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ladybird
11-14-2014, 12:35 PM
Could anyone share the peer-reviewed journals articles or other medical evidence they have used to persuade insurance to approve Kalydeco off-label, for residual function or other mutations?

So far the best I have found is the Journal of Cystic Fibrosis - the slide from Van Goor, F et al. J. Cys. Fibrosis. 2012; 11 (Suppl. 1):S31. This slide shows the change in CFTR chloride transport caused by VX-770 in various mutations including R117C.

I also found an article that supports the idea that even a small improvement in CFTR function is clinically significant and thus of benefit to the patient:

Five Percent of Normal Cystic Fibrosis Transmembrane Conductance
Regulator mRNA Ameliorates the Severity of Pulmonary Disease
in Cystic Fibrosis by
Anabela S. Ramalho*, Sebastian Beck*, Michelle Meyer, Deborah Penque, Garry R. Cutting,
and Margarida D. Amaral

I also found the following from the European drug application for Kalydeco (Assessment report - Kalydeco - ivacaftor - Procedure No.: EMEA/H/C/002494//0000 ):

2.3.6. Discussion on non-clinical aspects
Ivacaftor increased in vitro the chloride transport of multiple mutant CFTR forms associated with a
variety of protein defects and disease severity.
The increase of chloride transport by ivacaftor was most pronounced in cells expressing CFTR gating
mutations when compared to other types of CFTR mutations. This group included, G551D, G178R,
S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D. The fold increase in chloride
transport for all 10 studied gating mutation proteins was greater than 10.
Ivacaftor also potentiated chloride transport, of cells carrying CFTR mutations that are associated with
residual CFTR function, although to a lesser extent than that observed for CFTR gating mutations,
including CFTR conductance mutations (R117H, D110H, R117C, R347H and R352Q), mild CFTR
processing mutations (E56K, P67L, L206W, A455E, D579G, S945L, R1070W and F1074L) and CFTR
mutations with uncharacterized defects in the CFTR protein (D110E, D1152H, S1235R and D1270N).
Finally, ivacaftor showed minimal effects in vitro on mutant CFTR forms that were associated with
minimal chloride transport, including severe CFTR conductance mutations (R334W, T338I, R347P and
L927P), severe CFTR processing mutations (F508del, A46D, G85E, E92K, S492F, I507del, V520F,
A559T, R560T, R560S, A561E, H1054D, G1061R, L1065P, L1065P, R1066C, R1066H, R1066M,
L1077P, H1085R, M1101K and N1303K) and CFTR synthesis mutations (G542X, W1282X, 2184InsA
and 2789+5G->A).
Studies that may be classified as secondary pharmacodynamics studies have been performed and
discussed under Safety Pharmacology. In view of ivacaftor CFTR target selectivity, the CFTR
dependence of the disease, lack of adequate animal disease model and low incidence of observed side
effects in animal and clinical studies, it is scientifically justified not to perform additional studies on
secondary pharmacodynamics. Similar reasons justify the absence of pharmacodynamic drug
interactions studies in the application (i.e. high CFTR selectivity, absence of other CF therapies
targeting the CFTR receptor).


In addition, the laws of many states including California require insurance coverage of off-label drugs if they have been recognized for treatment of that condition by either the American Hospital Formulary Service’s Drug Information or two articles from major peer reviewed medical journals present data supporting the proposed off-label use as generally safe and effective unless there is clear and convincing contradictory evidence presented in a major peer reviewed medical journal. See HSC 1367.21

My doctor needs help with this as it's a huge field with hundreds of articles. I don't want to miss out on the best ones.

Thanks!

jaimers
11-14-2014, 07:39 PM
you may want to post this on the main adult forum. there are definitely people here that have gotten Kalydeco off label and I'm sure they would be more than happy to share their process with you!

jricci
11-14-2014, 11:26 PM
Here is Vertex's press release from the proof of concept study for residual function mutations:

http://investors.vrtx.com/releasedetail.cfm?ReleaseID=852372

stephen
11-15-2014, 11:05 PM
ladybird,

I don’t know if you looked at these two sites. They may be of some use, or may hopefully lead to something of use.

http://sixtyfiverosesblog.wordpress.com/kalydeco-with-other-mutations/

http://forum.cysticfibrosis.com/entr...lp-You!-Part-1 (http://forum.cysticfibrosis.com/entries/127-Kalydeco-It-May-Just-Help-You%21-Part-1) -

ladybird
11-17-2014, 09:43 PM
Thanks Stephen for the info.

