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.    





Monday, October 21, 2013

Plenary 3--CFRD

The third Plenary Session of NACFC 2013 explored the topic of Cystic Fibrosis Related Diabetes (CFRD) and was entitled: CFRD: From Bench to Bedside & Back again.  Andrea Kelly, M.D., MSCE was the first speaker in this session.

Patients with CF are living longer than ever before (YES!), but age can bring new health issues--including CFRD.  CFRD is very common--50% of CF patients will develop it by age 30.  Current guidelines recommend annual oral glucose tolerance tests beginning at age 10.

Insulin secretion defects are present early in CF patients, and are progressive. We know that CFRD doesn't behave exactly like Type 1 or Type 2 diabetes...so what is the mechanism driving the impaired glucose tolerance here? Understanding precisely why so many CF patients develop CFRD could lead to better, earlier therapeutic interventions.  After all, CFRD is associated with a lower survival rate and higher rates of lung transplant in CF patients.  Not good.  Not to mention that CFRD can have a real negative impact on your life. Successfully managing CFRD can be burdensome and time consuming. Symptoms can include decline in BMI and FEV1.

 

Some readers might be thinking, "My child is young and her sugars are normal--this doesn't apply to me."  Dr. Kelly would argue that it DOES.  She goes on to explain the typical oral glucose tolerance test (OGTT)--a sugary drink (75 g glucose) is administered, and after 2 hours, the patient's blood is drawn to test blood glucose levels.  Levels below 140 mg/dL are considered normal.  140-199 classifies as "glucose sensitive." Levels above 200 mg/dL are diagnostic for CFRD.  Dr. Kelly believes that that the standard OGTT may actually miss many CF patients exhibiting early signs of glucose intolerance and goes on to show some evidence.  She suggests that CF patients have an initial delayed and blunted insulin secretion, similar to type II diabetics, and believes early indications of this could be picked up more accurately with the non-fasting, 50g glucose test, where blood glucose is tested after 1 hour instead of 2.  Her argument is that early insulin abnormalities can be seen in the time immediately after ingesting glucose, and this test could be better at identifying and treating those individuals exhibiting the earliest signs of CFRD.  If dealing with CF has taught me anything, it is that it is almost always better to nip problems in the bud before they get big and ugly. Controlling blood sugars is no exception.

She went on to describe how pancreatic enzyme replacement has an effect on insulin secretion.  Individuals who take their enzymes properly have improved insulin secretion and blood sugar control!  Some of those individuals who screen positive for early glucose intolerance might be able to see some improvement by simply tweaking their enzymes a bit (may need support to be diligent in taking them, others may need a dosage adjustment.)  That is nice to know.  Others may need alternate interventions.


The mechanism driving CFRD isn't completely understood, but Dr. Kelly describes important cells in the pancreas called beta cells--whose primary function is to store and release insulin.  Patients with CF have impaired beta cell function.  Preserving the function of these cells is crucial to controlling blood sugar levels.


There is also a question whether CFTR function could impact insulin secretion, and Dr. Kelly described a pilot study sponsored by the CFF to answer that question.  This study will examine if Kalydeco (Ivacaftor) has a direct impact on insulin secretion.






Before concluding her discussion, Dr. Kelly mentioned that standard nutritional recommendations for CFers may HASTEN the progression of impaired glucose control and development of CFRD.  Patients should still strive to meet the fat/calorie recommendations for CFers, but modifications to carb intake and regular exercise could lead to better glucose control. 


The next speaker in the Plenary session was Dr. John Engelhardt, who works with CF ferrets and CF pigs to gain understanding to the mechanism behind CFRD.  CF pigs and ferrets develop lung and pancreatic disease similar to humans, and provide an effective model of study.  Newborn pigs have severe pancreatic disease.  Ferrets have milder disease, but rapidly develop disease and pancreatic fibrosis.  Many have blood sugars greater than 200 mg/dL arising at about 1 mo. of age.  It is unclear whether infants with CF exhibit the same early abnormalities, but there is certainly evidence that we should study further.  



Engelhardt shows that 42% of patients aged 1-5 exhibit abnormalities in glucose tolerance.  He goes on to describes the current hypotheses to describe the pathogenesis of CFRD.  Some believe that the exocrine disease in the pancreas (inability to secrete digestive enzymes), spills over to affect the endocrine function (ability to secrete the hormone insulin) of the pancreas.  Others predict that insulin secretion is tied to CFTR function.  I am really curious to see the results of the upcoming studies to examine this link.


