Kalydeco and Class IV Mutations

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pjammer65

New member
Hi all, I am new to the site but look forward to being a part of the cf community that has formed here. I am a 34 year old male with the DF508 and R347P and currently in the early stages of transplant evaluation. I have been trying to get my center to prescribe Kalydeco but have been unsuccessful. At my last visit they said they spoke to a vertex rep that said that Van Goor is soon to publish a paper outlining the effects of Kalydeco on different classes of mutations. She also said that Van Goor stated that kalydeco had no effect on my specific mutation, R347P.
This is obviously upsetting to me as I thought that 770 potentiated all CFTR (as per previous Van Goor comments). I also was hoping since R347P is a conductance mutation, the probability that 770 would be effective was high. So maybe it potentiated but was not clinically effective?
Has anyone heard about this publication or having any information from it?
Are there any R347P'ers out there?
Has anyone found any info on class IV mutations and 770? (beyond the presentation slides Vertex distributed recently)
Thanks!
 
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saveferris2009

New member
I wish I had more information from you.

But, if I were you, I would go to any and every doctor (CF or otherwise) to get an Rx of Kalydeco. You don't have the time to wait for papers or for doctors to contemplate their navels.
 
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saveferris2009

New member
It's true! These docs don't have CF - no matter how empathetic they are, they will NEVER fully know what it's like to have this disease. So they don't have the same sense of urgency that we do. ESPECIALLY if you are near Tx. Does their life change dramatically when you get to end stage and need a tx? NO. Do they have to be on immunosupressants for the rest of their lives? Avoid big crowds? Worry about their future? NO NO NO! How could you NOT let a patient try this drug? The drawbacks/side effects are so minimal it's INEXCUSABLE not to let a patient with any mutation try it. If you aren't vocal, you can let these docs slowly take away your health. And your life. OK I'll stop now.
 
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moxie1

Guest
Saveferris,
I totally agree with everything you said. It's just that I've never heard that expression before and it just cracked me up!
I have a very good doctor. However, most of what has helped me, I have gotten for myself. Years ago, when it just came out, I read about the vest and advocated for one. I'm taking Bioadvantex NAC because of my own research and it helps me alot. I have an ElectroFlo 5000 percussor that also helps me alot. Did any physiciantell me that these things existed? No!
You do have to be your own advocate and you need to do your own research!
 
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ffevziyildiz

New member
pjammer65
I m from Turkey and my son's mutations are Delf508&R347P. He is 20 months old then i want to ask something. Can you help me?
Thanks.
 
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sandy52546

New member
My grandson has delta 508 and r347p. He is 4 and is pancreatic sufficient. I would be very interested in knowing how your health has been over the years. Thanks to you and I appreciate any feedback.
 
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JENNYC

New member
I agree saveferris2009!! I am trying right now to get my daughter a prescription and being met with some resistance. I took my doc a hand full of paperwork this weekend though!! I pray he reads it soon and gets back with me and does not drag his feet. And sweet Rebecca just gave me some more ammo this weekend to send to him! Keep your fingers crossed for me! <img src="i/expressions/face-icon-small-smile.gif" border="0"> I will let everyone know as soon as I hear something. Abby got tested for her 2nd mutation on May 8th so can't wait to find out her 2nd mutation as well.
 
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GenH

New member
pjammer65- I am not sure when you mention slides if you mean this: http://iom.edu/~/media/Files/Activity%20Files/Research/GenomicBasedResearch/2012-MAR-21/3%20-%20Peter%20Mueller.pdf , but this mentions that the following mutations may be helped (there may be other mutations as well, Vertex mentioned '55' in total):

Mild conductance mutations: R117H, D110H, R117C, R347H, R352Q
Mild processing mutations: E56K, P67L, L206W, A455E, D579G, S945L, R1070W, F1074L, D110E
Unknown protein defect: D1152H, S1235R, D1270N
Gating: G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N

R347P was not listed on that slide, maybe the paper will have more info. I have not seen any other research where the classes are mentioned, only the journal articles about G551D.

I am looking forward to the paper by Van Goor about the different mutation classes with Kalydeco.
 
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pjammer65

New member
@saveferris - Thanks for the reply. I totally agree with you, I do not see the harm in at least prescribing the med. I am not sure, but I think that part of my problem is that I belong to an hmo. They have told me that my insurance (their employer) definitely would not allow it off label without a strong case because of the cost. Over my past 3 appointments it seemed like my odds were looking good to at least get the rx. But then word of this new Van Goor paper shot that down. I will look into other doctors and see if I can get it elsewhere. When you do get the prescription, who battles with the insurance, you or the doctor? Do they want clinical data or just to be heavily persuaded?
@ffevziyildiz- Feel free to ask me whatever you like.
@sandy52546- I was diagnosed right after birth and led a pretty normal life up until later highschool. I was a baseball player and started to really notice shortness of breath when running. It got bad enough that when the team would do endurance runs, I would do other activities. Prior to that, I was hopsitalized or did home iv 'tune ups' around every 2 years. Following highscool I went to college full time, and worked full time. I believe this hit my health pretty hard and if I could do it over I would not have worked so much. In this time, at the age of 25 or so, my fev 1 dropped to the 35% range. I am now 34, and in the past 9 years I have pretty much maintained my health. When 'maintaining' my fev 1 is maxes out around 33%, but when I am sick, it gets down to the 20-25% range. about 6 years ago I did have one particularily bad infection (Couldn't breathe, lost 40 pounds, etc.) that prompted my doctors to send me to get the transplant workup done. I bounced back, but still go to the tx docs and have been for about 5 years now. They continue to say I am too healthy (thank god!) but they want to keep evaluating me regualrily in case things change. I am not on oxygen and still exercise regularly. I feel as though I breathe better than my numbers show, and even my doctors are a bit baffled by it. When I am sick, they are surprised by the activities that I can still engage in. As for pancreatic issues, I am a little strange there too. I have no problem gaining weight without enzymes and my digestive system functions normally. But if I do take them, they mess with my stomach. But my nutiritionist tested me, and she says that I am one of the most deficient people she has seen, so who knows. Let me know if you have anymore questions!
@JENNYC- What is your approach in trying to get a script? Good luck!
 
