Tuesday, July 29, 2014

Conflict Free Zone

I do not have ANY AFFILIATIONS that I need to disclose.  I am not employed by anyone.  I hold several volunteer positions within The Cystic Fibrosis Foundation (Great Strides Spokane, WA Chair, Idaho State Advocacy Chair, Patient Engagement Advisory Committee member).  I have zero conflicts of interest.  In fact, my only real interest in this topic is to see my child, and others that need it, have access to Kalydeco and other new therapies that might be available soon to treat CF.  This entry is simply the way that I see the flood of recent media attention, as a parent of a child with CF. Brady has been taking Kalydeco since February 10, 2012.

I can feel the storm brewing as Vertex's VX-809/VX-770 combo approaches the doors of the FDA. Kalydeco, The CF Foundation, and the astronomical price of this little blue pill have also been very hot topics in economic, pharmaceutical, and medical journals lately. Bloggers all have their own point of view on the issue.  I think I know a lot about it, so I'm offering mine--

The Issue--The Price of Kalydeco.
First of all, let me say that Brady has been enrolled in the Vertex GPS (patient assistance program), since his 6th birthday.  The case managers at Vertex have been really phenomenal to work with.  They are total experts at getting things done with insurance.  Nothing but good things to say about this program. The tricky part is that you must fall under the FDA approved guidelines to qualify for this program.  We pay $15/month out-of-pocket for Kalydeco.  Seems too good to be true.  Before Brady turned 6, Kalydeco was covered by the private insurance (Blue Cross/Blue Shield of Idaho), that we have through my husband's employer (Yes, we got insurance coverage, "off-label" for Brady at age 4 1/2.). Even though the approved label has now been expanded to several other gating mutations, and patients in other countries, the price of Kalydeco has mysteriously climbed over $6K/month over the last 2 1/2 years. Why is that? According to Vertex, they set the price of Kalydeco based on "the perceived benefit for the limited patient population."  Shouldn't MORE patients lead to a LOWER price?  Ha!  Not in a market economy!

The truth is that Vertex, as a company, took a huge blow with the recent failure of their hepatitis drug Incivek.  When Incivek was approved by the FDA in 2011, it generated huge sales for Vertex--estimated at around $951 million for the first 6 months it was on the market.  Their sales came to a screeching halt, as Abbvie and Gilead came out with newer, superior Hepatitis drugs, making Incivek virtually obsolete.  This Forbes article discusses the financial impact on this failed Hep C drug, which prompted Vertex to cut 15% of their workforce.  The article describes how "This has created an enormous gap in future earnings and Vertex needed to cut costs to make up for this loss."

Vertex is a FOR-PROFIT company in a free market economy.  They want to remain profitable as a business, so they can keep their doors open.  Vertex is using the sale of Kalydeco--their one and only successful drug, to make up for their losses in other areas of research, and close the expected earnings gap.

How Can Vertex Do That?  
Why Doesn't The CFF Make Them Charge Less?

Vertex has set the price of Kalyeco so extremely high, that it has delayed access to the drug in some countries (Australia and Canada most notably) and caused push-back from Medicaid in Arkansas.  Lately, I have been reading some criticism on the role of the CFF in this mess, and it upsets me.  This is what I know.
The Cystic Fibrosis Foundation has invested millions of dollars into Vertex (formerly Aurora Biosciences). This money has been used mainly to set up and operate a high-throughput screening lab, to allow scientists to screen thousands of compounds in search of those with the ability to restore chloride channel function. When compounds are discovered that enhance chloride channel activity, they can then be tweaked and further devoloped, tested on human cell lines in the lab, and eventually progress toward clinical trials in humans.  That is exactly how Kalydeco was discovered.  The work done by Vertex with the money invested by The CFF has been nothing short of incredible.  This is the cutting edge of genetic science.   Our understanding of CFTR function has been enriched enormously by their work, which has really set the stage for the whole "small molecule treatment based on mutation class" era that we are entering today.  Even if Vertex hadn't uncovered a blockbuster compound like Kalydeco...we still would have gotten our money's worth.  They did EXACTLY what they were given money to do, and they did a damn good job.  Never in the negotiation did The Cystic Fibrosis Foundation have the power to demand where Vertex must set the price of a drug--if it were to be discovered.  The CFF hoped they would find ANYTHING at all...and they found Kalydeco. Amazing!  At that point in time,  the CFF was knocking on doors begging pharmaceutical companies to do any CF research at all.  We didn't hold the power, or the stock, to have any real sway in setting the price point for Kalydeco.  That isn't how the free market operates.  Honestly, investing in research, there are MANY more failed projects than success stories.  The CFF has put millions of dollars into numerous companies over the years to do research that resulted in absolutely nothing.  That seriously happens all the time! Sometimes all we learn from our investments is what DOESN'T WORK.  Of course, some of those research risks also led to drugs like Pulmozyme, Tobi, and Cayston.  Ahhhh science--strikes and gutters. We paid Vertex to do the research so that it might not take their company out of business if they happened to roll a gutterball with their CF research.  Instead, they rolled a strike by discovering Kalydeco.

The money invested by The CFF into Vertex served to take away some of the huge financial risk of entering the realm of CF research.  Without development incentives, companies wouldn't bother getting involved at all.  The CF population is very small, and it is much more PROFITABLE to be involved in research for a cancer, diabetes, or cholesterol medication--that could potentially be prescribed to MILLIONS of people rather than a few thousand.  The fact that we are having this conversation means that the miracle drug exists...and falls into the "good problem to have" category, as far as I am concerned.

The Unfair Part

The major problem I have with the way this has played out, is that access discrepancies  leave some CF families PAYING TWICE.  The CF Foundation funded a significant portion of the the cost to develop Kalydeco, and the CF community works hard to keep money flowing to The CFF, through grassroots fundraising.  CFF execs also work hard to bring in millions in major donations. It just feels wrong and dirty that the price of Kalydeco is so exorbitantly high, that some eligible patients may never get the chance to try it. In the words of Dr. Francis Collins, "Drugs that are lifesaving, ought to be affordable." It makes me so sick to think about the patients in Australia, and other parts of the world that could benefit from Kalydeco, but don't have access to it because of cost negotiations. After all, it isn't the CF community's fault that Vertex's Hep C drug failed!  Why are we being saddled with the burden of recouping totally unrelated losses?  Because that is the way business works. Vertex charges $300K/yr for Kalydeco simply because THEY CAN. I obviously have some mixed feelings about Vertex.

