The KIWI study:Ivacaftor for 2-5 year olds

I know that many of you have been anticipating this information.  It wasn't presented until 4:00 p.m. on Saturday, and I apologize for the delay...

An Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Patients Aged 2 to 5 Years With CF and a CFTR Gating Mutation: The KIWI Study

Jane Davies

Early intervention with a CFTR modifier like Kalydeco holds exciting potential. The hope is that the progressive organ damage associated with cystic fibrosis could be PREVENTED by early treatment. 

The study was designed mainly to assess the safety of  Kalydeco.  Patients were given either 50 mg. or 75 mg.(for patients over 14 kilos) Ivacaftor twice daily, in a newly designed granular powder formulation.  The trial was not placebo controlled--all participants received the real drug.

While the study was open to children with any of the approved mutations listed on the slide below, the vast majority were enrolled with G551D.

Investigators collected data on pharmacokinetics, safety, sweat chloride, weight, BMI, Z-score, Fecal elastase-1 (measure of pancreatic function), Immunoreactive trypsinogen, and for the few kids in this age group that could reliably perform spirometry--FEV1. The majority of kids were unable to perform spirometry with good enough technique to be considered a valid measure.

You may recall that FEV1 was the primary endpoint in Ivacaftor trials in older kids and adults with CF.  This trial was focused more on the safety of the drug in the younger group, and the utility of the new granular formula of administration.

The most notable adverse events reported in the study were the 5 patients that experienced increased liver enzymes during the Kalydeco trial (>8X normal levels).  3 of those patients chose to ultimately withdraw from the study.  The speaker noted that all 5 of these patients entered the study with mild liver impairment.  The speaker also commented on the wide number of health factors that can lead to increases in liver enzymes such as: illness, vaccinations, other medication such as antibiotics... Liver enzymes monitoring is recommended for everyone taking Kalydeco, and this group is no exception.  During the question/answer period of the discussion, someone asked about the "high rates" of vomiting reported.  I actually found myself laughing a bit at this question...because 2-5 year old kids vomit a lot, whether they have CF or not.  Kids in this age group are fairly notorious for teething, getting viruses, not chewing up their food well enough, or the thousand other reasons they might find to puke.  The investigator seemed to be thinking along the same basic lines, and felt that if a placebo arm of the study had existed, similar rates of vomiting would have presented.  No opthomological effects (cataracts) were observed.

Researchers were astonished to discover the pancreatic function improvements in these patients, as witnessed in fecal elastase examination.  An audience member asked if patients were able to reduce or stop enzymes, and the speaker responded that they had not been instructed to, but she had heard that some patients had.  Another person asked about the potential to increase the risk of pancreatitis by giving patients "partial pancreatic function."  The speaker responded that she couldn't really answer that question (because she didn't know), but that there was no evidence of those issues in the clinical trial period. Investigators were also surprised to see changes in IRT levels, and weren't exactly sure what the clinical implications of these changes might be.  

I am extremely excited to see Kalydeco reach this younger population group.  If you follow my blog, you probably already know how strongly I believe in early intervention with CFTR modifiers to PREVENT the organ damage associated with cystic fibrosis, and enable these individuals to live longer, healthier, and more productive lives than ever before...

In closing, I want to share this testimony that I just sent to the FDA.  They are currently reviewing the application of Kalydeco for R117H. There is plenty of evidence that Kalydeco works to restore CFTR function for this mutation, but R117H is typically considered a "milder" mutation of CF. These individuals don't often present with serious lung disease until later in life, and did not show the same level of statistical FEV1 improvement in clinical trials.  I feel strongly that people shouldn't have to get sicker, as the only means to make themselves eligible to become well.  It just doesn't make sense. I want to see EVERY PATIENT THAT CAN BENEFIT, whether you are a 2 year old with G551D, or a 30 year old with R117H, have access to Kalydeco.  I want to see patients prevent damage with this drug and enhance the quality of their lives.  I encourage anyone who has experience with Kalydeco, or who has R117H to submit testimony of their own.  I also hope that parents of children 2-5 with approved gating mutations are poised and ready to make similar arguments in the coming weeks if testimony is requested as part of the FDA review process.   Submissions for R117H should be sent to Cindy Hong: PADAC@fda.hhs.gov by October 16th.  This is what I said:

My name is Rebecca Schroeder, and I have a 7 year old with cystic fibrosis named Brady.  Brady started taking Kalydeco on February 10th, 2012, at the age of 4 1/2.  Though he had maintained his lung health fairly well up until that point in time, he still spent approximately 2 hours a day on breathing and airway clearance treatments to maintain that function.  He also suffered from the classic pancreatic insufficiency associated with CF, which caused him considerable discomfort in the form of digestive dysfunction.  For Brady, cystic fibrosis also brought serious upper respiratory inflammation that manifested as sinus polyps. A CT scan revealed that the polyps were growing so aggressively, that they had begun to thin and shift the fragile bones in his face--and threatened to break through his eye socket, leading to possible blindness or brain damage.  Brady had absolutely zero sense of smell.  He underwent sinus surgeries as a 4 year old before beginning Kalydeco, and took frequent bursts of oral Prednisone, performed 3X daily steroid/antibiotic sinus rinses in an attempt to control the swelling.  Quality of life was poor, to say the least.  We did everything we could to battle the progression of the disease, but the symptoms he suffered through everyday made all of our lives hell, despite our best efforts.  Watching your child struggle to breathe is an indescribable torture.  

