Residual Functions Mutations going to be on label for Kalydeco

Aboveallislove

Super Moderator
Okay, I did read that right. It is 2 and older with: The 23 residual function mutations included in the sNDA are: 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+3A- > G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, and D1270N.
 

triples15

Super Moderator
Holy flippin' cow Love, you are right! They did submit it and the FDA accepted it for priority review slated for Febuary! Whooo hoo! What amazing news, thanks SO much for posting!
 

Aboveallislove

Super Moderator
Did you hear me scream Autumn all the way to the border!!! I was so excited reading I couldn't really read....do you need the pushy me to call your clinic, tell them to call Vertex for the info and script Kalydeco NOW!
 
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stephen

Guest
VERY welcome news! Thanks for posting it.

This should really help a lot of others who were not as fortunately as I've been in getting Kalydeco off-label.


Hopefully it could also lead to co-pay assistance, some of which is only available to those getting Kalydeco on-label. My co-payment is currently 5%, which is over $1100 a month. (That should indicate just how much I feel Kalydeco is helping me.)
 

Aboveallislove

Super Moderator
I hadn't even though that of the copay assistance as we hit catastrophic max early on we don't have copay after that...but that will be so helpful to so many!
 
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Dank

Guest
Well that's pretty awesome news. February is just around the corner. :)
 

nocode

New member
I wonder why R334W isn't on the list since it also is a residual function mutation. Does anyone know?
 
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stephen

Guest
I think anyone with R334W should already have tried to get Kalydeco off-label.

It's a Class IV mutation similar to mine, and my experiences with Kalydeco have been great!
 

Aboveallislove

Super Moderator
I absolutely agree with Stephen and think all class 3-5 should be on Kalydeco off label, but getting doctors on board and then insurance companies for some has been insurmountable.
Re the FDA filing: It is actually very rare to go to the FDA without clinical results, but with CF and the safe profile of Kalydeco, and the theory, Vertex thinks it can support approval. BUT because it is going based on the very small Phase 2 (Denver residual function), the safe profile, the theory and in vitro results, it is likely limiting mutations based on what it feels the FDA would approve. This slide shows that in vitro Kalydeco has limited improvement with R334. https://magicbluepill.files.wordpress.com/2012/09/slide9.jpg
Of course, minimal for in vitro might be amazing for CFers. Not trying to justify....just trying to explain why all residual function mutations weren't included in the sNDA. Hugs and prayers,
Love
 

concerneddad

New member
residual function and Vertex

I absolutely agree with Stephen and think all class 3-5 should be on Kalydeco off label, but getting doctors on board and then insurance companies for some has been insurmountable.
Re the FDA filing: It is actually very rare to go to the FDA without clinical results, but with CF and the safe profile of Kalydeco, and the theory, Vertex thinks it can support approval. BUT because it is going based on the very small Phase 2 (Denver residual function), the safe profile, the theory and in vitro results, it is likely limiting mutations based on what it feels the FDA would approve. This slide shows that in vitro Kalydeco has limited improvement with R334. https://magicbluepill.files.wordpress.com/2012/09/slide9.jpg
Of course, minimal for in vitro might be amazing for CFers. Not trying to justify....just trying to explain why all residual function mutations weren't included in the sNDA. Hugs and prayers,
Love
I actually wrote a letter to Vertex yesterday asking them why they did not include all residual function mutations in the sNDA. My daughter has a Class V residual function mutation that's not included in the golden list of 23 (the characteristic of her mutation is similar to several of the mutations in the list). She could have participated in the study, but she was just starting college on the east coast (in a small town) and the monthly travel to Denver would have been too much for her and her general well-being. I feel confident that Kalydeco would help her and believe that it is borderline immoral that her mutation (and others) are not included in the application simply because they were not involved in the study. There are far too many mutations (residual function and otherwise) upon which clinical studies can ever be conducted by Vertex. Are these patients going to be precluded from obtaining a drug that will likely help them (and more than likely will not adversely affect them to any greater degree those who are on Kalydeco through prescriptions)? Based on my experience with insurance companies and prescription drugs, I feel certain that it will be difficult if not impossible for my daughter to get Kalydeco off label. So, I asked Vertex to explain to me what it can do for my daughter (and others) if the sNDA is approved (with only the 23 mutations) to enable them to get Kalydeco. If the cost of Kalydeco were even a tenth of what it is, I would get it prescribed and have my daughter take it for six months to see what would happen. At $25,000/month, this is not feasible for me (and for most people). This is something Vertex can control (and/or the CF foundation can and should assist with), as far as I am concerned.
 
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stephen

Guest
Concerneddad,

I would suggest you try getting Kalydeco off-label through your drug plan. Push your CF doctor.