The Good--The scientists couldn't be any higher on a pedestal in my mind...
The Bad--but I have issues with some of the executive behavior.
The Ugly--Vertex execs have made multi-millions on questionable stock exchanges, and are being investigated by the SEC.  Some patients that desperately need the drug, still don't have it, because of price issues.

Rumors About "Conflicts of Interest" for The CFF

The Cystic Fibrosis Foundation owns a small % of the rights to Kalydeco and receives royalties on its sale. The money that comes in from royalties is re-invested in further scientific research.  The CFF invested $75 million in Vertex to develop Kalydeco.  The CFF then sold a portion of those rights for $150 million (double our original investment!), investing that money in further projects with Vertex, and new projects with pharma giants Pfizer and Genzyme.  Some people argue that it is unethical for The CFF to promote the sale of Kalydeco, which it now considers the standard of treatment for approved mutations, and receive cash royalties for every astronomically priced prescription that is filled.  This is an investment model that The CF  Foundation has used in the past, that has successfully generated millions for new research.  In fact, $20 million of the original $75 million that was invested in Vertex came from the royalties that The CFF made from sales of TOBI. Was THAT wrong? And I will argue that The CFF recommends Kalydeco as a standard of treatment because the science shows it is by far the most beneficial treatment for these eligible CF patients--not to line their own pockets.  It would be absurd if The CFF DIDN'T recommend Kalydeco!  This is certainly not the first time The CFF has used royalties to further scientific discovery, and it has resulted in some amazing improvements to treating CF.   This "venture philanthropy" model is precisely what sets The CFF apart from other disease non-profits.  The CF Foundation may not have the power to demand that Vertex charge a lower price, but they can choose to broaden their investment portfolio, in hope of giving Vertex some direct competition.  In this article, Dr. Beall says,

"Without the financial support of the foundation drugs such as Kalydeco would never get on the market".  He rejected the idea of using the royalty money to help patients pay for the medical care, noting that foundation needed the money to entice large drug companies such as Pfizer to get involved in risky cystic fibrosis drug research.  He said he could only express his concern about the price and invest funds with other companies that might develop competing drugs that someday could bring the price down.  

Bringing competitor potentiators and correctors to the market is how we are going to influence the price of treating CF, and The CF Foundation has been absolutely masterful at not putting all their eggs in one basket. The CFF now has numerous partners like Pfizer, Abbvie, N30, and Galapagos working to bring better, competitive compounds to market.  Vertex got burned when competitors made their Hep C drug Incivek obsolete...the same exact thing could happen to Kalydeco or the VX-809/VX-770 combo.  The CF Foundation is working to lower the cost of these treatments in the most effective, realistic manner our system allows.  And I honestly don't see the conflict of interest in re-investing a portion of the sale of Kalydeco back into research.  As a parent, and "paying customer," I would rather see at least a small part of the monthly payment from our insurance go back to The CFF for continued research.  I think that is the investment that will provide Brady with the greatest returns--in the form of a long healthy life.  The alternative is to see 100% of the money go to Vertex, and miss out on those research opportunities.  It isn't going to lower the price of Kalydeco a single penny if The CFF sells their rights.  It would just be someone else collecting the check at the end of the day.  You know how many Great Strides walks and family bake sales it would take to raise the $150 million in royalties we have received from Kalydeco?  I say we keep the damn money and put it right back into the laboratory.

Speaking of Fat Checks...I've Heard Some Complaints About the Salaries of The CFF Executives Also. 

The CFF has been lead by CEO Dr. Bob Beall, and COO Rich Mattingly for well over 30 years.  These men have dedicated their lives and careers to creating hope, where there was none.  In terms of non-profit disease organizations, The Cystic Fibrosis Foundation is the envy of the industry.  They have had more SUCCESS in changing the course of the history of a genetic disease than some people believed possible. That success came from a radical departure from the typical non-profit operations.  That success came from huge risks that others weren't willing to take.  That success came because our leaders are absolutely extraordinary.  Charitywatch.org reports Dr. Beall's salary at slightly over $1 million per year.  I believe that he is worth every single penny.  We simply wouldn't be where we are today without their unique vision and never quit attitude.  I am  not interested in a mediocre leader for this organization.  I want to cure this disease.  Our leadership is NOT where we want to settle for second-rate, and try to pinch pennies.  Just because it is a non-profit organization, doesn't mean that The CFF doesn't compensate it's own employees, and we want the best!  Of course, there are thousands of individuals that contribute great value to the organization on a volunteer basis.  The executive team, however, is made up of top notch professionals that have made curing CF their entire career.  Criticize all you want, but the fact is, that Dr. Beall's salary is a mere drop in the bucket compared to the multi-millions he BRINGS IN to The CF Foundation every year.  He secured $20 million from Bill Gates alone, in 1999, to get the initial project (The Aurora Project) with Vertex (formerly Aurora Pharmaceuticals) off the ground.  I will argue, until I am blue in the face, that the CFF execs are a HUGE NET WIN for the CF Community.  I admire them as heroes, and can't imagine trying to put an actual value on their worth.  If we want the best in the business, we have to be willing to compensate them appropriately.  And after 30+ years at the same organization, I can't imagine anyone accusing them of staying with CFF to get rich.  INDUSTRY is where the big money is made with expertise like that.  I stand in firm defense of The CFF execs, and their SUCCESSFUL venture philanthropy business model.  If you take Kalydeco, Pulmozyme, Tobi, Cayston, prescription digestive enzymes, or basically any other drug developed to treat CF, you should thank Bob Beall, Rich Mattingly, and Preston Campbell at the CFF. They are responsible for extending people's lives.