Everything changed the day Kalydeco arrived at our door.  Within a few days of beginning therapy, we began to see Brady's health completely transform.  As the committee is likely aware, Kalydeco treats cystic fibrosis at the root cause of disease, by restoring CFTR protein function to all the affected organs in the body--lungs, pancreas, sinuses, and the entire gut.  Almost overnight, the serious sinus polyps that Brady had battled on a daily basis for YEARS began to recede, and he discovered his sense of smell for the first time, in a long time.  Before Kalydeco, his sinuses were completely blocked.  I heard every breath he struggled through at night, because his bedroom is right next to mine.  He would frequently snore/snort himself awake during this struggle, making restful sleep impossible.  After 3 days of Kalydeco, all the awful sounds coming from his room stopped.  Brady's breathing became so effortless and silent, and he slept so soundly--that it scared me to death!  My husband and I found ourselves running into his room several times, every single night, to ensure that he was still breathing at all.  The change was truly remarkable. In the 6 months before beginning Kalydeco, Brady had seen his Ear/Nose/Throat specialist 11 times.  Post-Kalydeco, he has only seen that Dr. ONCE--to document the complete disappearance of symptoms.  Additionally, we observed that Brady's energy level shot through the roof, his digestive function improved dramatically, and the constant stomachaches disappeared.  He began to grow and gain weight beyond our wildest dreams.  He began to smile more.  Furthermore, the mucus in Brady's lungs became thin and watery, rather than thick and sticky as it had been before.  The mucus began to function as the vital organ lubricant it was designed to be, and has maintained his lungs FREE from the invading organisms associated with CF mortality.  His CT scan shows that he is FREE of bronchiectasis (irreversible widening and loss of elasticity of the airways).  Brady is now FREE from the hours of daily breathing treatments he used to rely on as ammunition in a losing battle... Today, Brady has those two hours he used to spend doing breathing treatments each day to simply play, and just be a kid. Because Brady hadn't suffered excessive lung damage when this miracle drug was added to his regimen, he no longer has to face an inevitable future of progressive lung disease. I don't EVER anticipate having to face the painful prospect of a double lung transplant, which is unfortunately, the only way to extend life for most individuals with CF.  

I feel that I am in a unique position to provide valuable testimony to the board considering Kalydedo for approval for the R117H mutation.  I have attended the North American Cystic Fibrosis Conference for the last 4 years, and seen proof that Kalydeco works to restore CFTR protein function for this mutation.  R117H is considered one of the "milder" CF mutations, which means that serious lung disease often doesn't present until later in life.  These patients ultimately still suffer the same fate as other mutations that have already have access to Kalydeco, like G551D--but the later onset of symptoms provides an ideal window of opportunity for intervention in disease progression.  I contend that the statistical improvements in FEV1 were smaller for this group of patients, because their lung function was higher to begin with.  Lung function must first be lost, in order to make those gains possible.  If large jumps in FEV1 are the main criteria for approving a disease altering therapy like Kalydeco--many of the patients that stand to benefit MOST, will be excluded.  Patients like Brady, who could represent the first generation of individuals to LIVE a normal life, and successfully manage the symptoms of CF would be denied their miracle.  If you took Brady to the lab today, and performed the sweat test on him--a diagnostic test which is correlated to CFTR function--he would test negative for cystic fibrosis.  The drug has changed the way his body functions on a fundamental level, and will likely add decades of time, and immeasurable quality to his life.  I urge you to consider the implications of denying patients this drug in the abcense of a larger jump in FEV1.  That requirement is akin to demanding that these patients first become more ill, before they are eligible to become well. One thing is for sure, if you wait long enough, the damage is guaranteed to happen in CF.  With the median life expectancy hovering around 40 years old, time is not a luxury we enjoy in this community. 

I beg you to examine the evidence on Kalydeco's powerful impact on CFTR function for this group, as well as the additional positive outcomes I have detailed.  After seeing the positive effects of this drug in my own child, the thought of delaying or denying access to R117H patients is unconscionable.  I am desperate to see this remarkable innovation reach R117H patients.  Kalydeco would help these individuals, and could make them part of this new generation, who easily outlive their parents.

