|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 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.
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.|
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.
|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.|
"Based on the Phase 3 data, Vertex submitted an sNDA in the U.S. and MAA variation in
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...