Back to the Value of Kalydeco  

Lastly, I've been reading plenty of speculation on the effectiveness of Kalydeco, mostly in financial papers.
Is Kalydeco really THAT good?  Is it really worth the price if patients don't experience close to a "cure"? What about the side effects?

Here is the deal--just as no two cases of CF are alike (even with siblings with CF), no two patients will respond in exactly the same way to Kalydeco.  One big factor is how much "permanent damage" or bronchiectasis, the patient has sustained.  When a patient (with a gating mutation) begins taking Kalydeco,
their Chloride transport is suddenly turned ON.  This new found functioning at the cell surface causes a flush of hydration to those tissues and can stir up some mucous plugs and pockets of infection that may have been hanging out for DECADES in some patients.  For most adults initiating Kalydeco, they go through a period of time that can last from several days to even a few months where their body sort of PURGES old mucous and adjusts to the new mode of operation.  Stirring up these old infections can cause fever, flu-like symptoms, almost unbelievable amounts of flying mucous, and an overall feeling of unwellness (from what I've heard).  HOWEVER, once the initial clearing phase is over, patients report deeper breathing, more watery mucous, and decreased coughing.  In general, well-being is IMPROVED when the body's chloride is functioning more normally.

Imagine a 40 year old man that had smoked cigarettes daily since the age of 15.  If he stopped smoking one day, his body would adjust, and he would experience some HUGE benefits to his breathing ability.  His lungs would start to clear some of the gunk, and greatly slow the rate of decline of lung function.  Still, he may have already developed some emphysema or COPD, and will never breath like someone who had never smoked a day in their life.  He may still need medications to treat his lungs, and may still succumb to illnesses like pneumonia more easily.  He may still, eventually die of lung related problems...even though he stopped smoking.

Hopefully, we don't have many smokers in the CF community, but you can relate the huge spectrum of responses to Kalydeco to this scenario, and understand that the type of maintenance therapies required to manage each person's disease from that point forward will be completely unique.  Scientists are learning more every year about how Kalydeco impacts the body, and have broadened their scope of interest beyond the lungs.  They are looking at how Kalydeco impacts digestion, liver function, sinus function, development of CFRD, etc...  I feel compelled to attend the NACFC each year to stay updated on the newest Kalydeco research.  So far, the more I learn, the better it gets.  Here are some of the highlights--

You don't need to be a scientist to read this graph.  I burst into tears the first time I saw it. Huge increase in FEV1% predicted almost immediately upon initiation of Kalydeco--maintained fairly evenly for the course of the trial.

Another clear example of the power of this drug.  We have NEVER had anything in our hands with the power to change sweat chloride levels--which are (at least loosely) linked to CFTR function.  This graph shows a huge decrease in sweat chloride for patients taking Kalydeco--again, sustained through the course of the trial.
This is a summary from the GOAL study, which examined different study endpoints than were reported on in the phase 3 trial.  Report represents longer term data...shows continued awesomeness.  

I saw data for the first time at The NACFC 2013 that patients experienced a decrease in hospitalization rate with Kalydeco.

Patients taking Kalydeco also have 35% reduced odds of culturing positive for Pseudomonas.

Ivacaftor has been shown to normalize the pH in the lung, enhancing the body's own natural lung defense--proper pH promotes the lungs own "killing power" of invading bacteria.

Ivacaftor has also been shown to normalize pH in the intestines, enhancing the function of the digestive enzyme replacements that most CF patients rely on at every meal.  The enzymes are designed to dissolve when their environment turns from acidic to basic.  This is supposed to happen at the beginning of the small bowel.  CF patients often have trouble achieving that basic environment because of impaired bicarb channel function (bicarb "neutralizes" the acid, changing the pH in healthy individuals).  Many CF patients take acid blockers of some kind to aid the body in achieving a basic intestinal pH.  Patients taking Kalydeco saw intestinal pH normalize, thereby bringing their bodies into the zone where their enzymes would work at their absolute best.  

I am hoping to hear more information on Kalydeco's ability to impact pancreatic function and the development of CFRD at upcoming Conference!  Still an unknown, but an exciting prospect!
Beyond all this "official data," you can read the most recent update on Brady's personal response to Kalydeco in this previous blog entry.

Bottom line: If you want to question the effectiveness of Kalydeco, please bring some real data to back it up. Published information, and what I have seen personally in Brady and the many others I have connected with on Kalydeco, show a highly effective, life-changing  drug for eligible mutation types.  I have heard individuals bring up the fact that those on Kalydeco still showed some decrease in lung function over time. That is very likely true, but the rate of that decline has been cut in HALF.  The long-term data presented at the European Cystic Fibrosis Society Conference still paints a pretty rosy picture, as far as I am concerned. Patients with COPD, asthma, or any other lung disease may experience a decrease in lung function over time also. We may not have achieved perfection with Kalydeco...but we have major improvement.  Patients taking Kalydeco first saw a huge jump in lung function, followed by a reduction in the rate of decline.  Win. Win.

Closing Thoughts
*I believe that The CF Foundation is fighting exorbitant drug pricing in the best possible manner within our system--by investing in competition.  If we want to be in the game at all, we have to follow the free market rules, and you've got to play to win!  I will also argue that CFF execs are worth every penny they are paid.

*Kalydeco wouldn't exist without the venture philanthropy model--which has fueled a large part of the CFF's drug development success.

*Vertex is behaving as many businesses do (despicable, but not overly surprising).  They have a blockbuster in their hands now with Kalydeco, and a recent failure with Incivek.  As far as anyone knows, they haven't done anything illegal.

*Lastly, I could never describe how deeply I appreciate the work done at Vertex Pharmaceuticals.  I mean, I have their molecule tattooed on my left foot.  All I am saying...is that it is my one and only tattoo, and I have plenty of empty real estate where I can place the next amazing compound that comes around!  I would love nothing more than to see my precious Kalydeco become obsolete (and cheap) when a competitor drug maker eventually comes to market with an even more effective potentiator!  Please be respectful in your comments, and remember that I represent no one but myself.