Thank you so much for your time and consideration.  Sincerely,

Rebecca Schroeder

Beyond Small Molecules--Gene Editing Strategies Provide Real Hope to Truly "Leave No Mutation Behind." NACFC 2014

Successful rescue of CFTR function with small molecules like Kalydeco, or corrector/potentiator combination therapies (VX-809/VX-770) hold a lot of promise for the immediate future of altering the course of CF disease.  The tricky part about small molecule therapy, is that different mutations produce their own unique issues.  As we know already, Kalydeco monotherapy is effective for a small percentage of CF mutations, but produces little or no effect at all, in others.  Finding novel combinations of correctors and potentiators to successfully rescue robust amount of CFTR protein function for the myriad of mutations will not be a simple task.  Each year, I hear about dozens of new corrector and potentiator compounds that may be combined in different ways to successfully affect CFTR rescue.  After seeing the potential of this type of therapy in my own son, I am anxious to see more small molecules treatments successfully reach the market.

The small molecule approach can be a very powerful way to impact CFTR function, but still represents a temporary fix for a permanent problem.  For patients like Brady, Kalydeco might be considered a "one day cure."  As long as he maintains sufficient levels of Ivacaftor pumping through his veins, his body doesn't really realize it has CF..., BUT, if he were to stop swallowing those expensive little blue darlings, his CF symptoms would return quickly.  Because of the temporary nature of the effects, small molecules don't really fit the bill as a true cure.  While the CFF has millions of dollars invested in the development of new small molecules, they are also looking even further toward the future. Ultimately, we would all love to see a LIFETIME cure, rather than a ONE DAY cure.  True to the "venture philanthropy" model that The CF Foundation has made famous, they are poised to make considerable investments in new exciting fields of research that could yield that lifetime cure that we all dream of, for each and every person with cystic fibrosis--regardless of their genetic mutations.  I was disappointed that the UK Gene Therapy Trial results were not presented at this meeting as scheduled, but there are plenty of other new technologies to get REALLY excited about.

Symposium Session 8: Gene Editing Strategies for Therapy and Research

In this session, two technologies were described to manipulate genes such as CFTR. What makes these techniques so attractive is that they have the potential to be tailored to treat diverse cystic fibrosis mutations. These techniques can be thought of as "mutation agnostic," and could provide functional results for the multitudes of CF mutations, no matter how rare or complex the dysfunction.

1) Genome editing by the CRISPR/Cas9 system
2) RNA editing--where mutations in messenger RNA are corrected without modification of the genomic DNA

Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of CF Patients
Jeffrey Beekman

To perform this study, adult intestinal stem cells were obtained from rectal biopsies of adults with CF.  Just to be perfectly clear--embryonic stem cells were not required in this research.  The tissue samples obtained from the rectal biopsies were then taken into the lab, where they were manipulated to create intestinal organoids for experimentation.  Most people have heard a lot about changes in sweat chloride levels as a measure of CFTR function.  Over the last several years, I've seen more and more evidence that, while correlated with CFTR function, sweat chloride levels may not paint the most accurate picture of how much functional CFTR is being rescued.  A better way to directly measure CFTR channel function is to examine intestinal organoid swelling.  

This slide details the methods used to grow organoids from adult stem cells. 

CFTR function can be directly measured via the amount of swelling that intestinal organoid cells exhibit.  The amount of swelling can be directly correlated to CFTR function.  This has been found to be a much more accurate measure of CFTR channel activity than sweat chloride measurements.

 For the record, CRISPR stands for clustered regularly interspaced short palindromic repeats--specific targets on a gene, containing short repetitions of base sequences, followed by short segments of "spacer" DNA. Cas9 is a single DNA targeting enzyme that serves to "code" for proteins related to CRISPRS.  In simpler terms, the CRISPR can be thought of as the specific portion of DNA targeted for alteration (the section where we find the presence of the CF mutation).  Cas9 can be thought of as a tiny pair of scissors, programmed to make a cut in the strand of DNA at precisely the right spot.

Here, the CRISPR-Cas9 gene editing system was used to repair the CFTR-F508 target.  Once the double strand cut is made in the DNA by Cas9, the DNA undergoes homologous recombination--or automatic repair to "fix" the break. After recombination, the repaired DNA no longer contains the problematic CF mutation.

Using this method, researchers were able to restore functional swelling of the organoids in homozygous DF508, indicating restored CFTR function.

This work is very preliminary...but extremely exciting.  This experiment serves as proof-of-concept for "regenerative medicine" approaches of CF using gene-corrected adult stem cells.  In addition, this study shows that intestinal organoid swelling can be an effective mode of measuring CFTR function for future studies.  At this point, researchers will need to work on improving the efficiency of correction, which is still very low.  They seem confident that refinement of technique can produce much higher efficiency in future studies.