Engelhardt described regions of the pancreas called islets, which contain insulin producing cells. Islets contain detectable levels of CFTR, which suggest that CFTR function may play a role in maximizing islet function.  The Plenary session concluded with the recommendation that tight nutritional control may have a large impact on the progression of CFRD, and that further studies in pig and ferret models may lead to therapies that slow the beta cell dysfunction in CF.  


The message that I took away from this Plenary session is that impaired insulin secretion begins early in life for CF patients, and can progress undetected by our current OGTT methods.  While there are many ways that CFRD differs from type II diabetes, similar management strategies may be useful for both groups (reduced carb intake and regular exercise).  It can be really tough to meet CF fat and calorie needs when you place ANY kind of restrictions on the diet, but it looks like we are going to need to get real about the amount of carbs being used to reach those dietary goals.  The earlier we are able to detect, intervene, and manage glucose intolerance--the longer beta cell function can be preserved, improving blood sugar control.     

Saturday, October 19, 2013

Roadmap to a Cure: Part II--Leave No Mutation Behind


Today started out with the second Plenary session: Roadmap to a Cure: Part II.  The discussion was given by Dr. Bonnie Ramsey, University of WA School of Medicine, Seattle WA.  Dr. Ramsey is also the Director of the CFF Therapeutics Development Network.  She is extremely smart and we are all lucky she has dedicated her career to CF. 


Dr. Ramsey’s talk went into detail about how the CFF is working to “leave no mutation behind.”  She talked about what was learned in the process of getting a successful FDA approval for Kalydeco and how we can use that “roadmap” to guide us toward successful treatments for other mutation classes.  I mentioned in the day 1 summary that knowledge of your personal mutations and their functional class will be crucial to take advantage of genetic modifying treatments like Kalydeco.  In the spirit of discovery, it is important to mention that the CFF has a free program to identify unknown mutations in patients called MAP—The Mutation Analysis Program.  If you have a CF diagnosis, but only 1 known mutation, the CFF will sequence your genome for free and find it!  This is so incredibly important. Standard panels to screen for CF usually include the most common 23-26 mutations.  NONE OF THE OTHER GATING MUTATIONS (other than G551D) ARE INCLUDED IN THE SCREENING PANELS!  If you still have an unknown mutation, it could potentially be in the gating class, and Vertex has already applied to the FDA to expand Kalydeco access to these patients!  Imagine what a pleasant surprise it would be to learn that your rare unknown mutation has a gating defect and you could soon begin taking and benefiting from Kalydeco!!!  I hope everyone with an unknown mutation will take advantage of this. http://www.cff.org/LivingWithCF/AssistanceResources/MAP/ If you know your mutations, but are unsure of which class they fall into, you may find that information on http://cftr2.org/.  Another valuable explanation of mutation classes and their dysfunction can be found at  http://www.cftrscience.com/ I wrote a blog in 2011 about mutation classes: http://luckycfmom.blogspot.com/2011/11/mutation-matters.html Of course, the CF clinic team may also be able to offer information on this as well.    

CF mutations are divided into 5 basic classes based on the nature of CFTR dysfunction they exhibit.  Mutations within the same class have similar cellular dysfunction, meaning that if a drug shows a positive response with 1 mutation within the class, there is potential that the drug may be therapeutic to the entire class.  In general, class I, II, and III are associated with more severe disease manifestation because they exhibit little to no functional CFTR activity.  Class IV and V mutations are associated with milder disease—patients may be pancreatic sufficient or slightly lower sweat test scores.  In these two classes, there is a very small amount of at least partially functional CFTR on the cell surface.  There are over 1900 CF mutations that have been discovered.  You can imagine that it is going to be a complex task to address each and every one, but the experience with Kalydeco shows us that IT CAN BE DONE. 



Ivacaftor clinical trials taught us that when approximately 30% CFTR function is restored, many clinical symptoms can be ameliorated.  Kalydeco is able to reach this therapeutic threshold for all gating mutations.  I am hopeful that the FDA will give this a quick positive ruling.  Kalydeco monotherapy may also soon be extended to children 2-5 who have G551D or any gating mutation.  The KIWI study (Kalydeco study in ages 2-5) has officially completed enrollment.  This is a 24 week study and results are anticipated in the second quarter of 2014. 