There are a number of us here who have been successful. I surprisingly had no problem. However, my doctor did have to expend considerable effort in getting Kalydeco approved off-label for some of his other patients, not all of which were successful.
 

jricci

Super Moderator
This press release brought mixed emotions for me. I am absolutely elated that 1,500 more people will hopefully gain access to this potentially life-changing drug much faster than I was expecting. I thought the label wouldn’t be expanded until the results of the VX-661-108 study came through. So hearing this news brought tears to my eyes. As someone who has been on Kalydeco off-label for almost a year, I know first-hand the potential that this drug holds for those with residual function mutations. However, it is extremely upsetting to me that all residual function mutations aren’t included. Only about ½ of the people with residual function mutations will benefit from this expanded label. At least 10% of the CF population is pancreatic sufficient. Pancreatic sufficiency is a clear indicator of residual function. I can’t understand why the inclusion criteria couldn’t include those with evidence of pancreatic sufficiency like the Denver proof of concept study did.
I am proof that in vitro results don’t tell the whole story. My mutation is a Class IV residual function mutation that did not show significant response to Ivacaftor in vitro; so it won’t be included on the expanded label. However, I’ve been on it for a year off-label and I can tell you, beyond a shadow of a doubt, that Kalydeco has slowed down my disease progression. My health hasn’t seen this stability in over 4 years. I’ve tried, through multiple avenues, to pass on my unexpected results to Vertex and the CFF; but because I’m off-label there was no way to officially document it. It has been extremely frustrating.

Anyone with residual function that isn’t included on the label should talk to their doctors about off-label prescribing. If your doctor isn’t in agreement about writing the prescription, then I would think about going to another facility. The evidence is there. There are journal articles to support and justify a trial of Kalydeco if you have evidence of residual function. Unfortunately, because of the astronomical (and in my opinion unethical) cost of this drug, your insurance company will most likely deny coverage initially; but this shouldn’t prevent you from trying. My insurance company covered it without any questions asked. But if coverage is denied, fight it and don’t give up! There are multiple levels of appeals that you can go through. There are people that have had their denial overturned at the 3[SUP]rd[/SUP] level of appeal. There is enough compelling evidence out there that could convince a physician on an external review panel to recommend approval.

I have been forwarding journal articles for Kalydeco appeals to CFF’s Patient Assistance Resource Center. Unfortunately I have met resistance from the CFF about this. They finally did agree to accept my information and disperse it if people call in specifically asking for articles. I am a strong supporter of the CFF. They have done an amazing job getting us to where we are. However, I am frustrated with the response I’ve received as I’ve tried to advocate for off-label use. Helping patients obtain access to Kalydeco, on or off-label, fits very clearly into their mission statement. Anyone from the Foundation that has done adequate research would agree that all patients that have evidence of residual function should be given the chance to trial Kalydeco now. They should not have to wait an extended amount of time until a study includes their mutation. This is especially the case for those with severe disease. They don’t have the luxury of time on their side; the quality of their lives will suffer unnecessarily.

concerneddad- I commend you for writing a letter to Vertex. I encourage you to forward your letter to the CFF as well. We need to make our voices heard. We may not have strength in numbers given the rarity of our disease, but we have the fortitude and drive that can make a difference.
 

triples15

Super Moderator
I actually wrote a letter to Vertex yesterday asking them why they did not include all residual function mutations in the sNDA. My daughter has a Class V residual function mutation that's not included in the golden list of 23 (the characteristic of her mutation is similar to several of the mutations in the list). She could have participated in the study, but she was just starting college on the east coast (in a small town) and the monthly travel to Denver would have been too much for her and her general well-being. I feel confident that Kalydeco would help her and believe that it is borderline immoral that her mutation (and others) are not included in the application simply because they were not involved in the study. There are far too many mutations (residual function and otherwise) upon which clinical studies can ever be conducted by Vertex. Are these patients going to be precluded from obtaining a drug that will likely help them (and more than likely will not adversely affect them to any greater degree those who are on Kalydeco through prescriptions)? Based on my experience with insurance companies and prescription drugs, I feel certain that it will be difficult if not impossible for my daughter to get Kalydeco off label. So, I asked Vertex to explain to me what it can do for my daughter (and others) if the sNDA is approved (with only the 23 mutations) to enable them to get Kalydeco. If the cost of Kalydeco were even a tenth of what it is, I would get it prescribed and have my daughter take it for six months to see what would happen. At $25,000/month, this is not feasible for me (and for most people). This is something Vertex can control (and/or the CF foundation can and should assist with), as far as I am concerned.
Dad,

While I am lucky enough to have my residual function mutation on the list, I agree with your sentiments and am so sorry for the folks with residual function who are being left out. I know for a fact I would be LIVID if my RF mutation was not included. With the evidence out there, we know that Kalydeco monotherapy works for most folks with RF, and it has been beyond frustrating to me to sit back and wait. That being said, I think Love is correct with Vertex's reasoning behind how they are going about this. Doesn't change the fact the our lives (or loved ones lives) are on the line here and the process seems incredibly frustrating at times.

