VX-661-108 (residual function study)

jricci

Super Moderator
https://tools.cff.org/Display/dsp_C...S=&BCepacia=&PLT=0&Therapy=&Char=&Keyword=661

See link clinicaltrial.gov site for all participating sites.
https://www.clinicaltrials.gov/ct2/...1+and+cystic+fibrosis&rank=2&show_locs=Y#locn

You need to have one df508 mutation and one of the following residual function mutations:

2789+5G?A, D110E, R352Q, A1067T,
3849+10kbC?T, D110H, A455E, R1070Q,
3272-26A?G, R117C, D579G, R1070W,
711+3A?G, E193K, S945L, F1074L,
E56K, L206W, S977F, D1152H,
P67L, P205S, F1052V, D1270N,
R74W, R347H, K1060T
 
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stephen

Guest
Since I have D1152H and have been taking Kalydeco for almost a year and a half with extraordinary results, I’m surprised to see that it’s included in this study.

While my other mutation is not F508del, it is a class 1 mutation, G542X. This results in “little to no total
CFTR activity”.

Therefore it appears that Kalydeco alone is extremely effective on those with a copy of the D1152H mutation - at least it has been for me.


PS: I just ran across an interesting site with easy to understand information on CFTR mutations and classes, CFTR Science, A Clinician’s Guide to CFTR. (Don’t be intimidated by the name.)

http://www.cftrscience.com/
 

jricci

Super Moderator
Since I have D1152H and have been taking Kalydeco for almost a year and a half with extraordinary results, I’m surprised to see that it’s included in this study.

While my other mutation is not F508del, it is a class 1 mutation, G542X. This results in “little to no total
CFTR activity”.

Therefore it appears that Kalydeco alone is extremely effective on those with a copy of the D1152H mutation - at least it has been for me.


PS: I just ran across an interesting site with easy to understand information on CFTR mutations and classes, CFTR Science, A Clinician’s Guide to CFTR. (Don’t be intimidated by the name.)

http://www.cftrscience.com/
Stephen-
Thanks for the link.
There are 3 arms of the trial: placebo, monotherapy with Ivacaftor, VX-661/ivacaftor combination. I guess they’re trying to determine if combo drug has even more of a benefit than Ivacaftor alone for residual function.

Based on Denver proof-of -concept study results and stories like yours told on this forum, I’m pretty certain that the VX-108 study will also show favorable results and Kalydeco label (or combo drug) will be expanded to include residual function mutations. I’m also on Kalydeco off -label and have had great results despite the poor in-vitro response. Sad thing is that my mutation isn’t on the VX-108 residual function study OR the VX-107 study for mutations that aren’t expected to respond to therapy. It’s upsetting that my experience (my own N-of-1 study essentially) wasn’t taken into consideration when deciding what mutations to include in residual function study. There has been no official way to document off-label usage in a way that responses can be accessed by other doctors/researchers. Because of this, there are 162 people with my mutation who won’t have access to a drug that will most likely benefit them.
 

Aboveallislove

Super Moderator
Actually, I'd love to be able to " game" the hetero trials by having all the cfers like jricci who don't have on label but will respond so well that it could pull ALL heterosexual on label!
 

ethan508

New member
Um... gaming the trials is not what we need at all. While I appreciate your enthusiasm to get these drugs available for all CF folks (and I image you are a bit tongue in cheek), the science, as slow and plodding as it may be at times, is there for our protection. Anecdotal just doesn't count in science. As a community, we just don't know much about these new drugs, only that they offer a ton of hope and seem to show some promise. Without scrutiny we leave ourselves open to snake oil salesmen.

A call or petition for more trials and more data gathering (conducted and reviewed in a speedy but sound manner) is the right way to understand if these drugs really should be administered to more classes of CF folks. I hope the studies in Tampa and Tucson show that these drugs work for all CF folks like they appear to be working for jricci.
 

Aboveallislove

Super Moderator
Well, my take is if the safety is there and it works for some mutations, that those who have no drug should have the opportunity to try to see if it works for them as well. But the way our system works, they won't, either because it won't be covered or because the trials cost too much to run. The companies already "game" the trials by limiting trials to the population narrow enough to assure success. I'd much prefer that the CFF fund nof1 trials, but if it won't and the trials are defined as they are, I personally would love to have the "gaming" done to give folks the option of having access and then deciding with the doctors and individual situations whether to try the drugs.
 

ethan508

New member
But if you game the trials to provide drug access, then what knowledge can a doctor and individual rely on to make an informed decision on what treatments would be best?