The KONDUCT study is another phase 3 trial that is already underway, and tests Kalydeco in the R117H mutation.  Results of this study are expected by the end of the year.  Right now, Kalydeco is approved to treat about 4% of the CF population.  If the label is expanded to include all gating mutations and R117H, we can bump that number up to about 7% of CF patients being treated with a gene modifier.  I want to reiterate that these mutations were not selected to be the first to be treated—in contrast, they were treated first because they are the absolute easiest to correct.  These patients have CFTR sitting on their epithelial cell surface, just waiting for a small molecule like Kalydeco to come along and open that dormant CFTR channel.     

There is a major focus on "fixing" the DF508 mutation, which falls into class II.  Mutations in this class exhibit multiple, complex dysfunctions within the cell.  The CFTR protein is 1) misfolded, 2) thermally unstable (the protein is sort of “floppy” and often unravels at normal body temp), and 3) also exhibits a “gating” defect.  In other words, even if you were able to correct the folding and thermal instability, you would still have a CFTR protein sitting on the surface unable to open—like G551D and other gating mutations.  To restore any meaningful function, a combination of correctors and potentiators must be used.  Correctors are small molecules that target misfolding, instability, and trafficking to the cell surface (problems inside the cell).  Potentiators target the gating defect (inability to open and close properly), once the CFTR protein reaches the appropriate place in the cell (cell surface).  Lab studies have shown that multiple corrector compounds plus a potentiator like Kalydeco, may be needed to obtain the level of clinical benefit seen in with Kalydeco in gating mutations.  When you pair multiple corrector molecules together to target different problems within the DF508 protein, the amount of CFTR rescue is increased dramatically--up to 80% restored function (that is even BETTER than Kalydeco works for G551D patients!).  These multi-corrector combos are still a few years out though, and I am still very optimistic that we will see an FDA approval of a first generation combination like VX-809/VX-770.  There are 2 phase 3 trials moving forward right now examining optimal dosages and relative change in FEV1.  The hope is that within the next several years, a drug combination will be FDA approved to treat the DF508 mutation, which will hopefully translate to treatment for all of class II. Because 50% of the CF population is homozygous for DF508 and 90% of the CF population carry at least one copy of this mutation, an effective treatment for DF508 could benefit up to 90% of the patient population.  While the VX-809/VX-770 combo is currently only being tested in homozygous patients, there is the potential that many heterozygotes may also benefit to some extent from this combination. Remember, with Kalydeco and G551D, only one mutation is being treated.  Heterozygotes with one copy of DF508 should be hopeful about any combinations designed to treat double DF508--especially the second generation combos, which have proven to be significantly more powerful in their ability to rescue CFTR function.   


What about Class I nonsense mutations?  Last year, the Ataluren studies yielded some disappointing results.  They failed to meet their primary endpoint and found that there is a strong drug interaction between Ataluren and inhaled aminoglycosides (TOBI is this type of drug).  Patients who were NOT taking TOBI showed some statistically significant improvement on Ataluren (5.7% increase in FEV1), but those who WERE taking TOBI showed absolutely no benefit.  Last year, no one seemed willing to hypothesize on the future of Ataluren and I feared the antibiotic interaction problem might be too much to overcome.  This year, Dr. Ramsey announced that there PTC Therapeutics will be moving forward in an additional phase III study to test their drug only in patients not on Tobramyacin therapy. In addition to this study, the CFF has initiated new research to address this mutation class.  The CFF invested millions of dollars this year and enlisted big hitters like Pfizer to search for new molecules to treat Class 1 mutations.  I understand that the Ataluren results were extremely disappointing for many--but please know that book is not yet closed!  Not only is the search on for a brand new molecule to treat class 1 mutations, they are also screening compounds that are already currently FDA approved. There are already several other existing compounds that have been shown to promote translational read-through of the CFTR protein.  Imagine how much time could be saved if we didn't have to start at the absolute beginning, with a brand new compound!  All the human safety trials could be skipped and we could move right into end stage trials designed to prove the therapeutic effect.  Plus, it seems that there may still be a chance for Ataluren to turn out some positive data from this new phase III trial.  Class I--you have not been forgotten.  



