CFTR modulators are one area of Cystic Fibrosis research. These are medications which help the underlying cause of CF, the CFTR channel. Correctors (help the CFTR to get to the surface) and potentiators (help the channel to open, such as Kalydeco) are examples of CFTR modulation.
There are multiple pharmaceutical companies working on CFTR modulation, including Vertex, N30, Pfizer, Genzyme, Galapagos, Proteostasis and Calista Therapeutics. Vertex and N30 have medications in clinical trials.
F508del homozygotes (two copies F508del):
Vertex have two correctors in clinical trials with F508del homozygotes, VX809 and VX661. These help the CFTR channel to reach the surface. These correctors are being trialled in conjunction with Kalydeco, as Kalydeco can increase the function of the channel once it is at the surface.
VX809: Two 24 week phase 3 trials have commenced, data expected mid 2014.
VX661: Phase 2 results were released in 2013, a 12 week phase 2 study is planned for 2014. Read more about VX809 & VX661.
N30 have started a phase 1b/2a trial with their compound N6022, which is a CFTR corrector with anti-inflammatory properties. They are trialling their compound with F508del homozygotes: N30 News release and Trial info
The F508del homozygous group represents about 50% of the CFs in Australia.
F508del heterozygotes (one copy F508del):
VX809 and VX661 are also being trialled with F508del heterozygotes, but the results with VX809 have not been as strong as the homozygote results (VX661 heterozygote results have not been released). F508del homozygotes produce more F508del that VX809 can correct and Kalydeco can potentiate. People with one copy would still have some improvement but there is less F508del that the meds can help. Vertex are working on triple combination therapy, where Kalydeco, a corrector and a new second generation corrector are used together to further increase the improvement. The F508del heterozygous group represents about 40% of the CFs in Australia (but 15% or so of the heterozygotes have a second mutation that Kalydeco alone may help).
Second Generation Correctors:
VX809 & Kalydeco are able to produce 25% of normal CFTR function in the laboratory with F508del homozygotes. To put this in context G551D with Kalydeco reaches 50% function. Vertex are now developing a second generation of medications that are more effective than Kalydeco and VX809. In the lab, when a second generation corrector is added to VX809 & Kalydeco with F508del heterozygotes, approx 33% function is seen, and with homozygotes, 45% function is seen: Latest second generation corrector graphs.
Mutations similar to F508del:
Recent clinical studies found that VX809 increased the CFTR trafficking with E56K, P67L, E92K, L206W, V232D, H1054D, G1061R, L1065P, Q1071P, L1077P, H139R, R258G and S945L. See these two posts for more information: study one & study two
Ataluren helps class 1 mutations that have a premature stop codon (end in X), by helping the CFTR protein to be made past the stop codon. These mutations represent about 5% of the population in Australia. Ataluren has completed phase 3 trials, whilst the results were positive (positive results were seen with people who were not on inhaled Tobramycin) more trials are needed in order for this medication to become available. A second phase 3 study is planned to start in 2014 with nonsense mutations. The potential for combination therapy with Kalydeco was also mentioned during the August investor conference.
It is hoped that in the future all CFs will have personalised medications for their specific genes. If you are following this research and you do not know your mutations, I would advise asking your doctor.
These are some images from a recent Vertex investor presentation in Oct 2012. Kalydeco is also called Ivacaftor.
Source: October 2012 and Feb 2013 Vertex Investor Presentations. These are no longer available online: http://investors.vrtx.com/events.cfm