Correction of Genetic Mutations By Site-Directed RNA Editing
Joshua Rosenthal

The description of RNA editing involves a lot of technical jargon, so I am going to lay this out in two totally different ways—first the scientific version, and then my layman’s translation. 

Version 1:

Adenosine deaminases that act on RNA (ADARS) are a family of enzymes whose activity resembles a natural form of targeted mutagenesis.  Biochemically, ADARS convert adensosine to inosine—a nucleotide that is read as guanosine during translation.  ADARS are modular enzymes with distinct domains that perform different functions.  At one terminus, they contain a deaminase domain that catalyzes the deamination of adenosine to inosine.  At the other end, a number of double-stranded RNA binding motifs (dsRBMs) are found.  These dsRBMs bind to the tertiary structures in pre-mRNAs.  It is problematic to manipulate the ADARS targeting mechanism, so researchers decided to replace ADAR’s dsRBMs (the binding end of the enzyme) with a more easily manipulated, antisense RNA oligonucleotide—which could be easily directed to bind with any primary sequence along an RNA.  Researchers found, that when this antisense RNA oligonucleotide was joined with the dsRBM (via a small bacteriophage binding protein), they could selectively target and edit a single adenosine.  When editing occurs in mRNAs, codons can be recoded and the changes can alter the protein function.  For example, mutations which cause premature termination codons (UAA, UGA, UAG) could be recoded to tryptophan (UGG) to achieve successful protein read-through.  To test their editing system, and provide proof of concept for encoding CFTR, researchers selected the W496X mutation, which contains an early “stop” codon.  In vitro, they showed that their system of directed editing could correct W496X with near perfect efficiency.  In Xenopus oocytes, the genetically encoded version of their editase corrected CFTR mRNA, restored full-length protein, and reestablished functional chloride currents across the plasma membrane.  In human cell lines (grown in lab), their editing system was able to correct a non-functional version of enhanced green fluorescent protein (eGFP) with a premature termination codon.  The next step is to try and correct endogenous CFTR W496X, and other CFTR mutations caused by G-to-A transition, in epithelial cell lines. 

Version 2:

Since I am sitting in the airport, I will also describe RNA editing like this—Imagine DNA as our flight map.  This “map” tells the pilot what the final destination is, and how to get there.  The RNA can be thought of as the “pilot” of our flight, whose job is to follow the map, and deliver passengers where they are supposed to go.  Of course, the pilot (RNA) knows all the details about the trip: how high to take the plane, when to make turns, and how to land at the final destination.  The problem is that sometimes the pilot shows up drunk, and causes the flight to crash and burn.  In that case (as with premature stop codon CFTR mutations), none of the passengers reach their destination.  ADARS (paired with the antisense RNA oligonucleotide) can be thought of as “hijackers,” secretly coming onboard and forcefully changing the details of the flight plan.  They mask the pilot, steal his uniform, pilot hat, and cute little wings (to look “official” and keep the passengers calm) and take the plane to a different destination than originally planned.  Fortunately, the hijackers (in the case of RNA editing) are actually pretty cool (especially compared with to the passed out drunk previously in charge), and instead of taking the blissfully unaware passengers to their originally scheduled work conference in Shittsville, (no CFTR protein produced) decide to redirect the flight to an all-inclusive resort in The Cayman Islands (functional, full-length CFTR). 

 

I hope I was able to convey the fundamental concept behind this new research, because site directed RNA editing is truly a very promising and exciting strategy to correct a broad variety of genetic mutations, in both CFTR as well as other proteins.  The correction of genetic mutations at the mRNA level is attractive for several reasons. 

1) Compared to DNA, mRNA is easily accessible (genomic DNA is sequestered in the nucleus and tightly bound by histones).

2)  Mature mRNA is in the cytoplasm.  The delivery of a site-directed editor to mRNA would only entail crossing a single membrane.

3) Because RNA is transient (where DNA is not), off-target edits (targeting mistakes) are less dangerous.

4) Site-directed RNA editing does not affect mRNA expression level (expression level must be precise—as both under-expression or over-expression can result in disease). 

I've never actually visited The Cayman Islands before...but it seems like a really nice place.

LIVING with CF--updates from NACFC 2014

The NACFC discussions that receive the most attention are typically geared toward the scientific developments.  Obviously, I care deeply about progress toward a cure, but I try to balance those technical talks with some information on ways that we--as a community of patients and families, might be able to have a real positive impact on health through the informed choices we make today.  

The Relationship Between Exercise Capacity and Glucose Tolerance in a Pediatric CF Population Not Diagnosed with Cystic Fibrosis Related Diabetes.

