins in the membrane.

Baseline

Thursday afternoon, Brady’s Kalydeco was delivered!  We were on the road making our way home as quickly as possible from Arizona, so my parents came to our house to receive the delivery for us.  They were waiting with balloons, champagne, and Kalydeco when we finally arrived home!  The car trip home was fairly torturous.  We just couldn’t drive fast enough!  I could FEEL that the medicine was on its way to our house.  Thursday night, all I did was hold the bottle in my hand and stare at it.  Lots of tears mixed with sheer disbelief.  I’ve been watching VX-770 with an obsession since Brady’s infancy.  The chemist in me has always been impressed with the pharmacological possibilities of VX-770…the mother in me has always been desperate to help Brady escape the inevitable consequences of having cystic fibrosis.  For several hours, I think I really was in a state of medical shock.  My whole body felt numb, heart-rate was racing, clammy hands, and light-headed.  I didn’t get much sleep that night.  I was afraid to put the bottle down.

Meeting my new best friend Kalydeco

Friday morning, we went to Spokane Sacred Heart Children’s Hospital for a sweat test.  This test is typically used to diagnose patients with cystic fibrosis.  Brady was given a sweat test when he was 2 weeks old after a positive newborn screen.  They weren’t able to collect enough sweat off his skinny little leg, and the test came back inconclusive (so we had no previous sweat chloride data).  We moved on to the genetic panel, which is how he was actually diagnosed at 3 weeks old.  Brady also had a blood draw on Friday to establish baseline liver function.  We came home for lunch and then returned to the hospital later that afternoon to see Brady’s CF doc.  The Dr. typically only sees CF patients on Thursday, but he made an exception to see Brady so he could get started on his new medicine before the weekend.   I’ve never been happier to see Brady’s Dr. and nurse.  I shared a couple of the best hugs ever with them!  Then he examined Brady, which is what I really wanted to highlight in this entry. 

Brady's CF Doc

Brady’s Baseline

Brady is probably not your typical 4 ½ year old CFer.  He still has clean cultures, a completely normal chest X-ray, and has NEVER had a cough.  I mean NEVER!  He has only had a few minor colds in his life that never settled in his chest.  He has been on Pulmozyme since 6 mo. of age, and Hypersal since 20 mo. of age, completely as preventative treatment.  We can usually get him to cough a few times at the end of his Hypersal treatments…and then no coughing for the rest of the day.  Brady’s growth has also been exceptional for a child with cystic fibrosis.  This visit was his best ever, 75^th percentile for weight (for age), and 90-95^th percentile for height.  Brady’s biggest issue with CF at this point in his life has been the involvement with his sinuses.  He has aggressively growing nasal polyps that required surgery last October.  Within 2 months of his sinus clean-out, the polyps had begun growing back.  He has been through several Prednisone bursts since his surgery to slow the growth and help him breathe through his nose.  When his polyps are at their worst, he can’t breathe AT ALL through his nose.  He can’t smell, and loses his appetite.  He also snores like a drunken frat-boy and often snorts himself awake at night.  He recently started a new therapy for his sinuses; a nasal atomizer called the “Nasatouch.” (http://www.sinusdynamics.com/video-atomized-sinus-therapy)  We have been irrigating his sinuses with a steroid solution (Betamethasone), 3X daily to keep the polyp growth to a minimum.  We think this is helping, but it hasn’t completely solved the problem.  We are going to schedule an appointment with Brady’s Ear Nose Throat specialist next week to touch base with him since returning from our vacation.  It is very important to us to collect as much clinical data as we can on how Kalydeco is working in him.  Since he is already on the drug, he obviously won’t be participating in the clinical trial for 2-6 yr. olds starting this summer.  Still, Brady is in the National CF Registry, so we are trying to design the first few months of his treatment similar to the trial so we can add some meaningful data to the registry. Also, the insurance required a “pre-authorization” for the Rx.  When the authorization period has expired (they authorize for a specific length of time.  We are calling Monday to find out how long Brady’s Kalydeco is authorized), the insurance company has the option to re-evaluate the medical necessity of the claim.  Collecting lots of clinical data on how it is affecting his body will help us ensure that his claim will be approved again in the future.    The prescribing info on Kalydeco recommends repeating blood work every 3 months for the first year of treatment.  We are going to check his liver enzymes again in 1 month, just to be completely safe.  Also, we are going to repeat the sweat test in 2-3 weeks.  For this to be meaningful data, all other variables must be held constant—so his CF treatment will stay exactly the same…for now(except the addition of Kalydeco). 