For Reference

Here are some of the publications referenced within the blog...if you are looking for some more light reading.

This article, "Open Channels," was in The NewYorker Magazine in 2009, and details the CFF's financial involvement in the development of Kalydeco, and demonstrates the unique leadership style of the CFF execs.

"Cystic Fibrosis: Charity and Industry Partner for Profit."  This article explains the "venture philanthropy model" and outlines potential conflicts of interest.

"The Curious Timing of those Vertex Stock Sales," describes the questionable stock sales that led to the SEC probe.

"Charity's Investment a Prescription for Profits for Drug Maker." More info on Vertex stock profits, orphan disease drug development, and financial entanglement with industry.

Drugmakers Find Breakthroughs in Medicine Tailored to Individuals' Genetic Makeups was published in The Washington Post on June 1st, and discusses the expensive new era of genetic medicine.  Brady's Kalydeco Story is featured in this article!

"Vertex Failure Shows Biotech is Not Immune to Pharma Type Layoffs" Describes some of the damage control measures taken by Vertex to stay in the game.

"Kalydeco: A Miracle Drug With a Catch" describes access struggles in Canada.

In "The Miracle Drug That Has Changed My Life," read about access issues in Australia, and the absolute cruelness of the delays caused by continued price negotiations.

"Top 25 Compensation Packages" from The American Institute of Philanthropy reports on salaries of non-profit leaders.

"Cracking Your Genetic Code" is an awesome PBS NOVA special, that features Kalydeco story about mid-way through.  AN ABSOLUTE MUST SEE!

"Four Studies of Vertex's Kalydeco" presented at The European Cystic Fibrosis Society Conference this June.

Tuesday, June 24, 2014

Pure Speculation

Vertex released the data from their pivotal phase 3 combination trial today (VX-809 + VX-770), and reported "positive outcomes."  There has already been a huge amount of discussion about it on social media, so here is my opinion...

First of all, let's be clear about these results--they are modest improvements. This combination does not offer the same MAGNITUDE of results that Kalydeco did for G551D patients (but neither researchers nor the CFF expected it to).   Vertex knew prior to the trial, what the FDA would consider "statistically significant" improvements.  With the combo's relatively lackluster results in phase 2, everyone seemed to predict that the numbers from phase 3 would be "a close call," or just BARELY reach that significant threshold.  As hard as I have tried to pry for inside info on this trial, I was never able to get anyone "in the know" to give the combo better than a 50% chance of reaching the necessary trial endpoints.  I have been on the edge of my seat to see the data--not because I thought it would mirror data from the Kalydeco trial, but because I simply hoped it would be GOOD ENOUGH for FDA approval (and that is yet to be seen!).  It would be wonderful if every drug that came to market from this point forward were as effective as Kalydeco is for G551D, but I don't think that is a realistic expectation.  A reduction in pulmonary exacerbations by approximately 1/3 in the combo trial treatment group seems pretty significant to me, and a reason to celebrate this news!  My hope is that combo serves to stabilize/improve lung function for many with CF while BETTER drugs work their way to market!  Even if this is not the perfect drug, it may be a way to--
1) Buy some precious time for thousands of CFers by stabilizing or improving lung function,
2) Increase media focus on curing CF,
3) Keep fundraising momentum going, and
4) Maintain hope within the CF community about future advancements.  

Once the new drug application is submitted (Vertex says "last quarter of this year"), the FDA ruling should come very quickly thanks to the newly designated "breakthrough" status this combo holds.  Breakthrough is the most expedited review the FDA offers, and only a few drugs have been approved.  Recently, Novartis' cancer drug Zykadia was granted Breakthrough status, and on the market about 6 weeks later! Vertex has a good working relationship with the FDA. In other words, if the FDA approves this drug, a ruling could happen FAST--maybe even by the end of this year!

If the FDA approves the drug for marketing, it will almost certainly be labeled exclusively for homozygous DF508 patients.  I am really curious to see where they set their price point for this drug.  In an investor conference call I listened about 2 years ago, Vertex claimed they "set the price of Kalydeco based on the estimated benefit of this drug, for the limited population size."  So...does that mean that they are going to lower the price for the combo because the population group is much larger??  I doubt it.  Call me a naysayer, but when I see that $30K pricetag attached to Brady's Kalydeco statement each month, and see the access battles that have been waged abroad, I have little faith that they won't try to wring every last penny out of this drug also.  I worry how INSURERS are going to react to when 15,000 CF patients want access to drugs in the "ultra-expensive" category.  A large % of the CF population is on Medicaid, which comes back to taxpayer dollars.  There could be some push back for coverage--especially if it only has modest benefits, or ethical questions raised about who pays for these pricey advancements.  We are entering uncharted territory. This is why it is more important than ever to be an advocate for CF! 

I'm sure that some people are disappointed by the small increase in lung function reported in the Vertex data today.  Of course, everyone wishes that number was larger.  I maintain that these results are basically what was expected with the increasing knowledge of the DF508 specific CFTR dysfunction, and data from earlier phase trials.  Looking forward, I've already seen plenty of evidence that "second generation" combinations (many of which have already been tested in the laboratory), are several years away, but represent the huge clinical benefits we all hope for in this new treatment era.  In a nutshell, here is why--

There are a couple of problem sites within the folded structure of DF508 CFTR.  

VX-809 addresses one of those problems, which enables a small amount of CFTR to pass through "quality control" (endoplasmic reticulum) in the cell and make it to the cell surface--where Kalydeco acts on the protein to "open the gate" and allow Chloride ions to pass through.  Even further benefit might be seen if we could stabilize the protein at the surface, and prevent premature unraveling.  