Foster, K.E. Cincinnati Childrens Hospital

Hopefully, most people recognize that regular exercise can provide numerous health benefits to ANYONE.  Regular exercise is especially important for those with CF.  CF related diabetes (CFRD) is a frequently occurring complication of cystic fibrosis, and is associated with greater decline in lung function, poorer nutritional status, and lower life expectancy.  In this discussion, Foster examined the connection between exercise capacity, and the ability to successfully regulate blood sugars.  

Foster measured both exercise capacity, and glucose tolerance (via oral glucose tolerance testing) in 50 patients, and discovered a correlation between low exercise capacity, and increased 2 hour blood glucose values.  This suggests that patients with low exercise capacity have poorer glucose tolerance. Foster speculates that working to improve exercise capacity may help delay the onset of CFRD via improved blood sugar control.  

As you can see in this slide, there isn't hard data on this correlation, but rather, a strong suspicion that blood sugar control may be improved with regular exercise--leading to a delay in the onset of CFRD.  

Since I personally believe strongly in the value of exercise in health maintenance, I want to hammer the point home with one more discussion:

Yoga Improves Posture and Muscular Performance in Adult Persons with Cystic Fibrosis

Scott Russell, University of Southern California

"Persons with cystic fibrosis are prone to posture dysfunction, in part due to pulmonary hyperinflation and chronic coughing which can lead to injury, chronic pain disorders, vertigo, headaches, balance dysfunction, increased risk for vertebral fractures, and loss of physical functioning.  The purpose of this study is to investigate the effects of Hatha yoga on posture, neuromuscular performance, and self-reported psychometric measures."

In this small study, patients agreed to participate in twice weekly, 90 minute, outdoor yoga sessions over the duration of 8 weeks.  A couple of important points worth noting:

1) Strict infection control guidelines were observed--persons with CF were each provided with their own (vs. shared) yoga props, and were equipped with hand sanitizer gel, tissues, etc...  Yoga was also practiced in an open, outdoor area and the "6 ft. rule" was observed due to multiple CF participants in the same class.  Of course, if you decide to take up yoga, it is unlikely that you would be surrounded by other CF patients, and such strict precautions may not be required.  

2) Russell made sure to note that practice of yoga for CF patients often requires modification of poses to avoid the "head down" position, or "inversions," which can aggravate acid reflux/GERD for many patients.  It is very important to educate the instructor about the need for these modifications, since an increase in acid reflux symptoms would be an undesired effect, and could lead to a worsening, rather than an improvement in lung and postural health.

This is hard to read, but it says that the primary aims of this study are to discover 1) the effects of yoga on pulmonary functional, and chest wall mobility, 2) the effects on physical function and posture, and 3) effects on scapulothoracic posture.   Self-reported psychometric measures regarding quality of life were also recorded.  Ultimately, Russell wanted to determine the SAFETY and POTENTIAL BENEFITS of yoga for persons with CF.

These are examples of the "head down" positions that should be AVOIDED if you suffer from acid reflux/GERD.

Here we see an example of a modified downward-facing dog position.  Note that the trunk and head stay parallel to the ground, rather than the typical head down positioning.  A few extra props may be helpful for the appropriate modifications

Russell provided an example of the poses used by the instructor in the intervention.  

The results showed an improvement in chest wall excursion after 8 weeks of the yoga intervention.

Scapular positioning was also improved--positive effects on posture. 

Patients showed improvements in the "Sit to Stand Test" and several other fitness measures.

Patients had improved self-reported attitudes toward their weight/body image.

As I mentioned earlier, this was a small study, but I appreciate that we are discussing topics like this AT ALL, so I wanted to report on it anyway!  It is my blog, and I do what I want! :)

You might even consider doing your own "future investigation" on whether yoga is something that might be beneficial for you, remembering to follow the appropriate precautions.

In conclusion, Russell reported that in this phase 1 feasibility study, yoga improved posture, chest wall excursion, lower extremity muscle performance, and the self-reported body/image perceptions.  

In my opinion, exercise is an extremely underutilized tool to improve health outcomes for CF patients...and basically everyone else (in the U.S., at least!).  While we don't have a ton of evidence from a large scale study on the benefits of yoga specifically, there is PLENTY of evidence regarding the benefits of regular exercise.  Maybe yoga doesn't sound so great to you...and that is OK!  The best type of exercise will be something you enjoy, so that it will be done consistently.   Since no new breakthrough therapies are hitting the market today...why not try EXERCISE as a natural, effective way to provide multiple health benefits?  I know that when I recently attended a "restorative yoga" class with my friend Savannah, I left the class feeling awesome--both physically and mentally.  I think that the attention paid to breath control in yoga makes it a particularly attractive option for patients with pulmonary dysfunction.  