Secondly, if the drug companies weren't 'gaming' the system by limiting the scope of the trial then these drugs wouldn't be available at all because the statistics would have shown them ineffective. The exactness of the studies is what made the trials successful. This is call good science not gaming.

More good science will be when enough n=1 experiences are recorded (via the CF patient registry) to reach statistical conclusions about off-label usage. I hope that happens sooner rather than later.
 

Aboveallislove

Super Moderator
If the drug has a safe profile, the doctor and patient could basically see how it works for the patient. In a sense, that's really what is going on with the ddf508 and Orcambi because the results overall were good enough for approval, but there were definitely responders and "non-responders." During the lead-up, Vertex made clear it didn't believe a responder analysis for inclusion was needed because the overall results would be good enough for approval for all ddf508.

I understand why Vertex is "gaming" the system with the narrower definition of residual function; if they didn't, there'd be a chance no one would get the drug. And I don't criticize them for that...I just want to play the same "game." (And I doubt they would expand the inclusion criteria based on a petition...they want to know it will be good enough to get approved.)

Now, practically, there is no way patients could "game" the hetero-non-responder arm by CFers "agreeing" that only those likely to respond flood the trial. (I.e., CFers thinking they will benefit because of anecdotal evidence for instance because others with that mutation off label have responded, or for other reasons, such as low SC, PS, etc.). But that would be just as scientific as the ddf508 study which, for whatever reason, had some high-medium-low responders, but together it was good enough to get the label for all. And likewise, then the label would be good enough for all heteros that don't fit within any of the other "groups" they are now targeting.

So, I respectfully dissent. :)
 
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stephen

Guest
I think Ladybird and I are the only ones with Residual Function mutations who have written about using Kalydeco off-label. (I do realize that there may be others who are reluctant to write about it because of insurance concerns and that’s very understandable.)

Based on our reactions to Kalydeco, it would appear that everyone with a Residual Function mutation, unless they have specific contraindications, should at least have the chance to try it. It’s disturbing this isn’t the case.

While it’s understandable that insurance providers could be reluctant to approve it - why are doctors reluctant to prescribe it?

I was very fortunate, thank G-d, to have a doctor who was aware of the information supporting the effectiveness of Kalydeco for Residual Function mutations like D1152H and didn’t wait for another study or for FDA approval.

Ladybird had the fortitude to keep fighting until she finally got it.

Some have written that doctors are reluctant to prescribe Kalydeco off-label because of drug interactions. While these do exist, they are easily identified on a number of websites. By the way, try looking up the drug interactions for Zithromax - which most of us are probably taking.

Others seem to be concerned with the side effects and contraindications. These are less common than with many of the other drugs most of us are taking. They can be closely monitored, and if indicated, the Kalydeco dosage can be reduced or eliminated. Also, if Kalydeco is as effective as it has been for some, the need for some of the other drugs may be eliminated, or at least reduced.

I’m aware that prescribing Kalydeco off-label could, in some cases, lead to additional work for the CF team trying to justify it to insurance providers. This would be a horrible reason not to try.

Maybe some of you with Residual Function mutations who are having difficulties getting a prescription for Kalydeco now should try another CF Center. I live in the New York City area and can recommend two. Send me a Private Message or Email.

By the way, it is great to hear how well Occupyjapan and Humphery711 are doing on Orkambi!
 

jricci

Super Moderator
N-of-1 studies make the most sense given the fact that there are 1900 mutations, the vast majority of these being extremely rare. To complicate matters even more, there is great variability between people who share the same mutation combination. Genetic modifiers and environment, not just mutations, play a part in how CF presents. This means that people with the same mutation(s) may respond very differently to these meds (this seems to be the case with those with ddf508 on the Orkambi trials). So far the number of mutations that Vertex has targeted, including VX-661-107 and VX-661-108 studies, is 157 (about 8% of mutations that have been identified). Granted, this 157 is a large percentage of the CF population since many of these 157 are among the most common mutations. But this doesn’t negate the fact that there are people out there, regardless of how rare their mutation is, that deserve a chance to try these potentially life-changing, life-saving medicines if there is reason to believe they may work for them This is especially the case for those with unstable and/or severe disease. They don’t have the time to wait. They should not be put at a disadvantage because of the rarity of their mutation. For some, this disadvantage may cost them their lives.