Researchers discovered a ceiling of benefit when correcting only one site, and found that adding a second corrector compound to the mix to treat the other problem area, GREATLY increased the amount of CFTR that was able to reach the cell surface--where Kalydeco did it's job like a champ and opened that gate for a large amount of Chloride to flow through.
Sorry this one is blurry!
It shows that a 3 drug combo restored about 58% CFTR function in the lab.
These "second generation" combos are the ones that are going to give a lot of double deltas the magnitude of results they are hoping for...but for now, I'm going to celebrate a LITTLE BIT of improvement for SOME people with CF!  This is progress!

In the near future, we will also hear more about the VX-661/VX-770 combination. In some ways, VX-661 is known to be a superior corrector compound to VX-809. VX-809 is not highly compatible with VX-770 (The presence of VX-809 degrades the action of VX-770.  To get an effective dosage of VX-770, they had to pump up the initial dosage to 250 mg.--100 mg. more than the standard dosage for Kalydeco monotherapy.  Anytime you increase drug dosages, you run the risk of increased problems with metabolism by liver and kidneys, or other side effects).  VX-661 does not have this type of interaction with VX-770, and just seems to work better in general.  This two drug combo would still be considered "first generation," but could at least represent an option for some folks sooner than a second generation combo.

From this year's Volunteer Leadership Conference

The bar was set extremely high when our first venture into gene modification resulted in Kalydeco.  The announcement today may not live up to those expectations, but I would be thrilled to see the FDA approve this combo and give 50% of the CF population an opportunity to at least TRY a genetic modifying compound to see whether (or not), it works for them.  I AM CELEBRATING a step forward today! Cheers to The CFF!  Vertex Pharmaceuticals!  And all the individuals and families that donated time and/or money to make this possible! 

Saturday, March 1, 2014

A Different Filter

More than 2 years have gone by since Brady began taking Kalydeco.  I want to take the opportunity to recap what life looked like for Brady pre-Kalydeco, back in February, 2012...and compare it Brady's reality now.

Brady's Status--Pre-Kalydeco, Age 4 1/2
Kalydeco was approved by the FDA on January 31st, 2012.  Brady took his first dose on February 10th, 2012.

Lung Health: Brady had very good lung health.  He had always presented with "clean/normal" cultures, and did not have any baseline cough.  A chest CT scan performed 1 month after beginning Kalydeco showed "no visible structural damage" to his lungs.  The hope was that initiating a treatment like Kalydeco at this earliest stage of lung disease may actually be able to PREVENT disease progression.  Prior to beginning Kalydeco, Brady's nebulizer schedule was:

Morning-Albuterol, Pulmozyme, and Hypersal (7%), followed by 20 min. in the Vest machine, for a total treatment time of 45-60 min.
Evening- Albuterol and Hypersal (7%), followed by 20 min. in the Vest.  Total time 30-45 min.

Upper Respiratory Health: Brady may have enjoyed good lung health at that time, but had a really tough time with upper respiratory inflammation.  Brady had undergone 2 surgeries as a 4 year old--tonsil/adenoidectomy, and an endoscopic sinus clean-out.   He had aggressively growing polyps that had completely shut off the air flow through his sinuses.  The polyps grew so large that they had begun thinning and shifting his delicate facial bones.  A CT scan of his sinuses showed that there was a risk of the polyps actually breaking through the eye socket on one side, and causing potential eye or brain damage.  Not cool.  The sinus polyps had also completely robbed Brady of his sense of smell.  He snored, snorted, and struggled to breathe at night and woke up frequently.  Brock and I could hear every breath he took at night, and we also struggled to sleep.  Brady never complained about any pain associated with the polyps, but I can't imagine that this felt good.

He took frequent bursts of Prednisone and antibiotics to deal with upper respiratory inflammation/infection and we used a device called "The Nasatouch" to irrigate his sinuses with steroids 3 times a day.  

I think the Nasatouch is an extremely useful device, but irrigating a 4 year old's sinuses, 3 times a day, is honestly just one step away from full blown HELL.  We basically had to hold Brady down like a criminal and shoot steroids into each nostril--10 seconds on each side.  I'm sure it burned and wasn't very much fun...but we did it.  Even with all our efforts to keep his sinuses open, the polyps began growing back just a few months after the surgery to remove them.  When Kalydeco was approved, Brady had just finished a Prednisone burst for inflammation, but it wasn't helping enough.  His sinuses were definitely getting bad again.   We had an appointment with his ENT coming up, and we were all dreading the thought of going through another sinus surgery.

Digestive Health:  Like many people with CF, Brady had severe pancreatic insufficiency.  I can pinpoint the exact day that his pancreas became completely clogged with mucus, and he stopped being able to digest food on his own (when he was between 2-3 weeks old).  He stopped gaining weight and began having all sorts of digestive distress.  He had already tested positive on the newborn screen for CF by this time, and was diagnosed with CF and put on digestive enzyme replacements within a week.  Brady was not born with meconium ileus, but he did have several soft/partial bowel blockages in the first 4 years of his life.  Like many with CF, I think he suffered with some low grade stomach pain and irregularity, as a rule.  Still, Brady was doing pretty well nutritionally, and his Dr. was pleased with his weight and height at age 4.

Brady's gut functioned best when he was taking approximately 2000 units of lipase/Kg body weight, at meal times.

Then it happened.  Our family was on vacation in Arizona when Kalydeco was approved by the FDA, ahead of schedule.  We were in a small town called Verrado, just west of Pheonix when we heard the news.  Within a week, we had gotten a prescription and insurance approval.  We rushed home for a baseline visit with Brady's Dr., so he could begin the drug immediately. 


Brady's Status Today, 2+ years taking Kalydeco.  Age 6 1/2

Lung Health: In the past two years, we have slowly eliminated almost all nebulizer treatments.  Currently, Brady does 2 puffs of Albuterol with a Vortex spacer, and a single vial of Pulmozyme, once a week, for maintenance.  The environment in his lungs has changed so drastically, that he can no longer tolerate 7% Hypersal, and we don't use it at all anymore.  We also questioned whether or not Brady needed Pulmozyme for maintenance, and decided to slowly taper down from this medicine also.  I feel really comfortable doing it once a week, and having it on hand in case Brady comes down with a virus (if he gets gunky, we will do Pulmozyme daily until the virus is gone).  His current schedule looks like this--

Morning-15 minute session on the Vest is all we do on most days.  Once a week he does a vial of Pulmozyme before the Vest.
Evening-We do NOTHING to manage CF.    