The next talk I want to summarize deals with a topic that some people wouldn't consider CF related at all, but I will argue that mental health issues can have deep and long lasting effects on health for both CF patients themselves, as well as their family members.  As a CF mom, and a member of the Patient Engagement Advisory Committee for the CF Foundation, I've come to realize that mental health simply cannot be segregated from our physical health.  Babies and young children are absolutely dependent on their parents for everything from proper nutrition to adherence to their prescribed CF treatment regimen.  If a caregiver is struggling, negative effects can ripple throughout the family, and ultimately affect the child.  When I was a new mother struggling with Brady's CF diagnosis, I would have never even considered bringing up my own mental health struggles with Brady's CF clinic team...even though I realize now that I probably should have.  It didn't seem like the time or place for me to air my own concerns about how out of control I felt over my emotions, and life in general.  Parents of children with special needs often put their own problems on the back burner, and find the topic to be too personal and painful to discuss.  I struggled with depression, crippling anxiety in regard to clinic visits, and persistent sleep problems during Brady's infancy.  I didn't want to admit that this time in my beautiful son's life was a really dark and scary period for me. I just figured that because CF sucks so much, I would probably never feel really good again, and that the depression and anxiety were par for the course.  I'm sure that my struggle is not unique, and that many of you may potentially relate to the helpless state I found myself in.  

What Healthcare Providers Need to Know About Postpartum Depression (Associated with Newborn Screening), But Were Afraid to Ask.

Audrey Tluczek

This discussion dealt particularly with postpartum depression associated with a CF diagnosis following newborn screening.  The speaker explained that she uses the term "postpartum depression" simply because it is defined by the onset of depression symptoms coinciding with the birth of a child. Unfortunately, for families with a newly diagnosed infant, that early period can be so overwhelming and scary.  Many would probably consider postpartum depression/anxiety a problem exclusive to mothers--but when management of a chronic disease in a child is required, it can be just as pronounced in FATHERS, GRANDPARENTS, or anyone that is functioning as a care provider for the child.  Tluczek discussed the need for more formal depression screening as a part of the regular clinic visit for families with newly diagnosed infants, and training of the clinic care team to provide useful interventions.

Clinic teams are becoming aware that mental health assessments NEED to become an integrated part of CF care.  Unfortunately, many members of the care team may not be formally trained to recognize the symptoms.

For family members exhibiting signs of depression in association with care of the infant, treatment options can include psychotherapy, support groups, medication, and hospitalization for the most severe cases where the health of the individual or child is believed to be endangered.

This is important, because depression negatively impacts parent/child interaction.

I didn't realize how much my own mental health might be negatively affecting the precious child I wanted so desperately to protect.

Having a good relationship with a stable partner, family support, and the ability to provide for the basic social and economic needs of the family were found to be important factors in lessening the negative effects of post diagnosis depression. 

The CF Foundation recommends that mental health screenings should be a part of the regular clinic experience for both CF patients, and their families.    

In this day and age of comprehensive care, I think it is so important that we feel that we can discuss depression, anxiety, OCD symptoms, or any mental health concerns with the CF care team.  Looking back, I certainly wish I hadn't suffered in silence for so long.  It is equally important that care teams are appropriately trained to recognize the symptoms of mental health issues, and provide options for treatment that may include referral to an outside professional.  This topic is simply too important to remain taboo.  It should be noted that while this talk focused specifically on postpartum depression, mental health concerns can come up at any time, especially with the demands of chronic disease management.  These issues are important to address at any stage of life.

I know many of my readers tune in to the blog for science updates.  I hope I haven't tarnished my rep by devoting this entire entry to the fine art of living and thriving with CF.  Tomorrow, I plan to return to the cutting edge...and honestly, I need a night to sleep on the information I heard this morning in Symposium 8: Gene Editing Strategies for Therapy and Research.  I believe that the future cure for EVERYONE with CF--regardless of their mutation, may become reality through one of techniques discussed in that room.   Until tomorrow...

Updates from the NACFC--Thursday Oct. 9th, 2014

I wait impatiently for the NACFC each year.  This is my 4^th year in attendance, and I love having the opportunity to share the newest information with all of you.  This year, I flew to Georgia a few days early, to spend some time with another CF family I have become close to via social media through the last several years.  As you know, CF is an isolating disease…and I typically take every chance I get to make that real life contact.  BE WARNED—if you invite me to visit—I might actually do it!  Thank you to Teresa, Savannah, and Sam, who spoiled me with the finest in Southern hospitality, and will have a permanent place in my heart. 

Teresa and I drove from Savannah to Atlanta on Wednesday afternoon, retrieved our registration bag o’ goodies, and began networking with the arriving attendees at the preferred meeting space—i.e., the bar.  I can’t tell you how good it feels, to be surrounded by so many brilliant professionals from around the globe working to cure CF.  For me, the NACFC not only expands my knowledge, it also expands my heart.