Meal where he took his 1st dose

Baseline Stats: Brady's Genetic Mutations are G551D and DF508

Cough: None

Chest X-ray: Normal

Sweat Chloride: 105

Liver Enzymes: We don’t have results yet, but in his last blood draw (3 mo. ago), enzymes were normal.  I will report the actual numbers of this draw when we get them.

Weight: 47 lbs

Height: 42 ½ inches

Blood Oxygen Saturation: 99%

Sinuses: Aggressive polyp growth

Pancreatic Function: Takes 3 Zenpep (10,000 lipase per) with meals, 1-2 with a small snack. Brady eats super slowly also, so I occasionally open a pill and give him a few extra beads (4-5) in the middle of a meal if he is eating a lot of fat and taking FOREVER!

Breathing Treatments and Airway Clearance: Morning--Albuterol and Hypersal via nebulizer followed by 20 minutes on his VEST. Evening--Albuterol, Pulmozyme, and Hypersal via neb.  followed by 20 minutes in the VEST.

Meds: Source CF vitamins, Prevacid, Singulair, Ursodiol, Periactin, Zenpep, and Kalydeco! Brady does an occasional round of Prednisone and Augmentin for his sinuses, but is currently not taking either one of those.

Forehead Lick: Salty.  I know, real scientific right?!  I just want to see if I can notice his saltiness going away.

I’ve seen a lot of questions about what will happen to the regular treatment regimen when patients begin Kalydeco.  My opinion is that each patient will be different and have to make those decisions with their Dr., based primarily on how much permanent lung damage is present.  Kalydeco can’t fix scar tissue, which many CF patients have a significant amount of in their lungs.  My hope for Brady is that he will be able to stop his breathing treatments and Vest one day in the future because he still has clinically normal lungs.  We are going to move very slowly and didn’t even get into too much detail with his Dr. about this yet.  We are determined to stay the course for now, re-test his sweat chloride and blood work soon, and then go from there.  My guess is that one day we will begin to taper him down off of treatments.  For example, he does Hypersal 2x a day right now.  Maybe we will drop down to once a day for a while before we stop it altogether.  Same with Pulmozyme and Vest.  I honestly have a hard time imagining the day when we don’t wake up and do his treatments.  I’m in no hurry to stop his regular treatments…but I also don’t want to have him doing hours of unnecessary breathing treatments if he has “normal” functioning lungs and functioning CFTR.  Brady’s Dr. told us that we probably won’t see much change in Brady’s lung health because his lungs are so good to begin with.  That is just music to my ears.  I have always had the dream of getting this drug to Brady in time to truly offer him a “normal” life expectancy.  I believe that dream is coming true right now and I couldn’t be happier.  I COULDN’T BE HAPPIER!  So far, Brady has taken 4 doses.  The only changes I've noticed are that he seems very energetic and is eating less.  He says he feels "very good."  This morning he had a huge bowel movement.  All sinkers, which indicates he is not passing a lot of fat into his stool and digesting pretty well. 

I want to conclude this post by promising to report the details of the changes we see in him physically and in his labwork as we go along.  Someone asked me for the link to our Great Strides fundraising video from last year so I watched it again this morning.  I cried my eyes out thinking about how we felt the day of his diagnosis compared to how we feel right now.  I didn't think I could ever feel this good again.  Take a look at how much has changed for us since last year... Keep working and hoping.  Anything is possible.

Hoop Jumping 101 for Kalydeco Off-Label

They say jump…you say how high?  As far as we are concerned, we received a SECOND miracle yesterday when our insurance company called us with the approval of our off-label claim for Kalydeco for Brady, who is 4 ½.  I know there are parents wondering what we did to get it approved, and so quickly, so I will share every detail! 

First of all, I have been discussing VX-770 with Brady’s CF specialist since he was an infant.  I frequently took newly published info to give to Brady’s Doctor on clinic days to ensure he was in the loop.  I absolutely love Brady’s CF care team, and honestly have to give them the majority of the credit for the approval.  I think the thing that I love most is their responsiveness.  I emailed Brady’s Dr. within a few hours of the FDA approval…and he emailed me right back.  I’ve been on the phone with Brady’s nurse every single day since the approval.  They always call me back right away if they can’t take my call.  The point of this is that you need a good Dr. on your side willing to fight with you.  Brady is lucky enough to have an excellent physician and nurse. 

