Gating Mutations and Kalydeco...A summary from the NACFC

Since I attended the NACFC in Anaheim this fall, I have access online to all the talks that were given there, synchronized with the Powerpoint slides that were presented.  Pretty awesome.  Since last Tuesday’s announcement of the FDA approval of Kalydeco, I’ve been sifting through research that I think might help our case in appealing to the insurance company for off-label approval of the magic pill for Brady.  Anyway, I went to a great presentation in Anaheim about lab results of Kalydeco in other gating mutations and watched it again recently.  People seem to be very curious now about how Kalydeco works on other mutations...and for good reason!  Vertex actually applied for regulatory approval for all gating mutations in Europe (EMA).  They also announced that their upcoming trial for children aged 2-6 will be open to all gating mutations, rather than exclusively G551D, as in previous trials.   This will be the first chance ever for other gating mutations to try VX-770!  I want to summarize a discussion at the NACFC given by Fred van Goor from Vertex (who actually “discovered” Kalydeco), entitled:   

Abstract 10. VX-770 Potentiation of CFTR Forms with Channel Gating Defects In Vitro. 

The aim of this investigation was to see if Ivacaftor(Kalydeco, VX-770) could potentiate other gating mutations (re-establish CFTR function and Chloride ion flow).  Gating mutations are found in approximately 5% of the CF population, with G551D being the most predominant of those.  Other mutations in this gating category include, but are not limited to: G178R, G551S, G970R, G1244E, S1255P, G1349D.  According to Van Goor, “Most of these mutations ARE NOT included in commonly used CFTR genotyping panels.”   These gating mutations exhibit a similar CFTR protein dysfunction to G551D: CFTR matures and reaches the cell surface in normal quantities, but channel does not open properly to allow Chloride passage. 

Patch-Clamp Studies

Van Goor presented a series of patch-clamp studies to show the effects of Ivacaftor on these other gating mutations.  Patch-clamp investigations basically show a little graph that illustrates exactly when and for how long the CFTR channel is open.  Longer open channel periods result in greater chloride transport, which is the ultimate goal.  Here is a picture of a slide from the presentation, showing patch-clamp results on the other gating mutations studied in the lab.  On the far left of this slide, are the patch-clamp graphs showing the reduced open channel probability of these gating mutations before treatment.  You can see that in all cases, the graph goes along pretty steadily and then has a tiny little blip upward.  This little upward blip represents the time that the CFTR channel is open (close to never).  To the right of that column of graphs (middle of page), are the patch-clamp graphs showing the channel opening when treated with VX-770.  You can see that the graphs completely change from being almost never open…to being almost constantly open.  To the right of that is a bar graph showing “open channel probability” for these mutations.  The bar marked “normal” (furthest bar to the left on this graph, bar shown in white), shows an open channel probability of 0.4 for normal CFTR.  The other bars in blue show the open channel probability of the other tested gating mutations when treated with Ivacaftor.  You can see from the graph that several mutations reach near or even above normal levels!!  Van Goor went on to describe how Ivacaftor increased the open CF channel probability for ALL TESTED GATING MUTATIONS!

In addition to the gating mutations shown on the slide and mentioned previously, three additional CFTR gating mutations were identified and trialed in the lab: S549N, S549R, and S1251N.  Little has been published on these three mutations, but Van Goor showed through patch-clamp studies and open channel probability, that Ivacaftor works very well in these mutations also.  In the case of S1251N, for example, open channel probability was restored to very close to “normal” levels. 
In conclusion, the data presented by Van Goor showed that all gating mutations respond similarly to treatment with VX-770 in the lab.  “This supports the use of…or rather, the investigation of the potentiating benefit of Ivacaftor in patients who have CFTR gating mutations beyond G551D.” (Van Goor)
Q and A:
*Van Goor took a few questions from the audience.  One Physician asked about splicing mutations.  Since some splicing mutations manage to get a small amount of CFTR to the cell surface, would they be possible candidates for treatment with VX-770?  Van Goor responded that he believed they may certainly be candidates.  He described how VX-770 might be able to compensate a bit for the lack of CFTR channels available by the fact that it is basically able to keep the channels that are there, open ALMOST ALL OF THE TIME!  VX-770 is an extremely effective potentiator(increases that open channel time).  Even normal CFTR is potentiated by VX-770.  That means that even if a healthy, non-carrier took VX-770, they would transport more Chloride. Here are a few example splicing mutations: 3120 + 1 G-A, 3849 + 10 kb C-T, and 2789 + 5 G-A

*Another person asked if there were any gating mutations they tested that were NOT potentiated by VX-770.  Van Goor responded, “No.  Ivacaftor potentiated all gating mutations tested, even normal CFTR.” 

I want to wrap up this blog by saying that I truly believe VX-770 will be part of the treatment regimen for most CF patients one day.  It is the first giant step toward making this type of treatment a reality for everyone with CF.  For many mutations (DF508 included), a combination of potentiator(VX-770) + corrector(VX-809, VX-661, or other) will likely be needed to achieve similar clinical benefits.  It is still very exciting to see the patient population that might benefit from VX-770 expanding.  I assume that they are working to add these gating mutations to genetic screening panels, so these individuals can be identified and treated.  I know that the CFF now has a program to help cover genetic testing for those who don’t have genotype information.  Additionally, Vertex has added the mutation R117H to the list of mutations they plan to test Kalydeco on in trials in 2012.  While there is no data about R117H in Van Goor’s discussion, this inclusion means they have similar positive in vitro (in the lab) data for this mutation also.  I would encourage patients with R117H or the previously discussed gating mutations to be in contact with their clinic about upcoming Vertex trials. 

One last interesting note.  Most people know that the trial results of VX-770 alone in homozygous (two copies of same) DF508 patients did not show meaningful results because DF508 patients typically do not have any mature CFTR protein at the cell surface.  However, the trial revealed a small subgroup of double DF508 patients that DID show benefit to treatment.  For reasons unknown to researchers at this time, some DF508 patients DO exhibit some cell surface CFTR, which was, in turn, potentiated by VX-770.  This was a very small percentage of their total trial patient population, but it became extremely interesting to them to find out what made those patients different and how we might be able to identify them.  How do we go about finding out which people might fall in this subgroup?  My guess is that they are working on answering those questions right now!  Keep hoping and working for the CFF because anything is possible! Exciting stuff people.