D508 and E92K. Is there any chance Orkambi will help?


New member
Hi, i'm new to the forum but I've been lurking for years. I am 35 with CF and I have an 8 year old boy. My health has been very slowly declining over the years, FEV1 never went over 40% after I had my son ( I was at 55% when became pregnant), I am currently sitting between 22%-32%. I have tried not to get my hopes up about any new drugs, I find it easier to cope with life that way. However, I now feel like time is running out and I guess I am starting to get desperate to find something to help me stay around for my little boy as long as possible.

I have tried to do some research about my mutations (d508 and E92K) and I have found some information on E92K and VX809 shown in the link below. The way I understand it, VX809 will correct E92K at high concentrations but when combined with d508, it somehow doesn't work. Have I understood that correctly?

I know that Orkambi is primarily for dd508, but given that VX809 does seem to have an effect on E92K do anyone think this may help people with my mutation too?

Thanks in advance



In particular:

VX-809 suppresses folding defects in CFTR caused by disease-related mutations in MSD1

Data presented thus far suggest that MSD1 is the minimum-length fragment required for VX-809 action. There are several CF-associated mutations in MSD1 that cause defects in CFTR processing and function: N-terminal tail (E56K and P67L), TM1 (E92K), TM2 (L206W), and TM4 (V232D) (Figure 4, AE). The severe folding (Figure 4, AB) and functional (Figure 4E) defects exhibited by E56L, P67L and L206W were completely corrected by 5 μM VX-809. In contrast, 5 μM VX-809 only partially restored folding and function to E92K and V232D (Figure 4, A and andE).E). Interestingly, VX-809 demonstrated reduced potency for E92K-CFTR relative to F508del-CFTR, for both correcting folding and function (Figure 4, B and andC),C), yet was able to fully restore E92K-CFTR at 30 μM. However, Corr4a could not restore E92K-CFTR function (Figure 4D).
Functional defects in CFTR caused by disease-related mutations in MSD1 are suppressed by VX-809. (A) Folding defects caused by mutation of CFTR's N-terminus are differentially suppressed by VX-809 (5 μM). (B) Dose-dependent correction of E92K-CFTR ...

V232D-CFTR was the least responsive to VX-809, and higher concentrations of the compound did not restore function beyond the 25% of normal CFTR observed in the presence of 5 μM VX-809. Taken together with the observation that Corr4a restored V232D-CFTR biogenesis and function to normal levels (Caldwell et al., 2011
), these data suggest that correctors such as VX-809 and Corr4a can act to selectively suppress folding defects in CFTR caused by different disease-related mutations in MSD1.

Because E92K-CFTR was corrected to normal levels of function but F508del was corrected to ∼15% of normal function, the impact of VX-809 on the double mutation E92K/F508del-CFTR was tested. (Figure 4B). The effect of VX-809 on the C-band of E92K/F508del-CFTR was consistent with the dose response for E92K-CFTR, while the level of efficacy was consistent with that for F508del-CFTR. Thus the E92K mutation causes a folding defect in E92K/F508del-CFTR that requires a higher compound concentration, but the folding defects caused by F508del limit the efficacy of VX-809. These data support the concept that VX-809 action on MSD1 aids in suppression of some but not all of the folding defects caused by ΔF508.
VX-809 is highly efficacious at correction of folding defects in CFTR caused by some, but not all, of the missense mutations in MSD1 that were evaluated. E92K is unique among these mutants, as it alters the potency of VX-809, yet the biogenic defects caused by this mutation are completely corrected by VX-809. Mutational analysis of E92 suggested that mutation of this residue disrupts a salt bridge in MSD1 that is required for CFTR folding (Figure S3). E92 may therefore not be directly involved in binding VX-809 and instead appears to be required for folding of MSD1 to a conformation that binds VX-809 with high affinity.


Super Moderator
Hey Mom,
I'm so sorry I can't really follow, but I know that there were studies saying that VX809 does something to the CFTR that is negative in ddf508 yet in clinical trials it still showed that it worked. I'm wondering if that study/quote is part of those studies where some scientists were questioning where questioning whether vx809 works because it denigrates a component of the cftr function for ddf508. If that quote is part of the study, the "good news" is that when the drug was given clinically (as opposed to in vito) whatever denegration happened didn't keep it from working for ddf508, so there is hope it could still work with your mutations. Given your situation I would hope the doctor will be willing to try Orkambi for you. Another option to consider is discussing trying Cystagon off label. This link has some good info: http://newhopeforcf.blogspot.com/p/why-cysteamine-for-cf.html. Right now the studies on CF are very preliminary, but it has a safe profile and has been FDA approved over 20 years for another disease. Given your situation, your doctor might be open to trying that off-label. (Maybe contact the blogger for more info...I know there are several who are on off label).
Praying for you and your precious blessing!


New member
Hi Aboveall,

Thanks for your reply. I am struggling to understand all this scientific speak and got a bit excited when I finally found an article talking about VX809 and my mutations. I admit I still don't fully understand what they are trying to say! I will have a look at Cystagon and the link.

Thanks for your kind words.


New member
Keep fighting and like Aboveall said check out the possibilities of new drugs. I think most doctors are conventional on how they approach the disease so the more you can advocate for yourself the better. I've been the first in my clinic to try new things I found out about from forums like this.

Has your doctor ever spoken to you about lung transplantation before? Is this something you have thought about or might want to consider?


New member
So according to your included article the E92K strain is effected positively by orkambi but the benefit is very minimal and I would assume the dosage to have beneficial results is too high for them to consider it beneficial for your exact mutation pairing. Orkambi is already only marginally beneficial to double copy f508del as compared to Kalydeco for g551d. Either way without an fda testing and approval for your mutation pairing it is unlikely that your insurance would cover the cost and with Kalydeco costing $300,000.00/yr its not even remotely affordable for anyone off label and I haven't seen a price tag for Orkambi yet but I don't imagine it'll be much different.

That's not to say it can't help you, just that Orkambi doesn't seem to be the " miracle " that Kalydeco seem to be, even for its target f508del. So it is possible you could see some improvement but Vertex Pharmaceuticals didn't see enough in their testing to consider it worth further testing.


New member
I will keep fighting, I have the best reason in the world to fight - my son. I was assessed for transplant and told I was too well for the moment, I really would like to leave that as the absolute last resort. If they found a way to stop any further decline, I would happily live in the current state I am in. Transplant terrifies me, I feel like it is admitting defeat and that everything from then on would be totally out out my control. But at the end of the day, I will do whatever it takes to stick around!

The way I read the article, was that E92K CFTR was totally corrected by VX809 to normal levels but only by using 6 times the dose that was needed for other mutations. In contrast F508del only corrected to 15% . And when they tested the combination F508del/E92K, at the high dose, they still only managed a percentage similar to 15% suggesting the F508del was preventing the correction previously seen with E92K on it's own.

If they are now saying Orkambi works (marginally) for F508del/F508del, then my hope was that it may help me as it seems the F508del was limiting the positive effects on E92K. Although whether the high dosage required would be a problem, I don't know. Is there a way to find out if Vertex has tested other mutations with Orkambi?

I don't know if that makes sense to anyone reading, I'm not a scientist, so please do correct me if I am wrong.


Super Moderator
Your doctor can ask vertex for any information or studies on orcambi and your mutations....vertex cannot market off label but if a doctor I intimates the questioning then vertex can provide the information. Once it is approved I would call vertex and find out the contact for your doctor and the. Give it to him to call...make his life as easy as possible to try to get it for you to support off label use.