His prescription was faxed into CF Services Pharmacy on Thursday Feb. 2^nd.  We also faxed in our enrollment forms for the VertexGPS program.  We called on Friday to make sure it had been received.  At that point, CF Services said that they had Kalydeco in stock, but were waiting on insurance companies to get the drug in their database before they could start billing.  We called our insurance company (Regence Blue Shield of Idaho) and started bugging them about updating their database.  When we called back Monday morning, Regence had just added Kalydeco.  We called CF Services back and asked them to get moving with our insurance.  Monday afternoon, we heard back from Regence that our claim had been automatically flagged because of the price (any drug over $10K/month gets an automatic flag and a “request for more documentation of medical necessity”), and also because of Brady’s age.  We were expecting this.  We called Brady’s clinic back and asked his Dr. to write a “letter of medical necessity.”  They faxed this letter, along with something called a “pre-authorization form,” and lots of Brady’s medical notes into both the Insurance company and CF Services Pharmacy.  The woman we were working with at CF Services was super helpful to us.  The pharmacy didn’t require all this stuff we were faxing them, but it is helpful for them to have in hand when/if the insurance comes back to them with questions or tries to deny.    

Tips for jumping through flaming hoops:

1)      Call all involved parties every single business day.  The squeaky wheel gets the grease.  When we would call our insurance, our claim would get pulled out of a huge pile of claims and actually get some attention.  It would get marked urgent and sent to a manager. 

2)      Write it all down!  We kept a log of every phone call we made concerning Kalydeco.  Time/Date/Who you were speaking with/their extension/will they be working tomorrow?  Get all the information you can to get back to the same person the next time you call.  Keep fax numbers and phone numbers handy in your log.  That way, if you get your Dr.’s office on the phone, you can easily tell them, “I’ve been working with Roger at Regence.  His phone number is…ext…fax…”  You will care more about this than anyone working with you, so you have to be the one responsible to keep all parties in the loop.

3)      Confirm receipt of everything.  Confirm the pharmacy has received the script.  Confirm the insurance has been billed.  Confirm with insurance that the claim has been received.  Confirm receipt of any faxes, etc…  We had to fax Brady’s “pre-authorization form” in 3 times before it was actually received and put in his file.  Don’t assume that just because it was sent, that they have it.  Always call to make sure! 

4)      Provide as much detail as you can if they request more information.  Brady’s Dr. included a lot of his medical chart notes.  Even with as wonderful as our clinic team is…they get busy.  I would always ask the nurse to please email me and let me know when she sent information into insurance or the pharmacy.  I also requested copies. 

5)      If you are attempting an off-label prescription, don’t worry too much about Vertex.  You will be enrolled in Vertex GPS, but Vertex can’t offer you financial support or much guidance for off-label use.  They don’t really have anything to do with the distribution.  In fact, today our Vertex GPS coordinator called us to tell us we didn’t qualify for financial support because of Brady’s age.  I responded, “Thanks for the call.  We don’t need financial assistance.  Our insurance approved it and we are getting it delivered today.”  The Vertex rep was SHOCKED and happy for us.  Don’t even waste your time worrying about Vertex.   You don’t need any kind of approval to get your Kalydeco.  The main issue is getting insurance coverage.  If you get coverage of your claim…you’re golden.  Also, Kalydeco does NOT have to be obtained only from their "authorized distributors."  If you have insurance coverage through specific pharmacies only...turn it in to them and let them call their wholesalers for details.  They will likely be able to get it. 

We have always assumed that our insurance would deny our off-label claim for Kalydeco, which is why we went about getting the Rx so meticulously.  We figured that we would probably need all these details to give to our attorney for the appeal process.  Even though we didn’t end up needing the lawyer, staying organized about the process was extremely helpful.   By Wednesday morning, the insurance company had all the extra information they had requested.  Later that day, they called us with the approval.  They had already called the pharmacy and our Dr. to inform them of the approval also.  I can’t tell you how shocked I was when Brock came running down the stairs yelling “APPROVED!!”  I mean, totally, utterly shocked.  Everyone, including our attorney, had been telling us that this claim had a snowball’s chance in hell of getting approved.  I can only assume that the letter of medical necessity was a big factor in their decision.  With that being said, I will share what Brady’s Dr. wrote in that letter:

“To Whom It May Concern:

 Brady is an almost 5 year old little boy with Cystic Fibrosis [genotype G551D and deltaF508].  I have recommended and prescribed Kalydeco for him, to be started as soon as available.

