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. If you know your mutations, but are unsure of which class they fall into, you may find that information on  Another valuable explanation of mutation classes and their dysfunction can be found at I wrote a blog in 2011 about mutation classes: 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 to receive the latest and greatest clinical trial news!
Of course, you can also find information on clinical trials at

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!


  1. Thanks for the awesome information. Cf patients and their caregivers are some of the smartest people I know, and I wish we got more credit for that. Anywhoo, I did want to ask about the inflammation issue. As I understand it, the azythiromycin therapy that is given on MWF, has anti-inflammatory properties. I have read some articles and will see if I can find it. The ibuprophen treatment comes with some issues that at certain does the neutrophils increase. There is also and increased risk of bleeding, and with fragile lungs that can be an issue.

  2. I am a DF508 and R785X ... I went to the website you provided above regarding finding out if a mutation was a gating mutation. I found a list of mutations, in which both of us these are on, but it didn't provide any info on whether R785X was a gating mutation (or what type of mutation it is). Perhaps I was misreading the table.

  3. Michael a mutation that ends in X is a nonsense class 1 mutation, these have been involved with Ataluren trials.

  4. Great update - many thanks! Could you please point me towards the source for this stat: "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!)."

    I'd love to read the research paper (or whatever) that held such a promising number for a combined therapy approach.