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.”

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.