 Based on my review of the supportive scientific data, Brady is an ideal candidate for starting the drug.  His genotype predicts that it will be efficacious in preventing or slowing development of lung damage in him.  Kalydeco is the first drug to treat the root cause of CF by correcting underlying CFTR dysfunction.  Every other drug he takes treats only the symptoms. Every day that he spends with dysfunctional CFTR puts him at risk of significant lung deterioration due to CFTR dysfunction, which results in abnormal airway secretions, infection, inflammation, and irreversible damage.  With permanent lung damage being the primary ultimate cause of death in cystic fibrosis, PREVENTION of such damage is our #1 goal.  Brady so far has mild lung involvement, making early institution of the drug all the more important; it is proven that damage can be prevented by this new drug, but unlikely that damage can be reversed by this or any other drug.  Additional benefits of Kalydeco which may accrue include prevention of liver damage and possibly other organ dysfunction, though these benefits are not yet proven.

Brady is slightly younger than study subjects, but close enough in age to allow clinical confidence that a dose of 150mg twice daily will be safe and effective.  Delaying institution of the therapy until he meets current age criteria (about 1.5 years) or until studies with younger subjects are completed and published (unknown timeline) will jeopardize his lung health and ultimate prognosis, as well as increasing ultimate costs of care.

I look forward to a rapid positive determination in this case, and would be glad to provide more information or to discuss Brady’s case by phone if it would be helpful.

Thank you very much.”

Immediately following insurance approval, CF services called us to discuss shipment and co-pay.  Our insurance lists Kalydeco as a brand name non-formulary drug, which carries a 50% co-pay.  However, we have an annual out-of-pocket maximum of $4K for prescriptions.  We always meet this annual max.  This year we will just meet it sooner, rather than later!  Our co-pay this month is about $3K for Kalydeco…then we are maxed out and all his meds (including Kalydeco) will be covered at 100% for the rest of the calendar year.  I wrote this on the drive home and am so exhausted.  I can’t wait to get to the hospital in the morning for Brady’s baseline sweat test and blood work.  He will see his CF specialist after that for his first dose of Kalydeco!!

Gating Mutations and Kalydeco...A summary from the NACFC

Since I attended the NACFC in Anaheim this fall, I have access online to all the talks that were given there, synchronized with the Powerpoint slides that were presented.  Pretty awesome.  Since last Tuesday’s announcement of the FDA approval of Kalydeco, I’ve been sifting through research that I think might help our case in appealing to the insurance company for off-label approval of the magic pill for Brady.  Anyway, I went to a great presentation in Anaheim about lab results of Kalydeco in other gating mutations and watched it again recently.  People seem to be very curious now about how Kalydeco works on other mutations...and for good reason!  Vertex actually applied for regulatory approval for all gating mutations in Europe (EMA).  They also announced that their upcoming trial for children aged 2-6 will be open to all gating mutations, rather than exclusively G551D, as in previous trials.   This will be the first chance ever for other gating mutations to try VX-770!  I want to summarize a discussion at the NACFC given by Fred van Goor from Vertex (who actually “discovered” Kalydeco), entitled:   

Abstract 10. VX-770 Potentiation of CFTR Forms with Channel Gating Defects In Vitro. 

The aim of this investigation was to see if Ivacaftor(Kalydeco, VX-770) could potentiate other gating mutations (re-establish CFTR function and Chloride ion flow).  Gating mutations are found in approximately 5% of the CF population, with G551D being the most predominant of those.  Other mutations in this gating category include, but are not limited to: G178R, G551S, G970R, G1244E, S1255P, G1349D.  According to Van Goor, “Most of these mutations ARE NOT included in commonly used CFTR genotyping panels.”   These gating mutations exhibit a similar CFTR protein dysfunction to G551D: CFTR matures and reaches the cell surface in normal quantities, but channel does not open properly to allow Chloride passage. 