I agree with others who have suggesting trying to get it off-label. I know that the likelihood of insurance covering it is low, but it can't hurt to try. Also, with the evidence jricci is referring to, your doc *may* be able to get it covered if they were willing to go to bat for you. My problem has been getting completely shut down now by 2 different docs at 2 different clinics.

Other thing, you mentioned she could have participated in the Denver phase 2, which leads me to wonder if she's looked into being screened for the phase 3 that's currently enrolling? I was screened at Denver but sweat test came back too high so I didn't get in. Now I've been waiting for screening to start at my clinic to try to get into the phase 3. There are many centers participating in the phase 3, so perhaps there's one near her?

Just some thoughts and once again I'm sorry! I hope I didn't sound insensitive in my earlier elated posts about my mutation being there. I was just so shocked and stunned by the news that I hadn't had time to realize/process that so many others were left out.

Take care are and keep up the good work advocating for your daughter,

Autumn 34 w/cf
 

triples15

Super Moderator
This press release brought mixed emotions for me. I am absolutely elated that 1,500 more people will hopefully gain access to this potentially life-changing drug much faster than I was expecting. I thought the label wouldn’t be expanded until the results of the VX-661-108 study came through. So hearing this news brought tears to my eyes. As someone who has been on Kalydeco off-label for almost a year, I know first-hand the potential that this drug holds for those with residual function mutations. However, it is extremely upsetting to me that all residual function mutations aren’t included. Only about ½ of the people with residual function mutations will benefit from this expanded label. At least 10% of the CF population is pancreatic sufficient. Pancreatic sufficiency is a clear indicator of residual function. I can’t understand why the inclusion criteria couldn’t include those with evidence of pancreatic sufficiency like the Denver proof of concept study did.
I am proof that in vitro results don’t tell the whole story. My mutation is a Class IV residual function mutation that did not show significant response to Ivacaftor in vitro; so it won’t be included on the expanded label. However, I’ve been on it for a year off-label and I can tell you, beyond a shadow of a doubt, that Kalydeco has slowed down my disease progression. My health hasn’t seen this stability in over 4 years. I’ve tried, through multiple avenues, to pass on my unexpected results to Vertex and the CFF; but because I’m off-label there was no way to officially document it. It has been extremely frustrating.

Anyone with residual function that isn’t included on the label should talk to their doctors about off-label prescribing. If your doctor isn’t in agreement about writing the prescription, then I would think about going to another facility. The evidence is there. There are journal articles to support and justify a trial of Kalydeco if you have evidence of residual function. Unfortunately, because of the astronomical (and in my opinion unethical) cost of this drug, your insurance company will most likely deny coverage initially; but this shouldn’t prevent you from trying. My insurance company covered it without any questions asked. But if coverage is denied, fight it and don’t give up! There are multiple levels of appeals that you can go through. There are people that have had their denial overturned at the 3[SUP]rd[/SUP] level of appeal. There is enough compelling evidence out there that could convince a physician on an external review panel to recommend approval.

I have been forwarding journal articles for Kalydeco appeals to CFF’s Patient Assistance Resource Center. Unfortunately I have met resistance from the CFF about this. They finally did agree to accept my information and disperse it if people call in specifically asking for articles. I am a strong supporter of the CFF. They have done an amazing job getting us to where we are. However, I am frustrated with the response I’ve received as I’ve tried to advocate for off-label use. Helping patients obtain access to Kalydeco, on or off-label, fits very clearly into their mission statement. Anyone from the Foundation that has done adequate research would agree that all patients that have evidence of residual function should be given the chance to trial Kalydeco now. They should not have to wait an extended amount of time until a study includes their mutation. This is especially the case for those with severe disease. They don’t have the luxury of time on their side; the quality of their lives will suffer unnecessarily.

concerneddad- I commend you for writing a letter to Vertex. I encourage you to forward your letter to the CFF as well. We need to make our voices heard. We may not have strength in numbers given the rarity of our disease, but we have the fortitude and drive that can make a difference.
Hey J,

Great info again, and thanks so much for all you do to help others with RF mutations get access to Kalydeco!

Wanted to mention that I saw some info that 2 CF centers in Philadelphia had put together regarding 12 of their patients using Kaly off label. I was glad to see that there ARE some clinics trying to document this! I'll try to attach the image but it's small and a bit grainy.