OK, so we have a plan for treating Class I, Class II, Class III (Kalydeco), and many in Class IV mutations (Kalydeco monotherapy or corrector/potentiator combo).  This still leaves approximately 10% of the CF population with rare mutations, who may not fall neatly into one of these therapeutic classes.  Many patients in this remaining 10% may have an unidentified mutation (utilize the Mutation Analysis Program to find out!), and may discover that their unknown mutation DOES actually fall into a class with an available drug.  If not...there is still a plan.  Yesterday, I described some techniques that have been developed to obtain a patient's own tissues to utilize for testing.  Truly personalized drugs may need the answer for these patients.  With the ability to obtain patient tissues for lab testing, compounds can be screened for a therapeutic effect in that individual.  When an effective drug is discovered, patients would participate in a "trial of 1," where the patient serves as their own control for the study--response guided therapy.  The trial of 1 concept is already being used in Denver to test whether Kalydeco might be beneficial for certain heterozygotes with splicing or other rare mutations that produce some residual CFTR function.  The CFF won't stop until a treatment is developed for 100% of mutations, and they have a plan on how to make that happen.  I haven't even mentioned that there are other therapies in the pipeline that are NOT mutation specific--in the realm of "gene therapy," it doesn't matter what mutation you have.  Anyone with CF would benefit, no matter their genotype.   By this time next year, researchers in the UK will be ready to present their data on their huge gene therapy trial.      

Changing the course of the disease at a basic level is obviously an important area of focus, and could provide amazing opportunities for all patients--particularly young children/infants that are able to be placed on these interventions at an early age.  That doesn't mean that we get to forget about treating traditional issues like inflammation and infection.  

Advancements in Anti-microbials
After laying out the roadmap to eventually treat the basic defect in all patients, Dr. Ramsey then turned to other areas of development in treating CF.  First she discussed a new way of improving treatment of Pseudomonas infections. It has been found that there is an excessive amount of Iron in the CF lung that contributes to bacterial overgrowth and the formation of biofilms.  Iron is basically food for bacteria, which makes the CF lung a smorgasbord for organisms like Pseudomonas.  Trials are moving into phase 2 for a drug called Gallium nitrate, which is a molecule almost exactly the same size as iron. The idea is that when Gallium nitrate is administered, it can slip right into the place in the cell where the iron normally resides--replacing the iron.  This disables the bacteria and results in disruption of the biofilm, as well as better antibiotic penetration, and better infection control.  Want to know the other good news?...Gallium is already an FDA approved drug for other indications, and it is moving into phase 2 trials in CF patients now!  



MRSA infection is very common, especially among CF patients in the U.S.(vs. UK).  There has been some debate about how harmful MRSA infection really is, but studies have shown that patients chronically infected with MRSA live 6.2 yrs less than those who are not.  In other words, they are becoming more convinced that aggressive treatment of this infection is necessary, and 3 studies are currently open and recruiting patients!  If you are interested in participating in one of these trials, contact your CF center!  I recommend that everyone sign up for "Clinical Trial Alerts" on CFF.org to receive the latest and greatest clinical trial news! http://www.cff.org/research/ClinicalResearch/Find/ClinicalTrialAlerts/
Of course, you can also find information on clinical trials at http://clinicaltrials.gov/



They are also investigating ways to improve treatment for Non-tuberculous myobacteria.


Treating Inflammation
Inflammation is a big problem for CF patients.  Inflammation can cause cell death, and subsequently, those dead cells leave behind waste products that are harmful to lung tissue.  Neutrophil elastase is one of those waste products causing damage in CF lungs.  According to the Australian ARESTCF study, patients as young as 3 months old, showed elevated neutrophil elastase levels in their lungs (a way to measure the level of inflammation), even in the absence of symptoms.  In other words, it is a problem that starts early in life and progresses over time.  We currently have only one proven efficacious therapy for inflammation--high dose ibuprofen.  


Thankfully, there are some ideas for future studies.  They will be looking at compounds that might be able to "sop up" some of that damaging elastase in the lungs.  In addition, the CFF has launched a Strategic Planning Initiative to evaluate more potential areas of anti-inflammation research.  



My thoughts on Day 2: Brock and I attended workshops and symposium talks all day and there is a lot more to write about.  It has been a real challenge for me to find time for all the Conference sessions, physical therapy, schmoozing with the amazing folks in attendance, and writing the blog.  Basically, I don't sleep while I am here, and Brock has been so good to chauffeur me around in the wheelchair and put up with all my craziness.  I feel like I still have so much to report, but I have to wrap up for now...I have a dance to get ready for!  I apologize for the quality of some of these slides and hope they are all at least readable.  The funniest thing about being here is that I have been recognized by the tattoo on my left foot about 25 times, "Hey, I know that foot!"  No one recognizes my face, but my foot is pretty famous!  I can't believe that the Conference is almost over now, and I survived!  Stay tuned peeps, more to come tomorrow!

Stupid escalators!