It has been really difficult for all of us (my husband, myself, and Brady's CF Dr.) to make some of these decisions about how to proceed with Brady's treatment schedule.  We have every indication that Kalydeco is working great for Brady, but the LAST thing we want to do is remove a medicine that he still needs.  Because Brady started Kalydeco in a place of excellent lung health--no known bacterial colonizations, no baseline cough, and a CT showing no structural damage--we hoped that Kalydeco alone might be enough to maintain his lung health and free him from the progression of CF lung disease.  Last week, we did another chest CT scan to offer us some feedback.  

I am ecstatic to report that the chest CT scan from last week was identical to his scan 2 years ago--NO VISIBLE STRUCTURAL LUNG DAMAGE 

There is plenty of documented evidence that CF lung disease can progress in the absence of symptoms, so we were really relieved that his lungs seem to be doing so well without daily maintenance (beyond that little blue pill!).  We feel a little more confident that we are following the appropriate path to maintain his lung health...and have the highest hopes that this will continue as long as he maintains functional CFTR with Kalydeco. 

Upper Respiratory Health: The upper respiratory inflammation that Brady had battled for years came to a screeching halt just a few days after beginning Kalydeco.  He was breathing freely through his nose within a week of starting K, and he hasn't needed steroids or antibiotics for his sinuses at all since then.  He stopped snoring at night and regained his sense of smell.  He never needed the next sinus surgery we saw looming on the horizon.  We stopped using the Nasatouch device and currently do absolutely NOTHING to manage this former "headache".  He is completely free of sinus polyps, and sinus symptoms.  It has been remarkable.  

Digestive Health: When Brady first began taking Kalydeco, we noticed some constipation (similar to what might be seen with an increase in enzyme dosage).  We wondered if Kalydeco had affected his ability to secrete digestive enzymes into the small intestine.  There is the hope that in patients without too much pancreatic scar tissue, some function might be restored with a drug like K, that works to thin secretions.  We experimented with lowering his enzyme dosage a bit, but ultimately decided that his gut still functions best with a similar enzyme dosage as always--approx 2000 lipase units/Kg body weight with meals.  To confirm this, we repeated a fecal elastase test last week, and weren't surprised to learn that Brady still has "severe pancreatic insufficiency."  Some patients have been able to reduce enzyme usage with Kalydeco.  I have even heard of some patients being able to stop altogether with enzymes...but not Brady.  His pancreatic damage seems "irreversible" at this point.  With that said, I can't stress how much IMPROVEMENT we have seen with his digestive function!  He hasn't seen a huge weight increase like some patients experience, but it is important to note that he started out with excellent growth percentiles.  So if Kalydeco hasn't improved his pancreatic function...why have we seen such dramatic improvement in his digestive function?  My theory is this--

1) When CFTR function is restored--the mucus in the digestive tract is restored to a thinner, more watery consistancy (similar to the normalization of lung mucus).  You can imagine that excessive, thick sticky mucus in the gut does NOT promote digestion and absorption of nutrients (in the same way that excessive thick mucus in the lungs does NOT promote the transfer of oxygen). Less mucus = better absorption.

2) CF patients typically have an overly acidic environment in both the lungs and gut, resulting in a cascade of chemical imbalances.  In the lung, an overly acidic environment reduces the lung's own natural "killing power" of foreign microbials.  In the intestines, the overly acidic environment causes problems with the efficacy of enzyme replacements.  The enzymes beads are designed to remain intact in an acidic environment (so that they can survive the stomach acid), and dissolve only when the environment turns basic.  In healthy individuals, bicarbonate is released as food passes from the stomach into the small intestine, changing the environment from an acidic pH to a basic pH.  This is where digestive enzymes beads SHOULD dissolve (or where a healthy pancreas secretes natural digestive enzymes) to break down food.  Individuals with CF often have a difficult time achieving the "basic" environment needed to dissolve the enzymes and allow them to work as well as they can.  Many patients take acid blockers like Prevacid or Prilosec to help lower their overall acidity and help their enzyme replacements work better.  Researchers have shown that patients taking Kalydeco were able to restore an optimal pH to their intestine, thereby maximizing the benefit of their enzyme replacement therapy.  In other words, Brady is still taking the exact same dosage of enzymes, but they are actually WORKING far better.  This normalized pH, in combination with the thinning of intestinal mucus has improved his digestive function greatly.  Brady's growth has continued at a healthy pace, and everything in the bathroom has been very "normal" (huge contrast from some of the unusual things I saw come out of that child before!) since Kalydeco came into our lives. 



As far as we are concerned, the changes in Brady's health over the past 2 years have been truly amazing.  I am so encouraged by his latest CT scan, and overall well being.  For my husband and I, finding our new normal has been surreal process.  This winter, we went back to the same small town in Arizona, where we were vacationing when Kalydeco was approved in 2012.  In my mind, Verrado, Arizona is a magical place.  We were so excited to go back, and in many ways, life looked very much the same...

We looked at dino bones before Kalydeco...
Then we did it again 2 years later.

We took desert hikes in 2012 before Kalydeco...

And did the same hikes in 2014.

He fed Giraffes before...(age 4 1/2)
And then did it again. (age 6 1/2)
Brady has grown so much, and he doesn't have his "Prednisone face" anymore, but otherwise you would never guess how much has truly changed in our lives over the last 2 years--all the invisible time, energy, sleep, and peace of mind Kalydeco has given to us.  Look more closely and you will see that the pictures are actually very different--to me, it feels as if Kalydeco has given us a new filter for the camera lens.  This filter is much less burdensome to carry, and every photo is enhanced by the warm glow of relief and gratitude.    

Saturday, October 26, 2013

Up for Debate

Every year at the NACFC, one symposium session is dedicated to debating hot topics in CF clinical care. This year's symposium addressed three important issues, where specialists have significant differences in opinion.  One expert presents the PRO argument, another presents the CON argument, and then the audience "votes" for the winner by applause.