If you follow CF research, you are likely aware that Vertex published data from their phase 3 clinical trial of a VX-770/VX-809 combination therapy for homozygous DF508 patients several months ago. The results from the study showed modest benefits in lung function and small decreases in sweat chloride levels.  To be honest, after the FANTASTIC results experienced by most G551D/gating mutations with Kalydeco alone—the results from the combo trial (while positive) were disappointing to some.    Vertex reports that they plan to apply to the FDA with a new drug application in “the last quarter of this year.”   There has been plenty of speculation on whether or not the FDA will consider the benefits of the combination therapy statistically significant enough to approve the drug for marketing.  I am hopeful...but why haven’t we reached a greater level of improvement with the combo for DF508?  Theoretically, an increase in CFTR protein trafficking to the cell surface (via the corrector action of VX-809), plus an improvement in chloride channel open probability (via the potentiator action of VX-770) should produce a more robust improvement.  Dr. Deborah Cholon thinks her data can help provide an explanation for the “smaller than hoped for” treatment effect seen with the combination of these two molecules.

Potentiator VX-770 Abrogates Pharmacological Correction by Destabilizing VX-809 or VX-661 Rescued DF508 in Airway Epithelial Cells.

First of all, let’s review.  The DF508 mutation has several issues contributing to the overall protein dysfunction—

1) Decreased stability in the folding mechanism of CFTR—resulting in decreased trafficking to the cell surface

2) Gating defect for any protein that does manage to reach cell surface (similar to what is seen with G551D) the channel doesn’t open and close properly—“rusty gate.”

3) Increased cell turnover at the cell surface (any protein that does successfully arrive in the correct place in the cell, rapidly “unravels” and doesn’t actually become a functional Chloride channel).

When researchers began exploring how to correct CFTR function for DF508, they quickly realized that the road would not be nearly as straightforward as it had been for the gating mutations.  To achieve a robust amount of functional CFTR, multiple problems must be overcome—requiring multiple compounds to get there.  Individually, both VX-770 and VX-809 produce the desired action on lab cultured cell lines.  Unfortunately, Dr. Cholon discovered that for the DF508 mutation, chronic exposure to VX-770 had a destabilizing effect on the amount of mature CFTR protein able to be “rescued” (successfully mature and reach the cell surface).  Furthermore, exposure to VX-770 also increased the rate of turnover (the unraveling process), ultimately reducing the amount of CFTR available for chloride transport.  The higher the dosage of VX-770, the larger the destabilizing effect on DF508.

Exposure to VX-770 reduces CFTR rescue (maturation)

Also reduces the stability of the protein--leading to premature unraveling.

The negative effect of VX-770 exposure on DF508 was also observed in combination with the other corrector compound in development at Vertex--VX-661.

Researchers have been focused on finding a great corrector compound for DF508, but what they didn't realize is that "one size does not fit all" when it comes to potentiator action. VX-770 works great for gating mutations, but "disagrees" to a certain extent with DF508.

Even with this crappy news--the fact remains that an overall positive treatment effect was still observed in the combo trial:

Relative improvement of 4.8% in FEV1 with combo treatment

Decreased rate of hospitalizations and IV antibiotic use with use of combo treatment for homozygotes.

Fewer exacerbations observed in trial group treated with combo therapy.

I believe that Dr. Cholon's research does indeed provide some valuable insight into the smaller treatment effect seen in the combo trial.  I think there there is still a decent chance for FDA approval of this combo therapy, but the hunt for a more suitable potentiator for DF508 is certainly ON.  In the Q and A portion of this talk, Dr. Cholon described that while VX-770 may act negatively on the maturation and stability of CFTR, the molecule may still provide "alternate benefits" such as the improved regulation of bicarb (which can help normalize pH in airways--increasing the lung's own innate killing power of invading organisms), and subsequent reduction of the "bacterial load" in the lungs.

I hate to report this as my first piece of Conference news, but there were several talks today, including an entire afternoon symposium session, focused on the negative effect of VX-770 on DF508 this year, and I'm not good at sugar-coating (Other titles along the same lines presented this afternoon:

Potentiator Ivacaftor Abrogates Pharmacological Correction of DF508 CFTR--Gentzsch,

Mechanisms of Potentiator Inhibition of DF508 CFTR--Bridges, Opposing Effect of the VX-770 

Gating Potentiator on the Corrected DF508 CFTR Function and Processing--Lukacs.

This info is certainly NOT what I wanted to hear or report, but it is also NOT A REASON TO FREAK OUT. The results of the combo trial were published months ago, and showed that the treatment effects of the combo were not as robust as we had hoped.  At least now we have some idea WHY that is happening.