Autumn
 

Aboveallislove

Super Moderator
First, I want to say I'm very sorry if my excitement on the filing came of as unkind for those that don't benefit. The reason I was absolutely thrilled was that this wasn't suppose to happen for anyone now. NEVER had there been a hint that after the Denver nof1 Phase 2 the FDA might approve for residual function mutations. Getting anyone with a residual function mutation on label looked like at least 18 more months and the end of the 661 trial and was shocked when this was announced. The thing is, though, the filings don't happen on their own. There are close discussions with the FDA and unfortunately given there is no Phase 3 data AND there isn't even clinical data on all of the mutations listed, the FDA would never approve it if more were included. Even the Phase 3 with residual functions includes more mutations than the filing based on the Phase 2 data. https://tools.cff.org/Display/dsp_ClinicalResearchHTML.cfm?id=406

But even the Phase 3 for 661 doesn't include that many more residual function. I truly believe as a community we need to "force" the CFF to fund nof1 studies. I too have the utmost respect for them, but this is clearly within its mission. What would make the most sense would be adding another arm for 661 which tests with df508 + all unincluded class 3, class 4, and class 5 mutations. I just don't know how to do this. I have some ideas and if we wanted to form a little "committee" I'd love to give input and help where I can, but life often intervenes...carrying full-time for 6 year old with CF, homeschool, working from home, coping here...But I'll do what I can. And this would also have a benefit down the road for those with two class 1 mutations and pushing a similar approach for a Phase 3 with the triple combo.

In the meantime, I second or third the off label approach. Most insurance policies are required to cover if peer review evidence supports it. jricci has work really hard to get that info disseminated. And if you pm me I'm happy to help you find relevant info in the insurance policy.

I know this sucks. But I am also not living it. Nor are we living the non functioning second mutations. And can never really know how horrible it is for you. I am sorry.
 

jricci

Super Moderator
Autumn and Aboveall- Please don’t apologize for your excitement. This is a huge win in the CF community. I, too, was extremely excited when I was told about this. I wasn’t expecting it at all. I didn’t even know it was a possibility to summit a NDA based on a Phase 2 study. I really did cry tears of joy. I contacted my CF center immediately when I found out because I needed to share my excitement with someone who understood how much this news meant to me, even if my mutation isn’t included. The fact that 1500 more people will have access to a potentially life-changing, life-saving medicine much sooner than expected needs to be celebrated!!

Autumn, you were the first person I thought of. I remember that we both hoped to get into the Denver trial back in 2012. Unfortunately it didn’t work out for us then. But I have been rooting for you ever since and I am thrilled that you will finally get the chance to try Kalydeco. Thanks for the attached document. i will forward to the CFF Patient Assistance Resource Center so that it can be used for appeals. I’m one of the 12 patients in the abstract :)
I am extremely thankful to my doctor for not only writing a prescription for me, despite my mutation’s lack of significant response in vitro; but also for recognizing the need to quickly disseminate the information he obtained from his own experience in off-label prescribing. I hate to think about where I’d be right now if he hadn’t written the prescription. I wasn’t in a good place a year ago with a lung function of 31%, multiple bouts of hemoptysis, unresponsive to IV antibiotics. I felt like I was a few bad colds away from being evaluated for a lung transplant. My gratitude is immense and that’s why I’m so passionate about making sure whoever is in the very position that I was in a year ago also has the opportunity to try Kalydeco NOW and not 18 months from now, or however long it is going to take to get this drug passed for the other ½ of those with residual function mutations.

Aboveall I appreciate your offer to help. I’ll let you know if I have any ideas on what our next steps should be.
 

Aboveallislove

Super Moderator
jricci,
Thanks so much for the gracious note.
One thing I want to clarify though is that the 661 study for residual functions still looks likes its mutation based and it only has about 3 more mutations than the filing with the FDA. I greatly fear that the approval will then not reach the other 1/2 of residual functions but just a few more mutations, albeit with a combo likely. That's why I really think we need to as a community to somehow get another arm of the 661 for df508 + anyone with class 3,4,5 (and maybe even 2 nondf508) now because otherwise it could be 5 years for the triple. Although it might also be another step they take with a follow-up for 661 with more mutations once it is approved (which is easier to do then). But the key I saw in pulling the data is that the residual function as we know it isn't the residual function being trialed.
 

jricci

Super Moderator
Yes, I know that 661-108 trial doesn’t include the other ½ of residual mutations. I guess I was being overly optimistic in estimating 18 months since there isn’t even a study in place to address the other ½ of residual function mutations. It’s just inconceivable to me that there is so much evidence supporting use of Kalydeco for those with evidence of residual function, yet it isn’t even presently being tested in ½ of those with residual function. I'm not sure where to start in trying to convince Vertex or CFF of adding arm. Any ideas?
 
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