Friday, October 12, 2012

Plenary 1

It will probably take me several months of blog entries to detail everything I want to say about this year's NACFC, but I have to start somewhere.  This entry will summarize what was discussed in yesterday's Plenary Session.

Plenary Session 1: Reversing the Basic Defect: A Vision for the Future
Speakers Steven M. Rowe, M.D., MSPH and William Skatch, M.D.

In my mind, the overarching theme of this talk was: OK, we've fixed G551D, we think that Kalydeco will be expanded to all Class 3 and 4 mutations, and some others with residual CFTR.  Here is how we are going to go about figuring out a similar treatment for every last CF patient.

First, Dr. Rowe presented some really interesting information from the GOAL study, which is an extended study on Kalydeco in patients to examine secondary endpoints not included in the previous trials.  They are interested in understanding some of the unexpected/unexplained effects that have been seen in patients on this therapy.   Exactly how has CFTR modulation affected the patient's mucociliary clearance (the ability of those little hair-like projections inside the lung to sweep particles and bacteria out)?  How does Kalydeco affect intestinal and/or lung pH and sweat rate?  His focus was on the mucociliary clearance (MCC) endpoint.

He showed how the typical CF lung has severely impaired MCC because those little hairs are bogged down by thick mucus and basically just stop moving all together. This is part of the vicious cycle of infection and inflammation that takes place in the CF lung.  When the cilia stop moving, the body's natural ability to rid the lung of harmful pathogens becomes severely impaired.  They were able to show that CFTR modulation with a drug like Kalydeco could restore mucociliary clearance and movement of cilia in patients.  Boom.  This is the first ever data to show a marked improvement in MCC in CF patients. 

He also announced that the Kalydeco trial for 2-5 yr. olds "officially" had been cleared to begin enrolling patients as of yesterday (10/11).  If you are interested in this trial and you haven't already spoken to your CF care center, do it now.

He also discussed how Kalydeco might be effectively used in other CF populations and how they plan on moving forward with testing this concept.  They are using two approaches: 1) The Genotypical Approach and 2) The Clinical Approach.  This means that they are using genotype information (which mutations the patient has) to identify some candidates (for example, the upcoming trial for R117h, which is a class 4 Conductance Mutation).  Other candidates might be found because they clinically present with symptoms suggesting some residual surface CFTR function--such as those who are pancreatic sufficient or have lower sweat chloride scores (in the 80 mmol/L) range.  He went on to describe the small study that will be taking place in Denver which is the new "trial of 1" design format.  In this format, there is no placebo and the efficacy of the treatment is based on the patient's response.  I am hopeful that this type of study design will open up a lot of doors for future trials in rare mutations, who might otherwise be excluded from large scale studies.  This is good news for heterozygotes because it is so incredibly difficult to predict how those patients will react, and right now they are being excluded from taking part in CFTR modulator studies.  We've got to change that!

Class 1 Mutations:
Next, he summarized the results of the Ataluren trial.  I wrote about this briefly yesterday.  Basically, Ataluren didn't produce statistically significant study enpoints, and also exhibited an antibiotic interaction with Tobi and other aminoglycosides--which completely nullified any treatment effect.  He mentioned a new compound called NB124 that seems like a promising candidate for promoting translational read-through of the protein to produce a full length functional CFTR.  He also discussed combining this compound with a potentiator to enhance its effect.  Getting NB124 to market is going to take some time.

Class 2--F508 and others
They are super focused on addressing the F508 mutation since 50% of the CF pop. is homozygous and 40% of the CF pop. has at least 1 copy.  F508 exhibits several defects in the cell which cause its ultimate dysfunction: 1) Improper protein folding and assembly, 2) Gating defect if any CFTR does manage to reach the surface, and 3) Instability at the cell surface (increased cell death/turnover).  I wrote a detailed blog about this after last year's NACFC, and this year they understand in even greater detail the various issues with F508.  Multiple corrections must be made for this protein to successfully form, move to the cell surface, and then WORK once it gets there.  The VX-770, VX-809 combo is able to rescue approximately 30% CFTR function, enough to produce meaningful clinical changes in patients.

Class 5 and 6 mutations
I didn't catch any concrete details on how to address these two classes, which are not as well understood as some of the others.  He concluded that "further studies" will be needed for all heterozygotes, which encompasses ALMOST everyone in these two groups.

Lastly, Dr. Rowe was excited to announce how many new companies had started CFTR modulator programs like: Pfizer, Genzyme, and N30.  Vertex DEFINITELY needs some competition! Now it is a race to the finish line!

Dr. Bill Skatch spoke next.  He is a member of the "CFTR Folding Consortia" as well as the "CFTR Structure Consortia."  In other words, he walks, talks, and dreams CFTR!!  His talk was very technical, but featured some of the coolest graphics I've ever seen to describe the steps needed to produce functional CFTR in the body.  His talk went much deeper into the details of F508 dysfunction.  He explained that CFTR is like a "molecular jigsaw puzzle."  There are twisted pieces, globular pieces, and straight pieces.  They must all be the correct shape and come together in a step-by-step fashion.  It is such a complex process that it takes the human body 7-8 minutes to make a single CFTR molecule!  There are other proteins called "chaperones" that help regulate folding and speed.  They are learning that these chaperones are an important part of this process.  He described that the final protein must exhibit exactly the right amount of stability, and flexibility at the cell surface to keep from "unraveling" and degrading to become useless in Chloride transport.  He described in great technical detail how they can test this stability by measuring how much energy (in the form of heat) it takes to cause the protein to unravel and degrade.  They need to make CFTR stable enough to remain functional and intact at human body temperature (F508 mutants are unstable at body temp).  He explained the "ceiling" affect that single corrector combinations inevitably hit because one corrector can't take each of these aforementioned problems into account.  Then he described how combining several correctors to account for the multiple dysfunctions was the path to restoring 70-80% functional CFTR for F508.  They know what they are doing. I am headed out the door to a dinner reception!  I may post more later depending on how much wine I drink...Please excuse any errors or typos.  I am trying to be fast!


  1. Again, thank you beyond words, Rebecca! I think I speak for just about everyone in the non-NACFC-attending CF community when I say how incredibly appreciative we are for your UNBELIEVABLY informative and quick posts.

    One quick question: do you know who is working on NB124? I'm guessing it isn't vertex based on the name, but I'd love to know which company it is.

  2. Thank you again for taking the time to write this Rebecca. Keep writing!

  3. Thank you so much Rebecca for all this wonderful information and news.

  4. Thank you for this incredibly encouraging post, Rebecca! I wish I could be there with you! My 2 year old son has an R117h mutation and we are full of hope when we think about what Kalydeco could mean to his health and longevity!