I don’t see the N-of-1 study design for individuals being adopted by Vertex anytime soon. So that leaves the options of getting in a study (which isn’t possible for many with rare mutations because their mutations aren’t included in study) and off-label use for those with mutations that have the potential to respond to Kalydeco or Orkambi based on in vitro studies and/or anecdotal evidence. Although this “anecdotal” evidence is actually much more than just patients accounts of their health status. There is scientific evidence involved-- just not part of an official study protocol. For the most part, I think people that have been given the chance to try off-label have had sweat chloride, PFT’s, Chest x-ray, weight checks, and symptom description documentation pre and post Kalydeco. They are officially documented in their personal health records. These results should be shared with other doctors somehow so that they can use this info. when making decisions on who to prescribe Kalydeco or Orcambi off-label. Information should also be shared with Vertex so that researchers can take results into consideration when designing future studies. Doctors need to publish their data in journals since insurance companies require journal articles when determining off-label use. Hopefully the CFF will recognize these needs and have a key role in encouraging all of this. They sold their royalties from Vertex. They no longer have a conflict of interest by promoting off-label use. Their interest should be to ensure that these drugs are accessible to those that will likely benefit from them.

Why am I so passionate about this? I had a lung function of 31% in November. I was not responding to IV antibiotics. Thankfully my doctor took the chance and prescribed Kalydeco off-label even though in-vitro results did not have promising results for my mutation (which is a residual function mutation). My lung function went up to 42% after being on Kalydeco for 5 days. I haven’t been on IV antibiotics since starting Kalydeco and my health has been much more stable than it was prior to Kalydeco. I have been granted the gift of years added to my life- all because my doctor had the chance to listen to other doctor’s accounts of off-label use at the CF conference last October. We need to get the word out there and expand off-label use. Please let me know if anyone has any ideas in helping to make this a reality.
 

Aboveallislove

Super Moderator
Jricci,

I too have been thinking of all you wrote and had actually had an idea when life intervened. I truly believe this is an area the CFF should invest and if it takes the CF community's pressure to force it, so be it. I know everyone has different takes on how the CF should spend the $3.3 billion and completely understand many choices such as not providing money to individuals. But funding n of 1 studies for Kalydeco and Orcambi fits within the stated goals of getting drugs to everyone; funding research, etc. I think the first issue is the feasibility of an n of 1 study. I have a former classmate who runs a biotech (who knows how to design studies etc.) and will see if I can reach out to see feasibility. If it is, then it would seem the next step is to approach CFF either through contacts or through a patient publicity effort. I know studies cost a lot of money and maybe part of the approach would be that the CFF doesn't fund patient reimbursement or travel or compensation to limit the cost to CF, while providing an opportunity.

Option 2: Someone in the CF community with a science background write work with off label patients to write a journal article detailing all known off label use with science results (tests you noted above).

Option 3: Presentations at the NAACF on off label use maybe even by a group of patients.

Thoughts????
 

jricci

Super Moderator
Aboveallislove,
Thanks for the response. I don’t have a lot of time to respond right now. I did want to say that my doctor, along with some other doctors in the area have submitted an abstract (? not sure if this is the right terminology) to be presented at NACFC this October, discussing their joint experiences with off-label use for those with residual function mutations. I think 20 patients are included in report. I’m so excited about this. This will be a great way to disseminate info. to other doctors and hopefully help with insurance appeals.
Anyway, let me put some more thought into everything and then I’ll PM you. I have a pdf document that I want to share with you.
 

jricci

Super Moderator
Hopefully I'm right about # of patients. But I think that's right. Very exciting! Just not sure if it will help with insurance appeals because it's not a published journal article. But I think some of these abstracts from NACFC are published as supplements in professional journals.
 

Aboveallislove

Super Moderator
Another mom I know is presenting to new doctors at the nacfc and once info is available on that abstract I'll ask her to encourage those new doctors that att no their sessions to attend the off label abstract presentations or at least read and get the info because it is not well k own...that should hit another group of doctors who are amongst the least familiar with the potential and hopefully they'll spread the word too others at their centers!
 
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jcro125

Guest
I got very excited to see A455E on this list. However, it sucks that you have to also have F508del. Got my hopes up for a moment. :-(
 

jricci

Super Moderator
Wonderful! The abstract with that many off label will have some impact! Looking to to pm.

Aboveallislove,
Just tried to PM you and received the message:Aboveallislove has exceeded their stored private messages quota and cannot accept further messages until they clear some space.
Looks like you're very popular : )
Let me know when you clear some space and I'll try again.


 
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