Moving on...

I didn't have to wait long for more positive news.  Later in the same workshop this morning, we heard from R. Fitzpatrick from The Flatley Discovery Lab (a privately funded research facility dedicated exclusively to finding new potentiator and corrector compounds).

Progress Toward a CFTR Modulator System

The Flatley Lab has high-throughput screening capabilities, and has tested over a million individual compounds, and more than 36,000 novel compounds for ability to positively affect CFTR rescue and open channel probability.  Their research has already yielded several potential drug candidates.

Potential compounds for development. 

Flatley Labs has found a compound with similar action to VX-809 called FDL169

And they are moving forward with development.

They have also discovered several new potentiator candidates, that could be utilized in a future novel combination therapy.  You may notice that the potentiators shown on this graph don't quite reach the level of benefit that is seen for VX-770 for G551D, but they may still prove superior to VX-770 if the DESTABILIZING effect described earlier on DF508 can be avoided. 

Sorry this is so hard to read!  The slide shows that Flatley Labs favored potentiator compound--FD2033129, does NOT inhibit CFTR correction in DF508.  This is reason to believe that it may be a more feasible molecule for use in combination with a corrector for DF508.

Flatley Discovery Labs is hoping to initiate trials on some of their discovered compounds in "December of this year, or January of next."  They are already discussing combining multiple correctors with their novel potentiator candidate to create a "second generation" combo therapy for DF508.

The last talk I want to summarize in this entry was given by Fred Van Goor from Vertex:

R117H is a Residual Function Mutation That Is Potentiated by Ivacaftor

As you may know, R117H is a mutation where the CFTR protein is observed at the cell surface, and SHOULD be effectively potentiated by Kalydeco.  In trials, Kalydeco was found to have a "less statistically significant treatment effect" for this group, and R117H was subsequently excluded from the FDA's expansion of approved mutations earlier this year.  Van Goor proposes that the smaller effect observed in R117H as compared to other gating mutations is NOT a consequence of diminished action of Kalydeco, but rather, a function of the milder nature of the R117H mutation itself.

R117H is generally considered a "milder" mutation.  Many patients with this mutation are pancreatic sufficient.  Serious lung dysfunction often doesn't present until later in life within this group, and I know of several patients with this mutation that weren't even diagnosed until adulthood.  

Patch-clamp studies show that Ivacaftor increases the frequency of channel opening of the CFTR protein at the cell surface for the R117H mutation.

Van Goor went on to show that treatment benefit to R117H could be increased by the addition of Lumacaftor (VX-809)

All signs indicate that R117H is a good candidate for both Kalydeco monotherapy, as well as combination therapy.

If Kalydeco is working so well for R117H, then why were smaller improvements in FEV1 observed in clinical trials?  Van Goor suspects that this group was unable to achieve the massive gains in lung function observed in the other gating mutations, simply because the lung function of patients in this group was already very good to begin with.  You can't gain 10% lung function if it has never been lost in the first place.  To further illustrate this point, let's consider my son Brady's response to Kalydeco. Brady has DF508 and G551D, and I have written VOLUMES about the benefits we have observed in him: disappearance of serious sinus polyps, huge drop in sweat chloride levels, increased energy, increased BMI and nutritional status, etc...  BUT, Brady did NOT see a huge improvement in lung function because his lung function was good to begin with.  The absence of a huge improvement in FEV1 DOES NOT mean that the drug is not working incredibly well.  You can't keep going up if you are already near the top!  Based on the evidence presented today, and over the last several years, I agree whole-heartedly with Van Goor's explanation.  According to the press release published by Vertex today,

"Based on the Phase 3 data, Vertex submitted an sNDA in the U.S. and MAA variation in Europe for approval of ivacaftor in people with the R117H mutation. Vertex's sNDA for the use of ivacaftor in people with the R117H mutation will be the subject of an FDA Advisory Committee Meeting of the Pulmonary-Allergy Drugs Division on October 21, 2014. In the United States, Vertex is seeking approval of ivacaftor in people ages 6 and older with the R117H mutation."

I am very hopeful that we will see an approval for R117H soon. There is so much more to say, but it is time to sleep so I can do it all again in a few hours!  Tune in tomorrow for news about:

The Relationship Between Exercise Capacity and Glucose Tolerance in a Pediatric CF Population Not Diagnosed with CF-related Diabetes--Karla Foster

Yoga Improves Posture and Muscular Performance In Adult Persons with Cystic Fibrosis--Scott Russell

What Healthcare Providers Need to Know About Postpartum Depression (associated with Newborn Screening) But Were Afraid to Ask--Audrey Tluczek

Plus,  news from an amazing Plenary Session and much much more!  As always, please forgive my typos.  These events involve wine...

Schmoozing