Patch-Clamp Studies

Van Goor presented a series of patch-clamp studies to show the effects of Ivacaftor on these other gating mutations.  Patch-clamp investigations basically show a little graph that illustrates exactly when and for how long the CFTR channel is open.  Longer open channel periods result in greater chloride transport, which is the ultimate goal.  Here is a picture of a slide from the presentation, showing patch-clamp results on the other gating mutations studied in the lab.  On the far left of this slide, are the patch-clamp graphs showing the reduced open channel probability of these gating mutations before treatment.  You can see that in all cases, the graph goes along pretty steadily and then has a tiny little blip upward.  This little upward blip represents the time that the CFTR channel is open (close to never).  To the right of that column of graphs (middle of page), are the patch-clamp graphs showing the channel opening when treated with VX-770.  You can see that the graphs completely change from being almost never open…to being almost constantly open.  To the right of that is a bar graph showing “open channel probability” for these mutations.  The bar marked “normal” (furthest bar to the left on this graph, bar shown in white), shows an open channel probability of 0.4 for normal CFTR.  The other bars in blue show the open channel probability of the other tested gating mutations when treated with Ivacaftor.  You can see from the graph that several mutations reach near or even above normal levels!!  Van Goor went on to describe how Ivacaftor increased the open CF channel probability for ALL TESTED GATING MUTATIONS!

In addition to the gating mutations shown on the slide and mentioned previously, three additional CFTR gating mutations were identified and trialed in the lab: S549N, S549R, and S1251N.  Little has been published on these three mutations, but Van Goor showed through patch-clamp studies and open channel probability, that Ivacaftor works very well in these mutations also.  In the case of S1251N, for example, open channel probability was restored to very close to “normal” levels. 
In conclusion, the data presented by Van Goor showed that all gating mutations respond similarly to treatment with VX-770 in the lab.  “This supports the use of…or rather, the investigation of the potentiating benefit of Ivacaftor in patients who have CFTR gating mutations beyond G551D.” (Van Goor)
Q and A:
*Van Goor took a few questions from the audience.  One Physician asked about splicing mutations.  Since some splicing mutations manage to get a small amount of CFTR to the cell surface, would they be possible candidates for treatment with VX-770?  Van Goor responded that he believed they may certainly be candidates.  He described how VX-770 might be able to compensate a bit for the lack of CFTR channels available by the fact that it is basically able to keep the channels that are there, open ALMOST ALL OF THE TIME!  VX-770 is an extremely effective potentiator(increases that open channel time).  Even normal CFTR is potentiated by VX-770.  That means that even if a healthy, non-carrier took VX-770, they would transport more Chloride. Here are a few example splicing mutations: 3120 + 1 G-A, 3849 + 10 kb C-T, and 2789 + 5 G-A

*Another person asked if there were any gating mutations they tested that were NOT potentiated by VX-770.  Van Goor responded, “No.  Ivacaftor potentiated all gating mutations tested, even normal CFTR.” 

I want to wrap up this blog by saying that I truly believe VX-770 will be part of the treatment regimen for most CF patients one day.  It is the first giant step toward making this type of treatment a reality for everyone with CF.  For many mutations (DF508 included), a combination of potentiator(VX-770) + corrector(VX-809, VX-661, or other) will likely be needed to achieve similar clinical benefits.  It is still very exciting to see the patient population that might benefit from VX-770 expanding.  I assume that they are working to add these gating mutations to genetic screening panels, so these individuals can be identified and treated.  I know that the CFF now has a program to help cover genetic testing for those who don’t have genotype information.  Additionally, Vertex has added the mutation R117H to the list of mutations they plan to test Kalydeco on in trials in 2012.  While there is no data about R117H in Van Goor’s discussion, this inclusion means they have similar positive in vitro (in the lab) data for this mutation also.  I would encourage patients with R117H or the previously discussed gating mutations to be in contact with their clinic about upcoming Vertex trials. 

One last interesting note.  Most people know that the trial results of VX-770 alone in homozygous (two copies of same) DF508 patients did not show meaningful results because DF508 patients typically do not have any mature CFTR protein at the cell surface.  However, the trial revealed a small subgroup of double DF508 patients that DID show benefit to treatment.  For reasons unknown to researchers at this time, some DF508 patients DO exhibit some cell surface CFTR, which was, in turn, potentiated by VX-770.  This was a very small percentage of their total trial patient population, but it became extremely interesting to them to find out what made those patients different and how we might be able to identify them.  How do we go about finding out which people might fall in this subgroup?  My guess is that they are working on answering those questions right now!  Keep hoping and working for the CFF because anything is possible! Exciting stuff people. 

 

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.”