This year, 3 important issues were debated--
1) Can Exercise Substitute for Airway Clearance?

2) Which should be the first drug introduced to manage CF--Hypertonic Saline or Dornase Alfa (Pulmozyme)?

3) Should glucose intolerance be treated aggressively in CF, or not?

I love these debate sessions each year because they expose the wide range of opinions that exist among CF professionals regarding the "right" way to treat patients.  Some people never question their Doc, because it is assumed that they always know best...  These sessions help illustrate why CF care can vary so much from center to center!  Feel free to put in your two cents on any of these topics in a comment!

Can Exercise Substitute for Airway Clearance?
Pro argument given by Dr.Cecilia Rodriguez Hortal.

For the purposes of this argument, Dr. Hortal suggests that vigorous exercise, with built in breaks for patients to "huff cough" and expectorate mucus, could be used as an alternative to regular airway clearance techniques, particularly in pediatric populations with milder lung disease.  She discusses the success of the "Swedish model"--which utilizes exercise and specialized breathing techniques as a form of airway clearance.  She also presents a few scientific studies showing the benefits of physical exercise on CF lung disease.  Exercise has been proven to reduce the viscosity of mucus, improve airway hydration, increase cilia beat frequency in the airways, and reduce markers of inflammation.

Dr. Hortal goes on to explain that physical exercise (both aerobic and anaerobic) offers health benefits far beyond airway clearance, and can be a fun, non-stressful way for patients to perform their airway clearance.  In her opinion, exercise is a more kid-friendly technique that could encourage patients to develop healthy habits for life.  She goes on to discuss one scientific study which showed exercise to be as effective as regular airway clearance techniques for children with CF. 

Can Exercise Substitute for Airway Clearance?  
Con argument presented by Dr. Shruti Paranjape

First, Dr. Paranjape presented the current guidelines for Airway Clearance Therapy:

He went on to explain that there are many methods currently available for effective airway clearance, and that the selection of technique should be tailored to meet the individual patient's needs.  

Even though Dr. Paranjape was presenting the CON argument in this debate, he spent a lot of time discussing the irrefutable benefits of exercise in the CF population.  Dr. Paranjape believes that exercise should absolutely be promoted to improve the health of CF patients--but should be an adjunctive therapy rather than a replacement for airway clearance.   

In the end, both presenters agreed that exercise is an extremely beneficial part of the CF care regimen, but Dr. Paranjape believes exercise should be thought of as an additional "prescription," rather than a replacement for other airway clearance therapies.  There was some discussion about the technique required to move mucus from the peripheral lung (small airways) to the central lung, where it could be coughed out.  Apparently, this peripheral lung clearance happens best during periods of long expiration (long breaths out).  There was concern that if a patient was exercising at an aerobic level, respiration rate would be too rapid for peripheral lung clearance to effectively occur.  It seemed that Dr. Paranjape won the audience vote by applause.  

Which drug should be the first used to treat CF?
Hypertonic Saline argument given by Dr. Margaret Rosenfeld.

Dr. Rosenfeld began her argument by showing some data from the ARESTCF study conducted in Australia.  This revealing study showed that structural lung damage and decreased lung function occur very early in children with CF--even in the absence of symptoms.  Furthermore, this lung damage was found to be progressive.  The ARESTCF study scared me big time when I first saw the data presented at the 2011 NACFC and I wrote a whole blog entry about it: 
http://luckycfmom.blogspot.com/2012/03/cf-lung-disease-does-symptomless-safe.html  The ARESTCF study utilized CT scan to detect structural lung damage like bronchiectasis in infants with CF.  They also utilized the BronchoAlveolar Lavage (BAL) technique to determine the microbiome in the CF infant lung.  BAL is much more sensitive and accurate at detecting infection than the more commonly used oropharyngeal "throat swab." BAL found that infants with CF begin colonizing harmful bacteria long before symptoms appeared, and prior to testing positive for infection on a throat culture.  

The idea is that earlier intervention may be able to PREVENT bronchiectasis (irreversible widening of the airways).  Dr. Rosenfeld believes that Hypertonic Saline is an attractive candidate for first use because it has been shown to hydrate mucus--improving mucociliary clearance. 

She shows that Hypertonic Saline acts fairly early in the cascade of dysfunction that leads to disease in the lungs, by improving water absorption.  

She also shows evidence that Hypertonic Saline has a positive impact on reducing exacerbations in patients over the age of 6...

...But Dr. Rosenfeld has one big strike against her in this argument, and she acknowledges the results of the ISIS study--which failed to show any benefits of Hypertonic Saline use in infants.  

Dr. Rosenfeld believes that the endpoints of the ISIS study may not be the most appropriate to show true benefit in this age group, and suggests that further studies, using alternate endpoints like LCI (Lung Clearance Index, which has been shown to be a much better prediction of lung function in infants than FEV or exacerbation status) or CT scan, may support use of this cheap, readily available drug in the infant population.  After her call for further studies, Dr. Rosenfeld sort of concedes her position before the other presenter even takes the mic!

Which drug should be the first used to treat CF?
Dornase alfa argument presented by Dr. Ran Anbar

Dr. Anbar opens with a little refresher course on what Pulmozyme is designed to accomplish in the lungs.  Neutrophils are white blood cells, which attack foreign organisms in the human body.  Neutrophils are an essential part of fighting infection, but these cells also secrete harmful substances that can cause lung damage (neutrophil elastase).  Neutrophil levels can be elevated in CF lungs, and when these cells die, they leave behind long strands of DNA that act to bind together thick sticky mucus (think about adding a bunch of cooked spaghetti to your jello mold--it is going to strengthen that otherwise flimsy structure.  All those internal connections encourage formation of the mucus "biofilm.").  Pulmozyme is designed to cut up the long strands of extracellular DNA left behind by neutrophils, allowing for better mobilization of mucus.  Dr. Anbar then goes on to present the evidence of Pulmozyme's benefits in patients.  For example, studies show that Pulmozyme slows the rate of lung function decline in CF, and also reduces the burden of infection.

