Kalydeco & Other Mutations

Kalydeco can help more patients beyond those with G551D (4% worldwide, 8% aus). Kalydeco helps other gating mutations (1% worldwide) and it is thought that residual function mutations will be helped (5-10% worldwide, based on mutations and clinical presentation). This means Kalydeco may help about 15% of the CF population.

Gating Mutations (Class 3)
Kalydeco helps the gating mutations G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. The phase 3 trial demonstrated an absolute FEV1 improvement of 7.5% from baseline at 8 weeks (p<0.0001). In Feb 2014 the FDA approved Kalydeco for use with these 8 additional mutations. G970R was also involved in the gating trial, however based on the data from 4 patients, the efficacy was not established to support FDA approval. Vertex have also applied to the EMA to expand the Kalydeco label to include these mutations. There is further detail regarding the gating results here.

Residual Function (Classes 4, 5 and 6)
Kalydeco has been trialled with R117H (3% worldwide).
The phase 3 trial demonstrated an overall absolute FEV1 change of 2.1% (p=0.2), with those aged 18 or older improving 5.0% (p=0.01). Vertex plans to meet with FDA in early 2014 to discuss this data and a potential FDA application. There is further detail regarding these results here.

Kalydeco is also being trialled with people who have other forms of residual function. The results from one of these phase 2 trials demonstrated an absolute FEV1 improvement of 4.7% (p < 0.0001) from baseline after 8 weeks and a 15.7 drop in sweat chloride (starting point 64.7). These results support initiating a phase 3 study with residual function patients. There is further detail regarding these results here.

There are specific mutations associated with residual function, as well as several clinical signs, including pancreatic sufficiency, a lower sweat test, a later age of diagnosis and milder than expected disease in patients with severe gene mutations. There are more details listed here: First Residual Function Trial & Second Residual Function Trial.

Known residual function mutations include (see graphs below): E56K, P67L, R74W, D110E, D110H, R117C, R117H, L206W, R347H, R352Q, A455E, D579G, R668C, S945L, L997F, S997F, R1070Q, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3272-26A->G & 3849+10kbC->T. Other rare mutations not included in this list may have residual function.

This image shows the effect of Kalydeco (Ivacaftor) with gating mutations:

CFTR Gating Mutations Kalydeco

These images show the effect of Kalydeco (VX770) with residual function mutations:

Slide 15

Sources: Peter Mueller Presentation March 2012
EMA November 2012 Presentation
Vertex Investor Presentations (no longer available online)


Join the conversation! 19 Comments

  1. Disregard last comment I posted, as my email was typed wrong. Try this one instead…..Hello! I have two children with cystic fibrosis. They are both delta F508 and 711+1G>T. It is hard to find much info on the second mutation. It is a class five. They are both pretty much pancreatic insufficient. My daughter is 6 and has only had one pneumonia, otherwise healthy lungs. My son is 9 months and he has a lot of sinus colds and breathes heavily but otherwise no lung infections. Can you tell me about any information you might know about the potential medication combinations for a class 5 mutation. I know what they are working on for DF508 but I would like to know if there’s anything coming out to help the other. Supposedly it is a more “mild” mutation, but I wouldn’t consider them to be mild based on both of them having a meconium ileus at birth. Our daughter also went undiagnosed at birth twice, even though both mutations were on the panel in Oklahoma. We knew our son had it because he also had a blockage and delivered early to keep it from being as severe as our daughters. He, however, also tested negative based on newborn screening and his mutations were on the panel in Kansas as well. Thanks for any help.

  2. Thank you for your information. However, I am a bit confused because I have valid information that 711+1G>T is a class V mutation, so I am a bit confused by this?????

    • Do you have a link to the info? I found multiple articles that said it was class 1 and added links to two of these here: https://sixtyfiverosesblog.wordpress.com/specific-mutation-info/ I did not find any that suggested it had residual function or was class 5.

      Also on CFTR2, it is reported that patients with 711+1G>T have a higher than average sweat test and higher than average rate of pancreatic insufficiency. This is consistent with a class 1 splicing mutation, residual function is thought to present with a lower sweat test and/or pancreatic sufficiency. CFTR2 also mentions this “This type of mutation is expected to significantly disrupt CFTR protein production and result in little or no functional CFTR protein in the cell.” http://www.cftr2.org/mutation.php?view=scientific&mutation_id=44

  3. A geneticist told me this four years ago and sent me the paperwork. I am seeing where you are correct. I normally research class V mutations. I am very upset and disappointed by the invalid information that I have received. Thanks for your help. I am under the understanding that they are working on medicine, Kalydeco combined with VX809, to treat DF508. Will this be something my children could qualify for, since they do have one copy? Do you know what the studies are revealing?

    • Yes I’m very sorry that I did not have better news, if the geneticist sent you any links to articles I would be interested to see these. It is also not unusual for an individual to present differently to what is predicted, even if there is evidence that it is most likely a class 1 mutation.

      Yes Kalydeco/VX809 is in trials with those who have one or two copies of F508del. Those with 2 copies have a stronger response as they have more F508del that can be helped, but those with 1 copy still have some improvement. Laboratory studies have shown that triple combination therapy can get people with one copy of F508del to about 35% of normal function https://sixtyfiverosesblog.wordpress.com/2013/06/13/vertex-second-generation-correctors-latest-graphs/ Several other companies are also working on medications for F508del.

  4. When will they begin combinations or trials for class I mutations? I don’t know how I missed this info over the years. I research all the time. I feel like I was mislead but also like I failed in my quest. My daughters FEVs or over 100% right now and she is now 7. She doesn’t culture pseudomonas and has only been sick once.

  5. Thats great news that she is doing so well.

    There is a VX809/Kalydeco trial currently running with people who have one F508del mutation and a second class 1 or 2 mutation: http://www.clinicaltrials.gov/ct2/show/NCT01225211

    It is planned to start trials with a second generation corrector by the end of this year. Triple combination therapy involves Kalydeco, a corrector such as VX809 or VX661, and a new second generation corrector. The second generation corrector acts at a different part of the folding pathway to VX809/VX661, helping to improve the overall level of folding and function.

    I regularly blog about these trials/developments in my Vertex Updates, there is more info here: https://sixtyfiverosesblog.wordpress.com/category/3-vertex-vx809-vx661/

  6. I do have another question, can Kalydeco help in any class I or II mutations?

    • Kalydeco alone is not thought to help class 1 and 2 mutations (where there is minimal protein making it to the cell surface), this is shown in the third graph above

  7. I took a great deal of time in reading ALL of your info from your blogs…..thank you.

  8. Any Idea when p67l might get FDA approved

    • The results from the residual function pilot trial are expected to be released mid year. Pending results, another trial may be needed before FDA approval, so it is hard to predict the future timeframe.

  9. About 711+1 GT mutation – this is a fairly common mutation in French Canadians and it is a class I mutation associated with pancreatic insufficiency. We did a small study to show that patients with 711+1 G-T and DF 508 tend to evolve in the same way as homozygote DF508 (both DF508) patients.

  10. Is r347p a mild conductant mutation? If so, why is it not included? thank you

    • Sandy, R347P is included in the third image above. It does not appear to respond to Kalydeco. I have read it is a class 4 conductance mutation, but based on the lack of response to Kalydeco, it may have a severe conductance defect.

  11. When will Kalydeco, be available for dd508 if at all? I am also diabetic(cfrd) (Northern Ireland) thank you.

  12. Will Kalydeco be avail for D508 and g524x. What is out there for these two mutations?

    Thank you


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s