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pjammer65

New member
@GenH- Thanks for the reply, Yes those are precisely what I was referring to. I had originally thought that one slide was a strong piece of evidence to get the rx, but it now might be the opposite. Especially given the registry data and the fact that there are twice as many known 347P's than 347H's, why would they include the H's over the P's unless there was little or no effect? I believe I understand the basic theory behind the mutation classes and how the drug works, but I am definitely not a biochemist, so who knows. I just know Van Goor has said himself that all CFTR, even wild type, are potentiated by Kalydeco. So, since class IV's make it to the cell membrane I assumed it would be effective. Maybe they all are but just not clinically substanitial?
@kristen- This is definitely awesome news for the cf community. And hopefully after their trials this summer they can quickly open up use to more mutations!
 
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saveferris2009

New member
You never know unless you try.
I never understand everyone saying "we don't think insurance won't cover it." OK. But have you TRIED? TRY!
I battled the insurance because, well, I told my doc I would. He said my insurance wouldn't cover it.
But they did.....because i TRIED!
 
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GenH

New member
Yes I see what you mean about including data about R347H but not R347P (given that there are more Ps). They did say they had genetic evidence for 55 mutations though, and they did not list 55, so there are some others. I found it interesting when I read in the slideshow that the normal CFTR channel can be potentiated by Kalydeco as well (doubled the probability of it being open), so yes I agree, if Kalydeco can still interact properly with the mutated CFTR channel that is on the surface, then it's likely there would be an increase in its function (could be anything from a small to large increase). The H and P amino acids are quite different, so even though the mutation is at the same spot Kalydeco may not potentiate it as well (the 3D structure of the channel would be different with the two amino acids, so Kalydeco may not interact in the same way).
 
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JENNYC

New member
I printed everything I could find on people taking it off label (Thanks to those for paving the way <img src="i/expressions/face-icon-small-smile.gif" border="0">) And I took him a huge stack of papers to back up why I believe my daughter should be allowed to try this life saving medication. I gave it to him Saturday and he has not got back with me yet. But I will definitely let everyone know when he does. <img src="i/expressions/face-icon-small-smile.gif" border="0"> Hopefully it will be good news, if not I will be asking for advice. <img src="i/expressions/face-icon-small-smile.gif" border="0">
 
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annalisa

New member
HI,
I think that currently they don't know if kalideco is useful for r347p, becouse it has not been tested. So, it could be!
Also becouse all the other mutation of Class IV tested have shown (at least) same positive effects.
I also know of on other patients (with r347p) waiting to start using kalydeco, off label.
So, there is HOPE!
Annalisa
 
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marcob

New member
Hi,
Can someone explain the main difference in mutation regarding the last letter?
What the latest letter means exactly?
I've got almost the same question mark at my side. My son is G970D and it seems that G970R is in the list of potential candidates for VX770.
How far are the mutations ?
Thanks for your help
 
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DrRoe

Guest
Here's some info from the abstract for Van Goore et al's study, I don't have access to this journal so if anyone else can post more info on this study I would love to read it.

==================================
Ivacaftor potentiation of multiple CFTR channels with gating mutations

Haihui Yu, Bill Burton, Chien-Jung Huang, Jennings Worley, Dong Cao, James P. Johnson Jr., Art Urrutia, John Joubran, Sheila Seepersaud, Katherine Sussky, Beth J. Hoffman, Fredrick Van Goore


"Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations."

"Conclusion

These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D."
 
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GenH

New member
The CFTR chloride channel is a protein that is made up of amino acids. There are 1480 amino acids in a row that make up the CFTR channel. The number in the mutation is the position where the mutation is (eg G551D has a mutation at amino acid 551). The letters represent the amino acids. In this case the 'G' amino acid has been replaced by a 'D' which means the change of just one amino acid causes the mutation. In your sons case the amino acid at position 970 has been changed from a G to a D. If an amino acid is changed (from the normal protein) the 3D structure of the protein might be altered, and the channel may not work in the same way compared to normal. (This is a simplified explanation, the amino acid change may also change other properties of the channel eg whether it is postive/negative- this can affect how well it works as well)Two mutations which both have the same number (so the mutation is in the same spot) may have very different amino acids. This means the mutations can be quite different despite the fact they are in the same spot. This is a link with the amino acids and their letter 'codes' http://upload.wikimedia.org/wikipedia/commons/a/a9/Amino_Acids.svgAlso the del or triangle in F508del means the 'F' amino acid is deleted at position 508.The X in G542X means the 'G' amino acid has been changed for a stop codon at position 542. This means the protein stops being made at that point (so a full length normal channel is not produced).There are also splicing mutations and frameshift mutations (more complex!).Kalydeco needs to interact with the CFTR channel in order for Kalydeco to improve the function of the channel. It is likely the 3D structure of the channel and the properties of the specific mutation determine how well they interact. Do you know what class G970D is?
 
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