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