I also wanted to post the following links concerning recent developements in research on Kalydeco - ivacaftor for residual function mutations:

Journal of Pediatric Pulmonology - has all the research results from the 2014 Cystic Fibrosis conference - http://onlinelibrary.wiley.com/doi/10.1002/ppul.v49.S38/issuetoc

Then there is the 'famous' Van Goor Study on all the different mutations in vitro - I found the full article at

http://www.cysticfibrosisjournal.com/article/S1569-1993(13)00113-6/fulltext - the title of the artlce is:

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function

JENNYC
11-18-2014, 01:57 PM
Hi ladybird! I don't have any medical journals..but I do have a 9 year old that has been taking Kalydeco for 2 years now with great success. My doctors are not really making calls about it but not sure that they wouldn't answer questions if your doctor was to call and maybe persuade them too. I on the other hand am an open book. I am willing to share anything that will help others get a chance to try this out to see if it will work for you or your loved one as much as it has helped Abby. I have been keeping up with a little chart in the event that our insurance company ever tries to deny. Keep in mind that I could only go back to June of 2010 on antibiotics taken so I'm sure there are many more. The main difference that we have seen is her sinus' are responding to Kaly very well. She also had a bad lobe in her lung that they had wanted to remove when she was little and it seems to be clearing up as well. It has truly changed her quality of life.




antibiotics
hosp
surgeries


2009

2
8


2010
8
2
2


2011
10
2
4


2012
11
1



2013
5
1



2014
1










**started Kalydeco in June 2012



**could only go back to June on antibiotics in 2010

ladybird
11-21-2014, 03:07 PM
Hi Jenny

Thanks for the info - that is very helpful. I am so glad that your daughter is doing so well.

Would your doctors be interested in talking to my doctor - maybe emailing? It would also be great if they might write up the study as an "n-of-1" study, which is the emerging study design for the residual function mutations, and publish it so that there would be more published support for Kalydeco off-label.

I know that Vertex is supposed to be in consultation with the FDA for phase 3 clinical trials, but even if they were started tomorrow, it would probably still be at least two-three years before any kind of drug is approved and on the market.

I will send you a PM.

Thanks for sharing this valuable info!

triples15
12-09-2014, 04:16 PM
Hi Ladybird,

Thanks for all the great info you have shared! I hope you are able to get Kalydeco!

Any chance you have all of the info you have gathered in some sort of file that could be emailed?? I'm going to clinic next week and would like to take another crack at getting it off label. I recently moved and have a new doctor, and I haven't tried whole-heartedly to get him to prescribe it yet. I did try with my previous doc probably about a year ago.. I had a few Vertex slides (screenshots someone had found on the internet), and the Van Goor article, as well as the Kalydeco patent that includes my mutation (residual function- S945L). This info was not enough to persuade him to even write me the prescription. Ugh.

Anyway, if there is any chance you could share your info with me that would be awesome. If not, I'll go through all the posts and try to find everything. I'm always trying to take the easy way out. ;)

Thanks again,

Autumn

ladybird
12-09-2014, 06:42 PM
Hi Autumn

I would be happy to email you the attachments. Just send me your email in a PM.

Also, if your doctor is not willing to prescribe it, I strongly recommend finding one who will. It's your health!

I'm still waiting on a decision from insurance but I am confident of getting it eventually.

Take care

triples15
12-10-2014, 12:42 AM
Yay! Thanks so much for your help!

ladybird
04-18-2015, 02:45 PM
Victory!

After taking Anthem to the CA Dept of Managed Health Medical Review Board, which reversed their denial of Kalydeco off-label, I have my first box of Kalydeco in my sticky little paws.

I have to wait 2 weeks to take the first dose, to let the Rifampin clear out my system.

Never give up! It took my 5 months, and I had to go through the process twice when our insurance changed at the beginning of the year, but I finally succeeded.

Thanks Stephen, Autumn and JRicci for all your help!

jaimers
04-18-2015, 05:36 PM
That is awesome! Way to keep fighting!

stephen
04-18-2015, 09:47 PM
“Ladybird”,

I (and my wife) were thrilled to hear you were finally successful in your battle to get Kalydeco. Fortunately you had the persistence, knowledge and resources not to give up.

Hopefully Kalydeco will prove to be of great benefit to you.

When I got the first box in my “paws”, I was very excited about actually getting it. I was also apprehensive that it might not work. It was several days before I actually started taking it.

Many of us are anxious to hear how well you’re going to be doing. Please keep us informed.

Hopefully it will not be too long before there is a drug or treatment that brings relief to everyone with CF.

triples15
04-19-2015, 12:11 PM
WHOO-HOO!!! Yay, soo happy for you!! How exciting!!

Keep us posted!

Autumn

Aboveallislove
04-20-2015, 06:06 AM
That's so great Ladybird! Please do post once you start! Also, any pointers you can share for folks who might be trying to do the same?

jricci
04-20-2015, 10:05 AM
This is such great news! It made my day! As your bio states, you certainly are "saving your life one day at a time". Great job advocating for yourself. I can't wait hear about your progress once you start. Please keep us updated.