Dr. Anbar says that Pulmozyme interrupts the vicious cycle of infection, inflammation, and obstruction in two crucial ways.

In conclusion, Dr. Anbar felt that the evidence for Dornase alfa to be the first drug used to treat CF was on his side, and the audience agreed.  I am, however, still curious to see what benefits might be seen using Hypertonic Saline in infants if different study endpoints were selected.  For now, Pulmozyme got the win from this crowd.  

    The last question debated dealt with the topic of treating glucose intolerance in CF patients.
Non-fasting Hyperglycemia Should be Treated Aggressively.
Pro argument given by Dr. Deepa Kirk.

Dr. Kirk, an adult endocrinologist, explained that there are guidelines to treat full blown Cystic Fibrosis Related Diabetes (CFRD)--but there is a grey area when it comes to treating early signs of glucose intolerance in CF.  She explains that CFRD develops differently than Type II diabetes.  Rather than a linear progression to disease, glucose tolerance in CF patients sort of toggles back and forth between normal range and CFRD range.  

She explains that glucose intolerance is also known as "pre-diabetes," and in other patient groups (pregnant women, steroid treated patients, the elderly) there is evidence that early treatment can have a positive effect on patient health.  Dr. Kirk goes on to explain how untreated hyperglycemia (high blood sugar), can lead to impaired lung function and further impairment of insulin regulation.  

Dr. Kirk described some small studies on CF patients that showed patients with impaired glucose tolerance gained weight and improved pulmonary function after initiation of insulin therapy.  Since BMI and pulmonary function often begin to decline YEARS before a diagnosis of CFRD, Dr. Kirk feels that early interventions to improve sugar control could lead to an overall improvement in health outcomes for patients.  She notes that untreated hyperglycemia can cause unpleasant quality of life issues for patients that should also be considered (headaches and fatigue).  She maintains that early interventions would not necessarily have to be as burdensome as managing constant insulin injections--in fact, the first therapies for impaired glucose tolerance may likely be dietary modifications, oral meds, or low dose insulin.  

Non-fasting Hyperglycemia Should be Treated Aggressively
Con argument given by Dr. Irl Hirsch

Dr. Hirsch defends the current line of thinking in the CF world right now, which is that non-fasting hyperglycemia does NOT warrant aggressive treatment.  First, he describes the criteria used to officially diagnose diabetes--hyperglycemia resulting in vascular damage known as retinopathy.  He argues that CF patients with non-fasting hyperglycemia do not present with retinopathy.  He goes on to explain the huge range of glucose levels considered normal or "average."  He claims that it is completely unclear how much of the "complications pie" in CF comes from impaired glucose tolerance, and that there is no data to support insulin therapy in this group.  Dr. Hirsch claims that the link between impaired glucose intolerance and lung function represents a "chicken or egg" argument.  Will interventions to improve sugar control improve lung function?  Or do unstable sugars simply go along with worsening CF lung disease and steroid use?  Dr. Hirsch feels that the treatment burden associated with an insulin intervention is too high for the modest benefits that might be seen by patients.    The crowd vote was pretty evenly split between the two presenters.  Regardless of the outcome of this debate, I think CFRD and glucose intolerance are going to be topics that we will hear more and more about in the coming years as scientists unravel the mechanism behind CFRD.  

No wonder it is so difficult to determine the "correct" way to treat CF...even the experts disagree!  I hope this entry inspires some further debate on these topics--ideally with your own clinical team! What additional perspectives could patients add to these pro/con arguments?  

Friday, October 25, 2013

The Breastfeeding Effect

The Conference may be over, but I am going to keep the information coming!  I am trying to overcome the feeling that I need to sit down and write this huge novel for a proper blog post...so this entry will focus on information from a single discussion I watched at the NACFC entitled: The Developing Gut and Respiratory Tract Microbiome in Infants with CF.  

The term "microbiome" refers to the community of microorganisms that live in our guts and lungs. Healthy biomes are generally non-pathogenic (not disease causing)--they exist in harmony with our bodies.  Problems begin to occur in both the gut and lung when certain organisms grow out of control and upset the delicate balance.  The biggest variation in the human microbiome occurs during the first 3 years of life.  

Researchers wanted to know:
1) Do exposure and interventions play a role in the developing microbiome in CF?
2) Are there patterns within the developing microbiome that predict clinical disease?  Do the gut and respiratory microbiomes interact?
3) Are there targets for a healthier pattern that could help PREVENT early disease?

The study utilized a relatively small group of patients, and relied on stool and respiratory samples to provide insight into the developing microbiome.  An overgrowth of pathogenic organisms in the microbiome is indicative of a CF "exacerbation."  

Researchers found that both the digestive and respiratory microbiome increase in diversity over time. There seems to be a relationship between the organisms in the gut and lungs.  As researchers began tracking their observations on these infants, they found one factor that seemed to have a strong effect on the stability of the microbiome in both the gut and the lungs--exposure to breast milk.  Infants given breast milk had more stable microbiomes. 

In addition, babies exposed to breast milk were able to delay the onset of their first CF exacerbation.

The breast feeding effect turned out to be so STRONG, that researchers had to statistically correct for breast fed infants, to gain any meaningful data from this study.  The presenter called breast milk the "gold standard probiotic," and explained that gut colonization patterns are predictors of lung colonization patterns.  The stabilizing effects of breast milk on the gut microbiome seems to spill over to lung microbiome as well.   Antibiotic use, on the other hand, did NOT have a significant effect on the microbiome in the gut.  

I felt strongly about sharing this information, because it represents an opportunity for an all-natural "intervention" for infants with CF.  I understand that the decision to breast feed, or not, is an extremely personal one...and this entry is not intended to pass judgement.  I simply want to share that for the youngest CFers, there is evidence that a dose of nature's gold standard probiotic has been shown to produce meaningful delays to onset of the first respiratory exacerbation.