Thursday, October 9, 2014

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

I wait impatiently for the NACFC each year.  This is my 4th 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...



  1. Our 6 month old daughter has Df508/R117h... this is great news and thank you so much for sharing! God Bless and #curecf!

  2. I love reading your summaries. Thank you!!

  3. Thank you so much for, as usual, bringing us such excellent information!! I especially appreciate the explanation of the df508 challenges in the initial part of your entry. As a child with one df508 mutation you can imagine how closely I follow these trials. I knew df508 was complicated to fix, but did not realize it was the potentiator causing so many of the issues... So we need another "Kalydeco type med" and if they know what they need and have the technology with which to loo for it, that brings us a step closer. Thank you. Knowledge is power for me and just better understanding the process helps. :)

  4. Time for the clinicians to try Vx809 with curcumin/genistein combo: