df508 Heterozygotes who might benefit from Orcambi

[Aboveallislove]

So, for those with heterozygous for df508, I’ve been pondering which mutations might benefit from Orcambi. Genevieve in her awesome Blog noted several mutations that studies showed VX809 improved. The blog is: https://sixtyfiverosesblog.wordpress.com/2013/10/18/how-does-vx809-help-f508del-part-2/


She identifies these mutations from the research as mutations likely benefitting from Orcambi in vitro: E56K, P67L, E92K, L206W, V232D (only to 25%), H1054D, G1061R, L1065P, Q1071P, L1077P H139R, R258G, and S945L.
Jricci recently posted the two new 661/Kalydeco combos that have the mutation lists, one with df508 with a second NOT believed to benefit from the combo and another for df508 + residual function. Some of the mutations noted above that should benefit from VX809 based on in vitro research are shown as residual function and some are shown as not believed to benefit and some neither.

It might be that Vertex is catergorizing the mutations based on its own in vitro assays which differ than those used by the studies Genevieve reviewed. I have a former classmate who runs a biotech that investigates various genetic diseases (not CF) and he told me that the biotechs will run all the mutations through their assays and know which ones benefit, etc. So, if your mutation is listed above as likely benefiting from Orcambi, AND IS NOT listed below as part of the two trials, Vertex likely has evidence that your mutation benefits from Orcambi (but isn't a residual function one), and that might be worth pursuing to get off label. Personally, if you aren’t in a residual function trial but are listed as below as included in the residual function mutation, I’d also try to get off label now. Finally, if your mutation is not listed anywhere here (and isn’t df508 or a gating one), that might also mean there is evidence Orcambi or Kalydeco works and also be worth pursuing off label. (Vertex might not include it because it is attempting to use the inclusion criteria in a way most likely to show positive results.) If anyone fits those categorizes and wants to brain storm re off label, let me know.


Not Believed to Benefit from Orcambi or Kalydeco:
Nonsense mutations: Q39X, W57X, E60X, R75X, E92X, Q98X, Y122X, L218X, Q220X, C276X, Q290X, G330X, W401X, Q414X, S434X, S466X, S489X, Q493X, W496X, Q525X, G542X, Q552X, R553X, E585X, G673X, R709X, K710X, L732X, R764X, R785X, R792X, E822X, W846X, R851X, Q890X, S912X, W1089X, Y1092X, E1104X, R1158X, R1162X, S1196X, W1204X, S1255X, W1282X, Q1313X

Canonical splice mutations: 621+1G?T, 711+1G?T, 711+5G?A, 712-1G?T, 405+1G?A, 405+3A?C, 406-1G?A, 621+1G?T, 1248+1G?A, 1341+1G?A, 1717-1G?A, 1811+1.6kbA?G, 1811+1G?C, 1812-1G?A, 1898+1G?A, 2622+1G?A, 3120+1G?A, 3120G?A, 3850-3T?G, 3850-1G?A, 4005+1G?A, 4374+1G?T

Frameshift mutations: 663delT, 2183AA?G, CFTRdel2,3, 3659delC, 394delTT, 2184insA, 3905insT, 2184delA, 1078delT, 1154insTC, 2183delAA?G, 2143delT, 1677delTA, 3876delA, 2307insA, 4382delA7, 4016insT, 2347delG, 3007delG, 574delA, 2711delT, 3791delC, CFTRdele22-23, 457TAT?G, 2043delG, 2869insG, 3600+2insT, 3737delA, 4040delA, 541delC

Missense mutations: A46D6, T338I8, R347P, L927P, G85E, S341P6, L467P6, I507del, V520F, A559T6, R560T, R560S, A561E, Y569D6, L1065P, R1066C, R1066M, L1077P6, H1085R6, M1101K, N1303K

Residual Function:


Eligible mutations for this study include:

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

 

[ToriMom]

Thanks so much for posting!! My daughter's mutation is one of the missense ones listed as not likely to benefit, unfortunately. I appreciate all information though. Knowing is better than not knowing for me.
Thanks again,
Michelle

 

[jricci]

Aboveallislove- I agree that we need some ideas on expanding off-label use when it's appropriate. The first hurdle is increasing awareness of patients and doctors that off-label use is possible and may be very effective for certain mutations. Just because your mutation is listed under “mutations that aren’t likely to respond”; I wouldn’t rule out the possibility that a significant clinical response is possible. This is especially the case with the Conical splice mutations. Interestingly, there are quite a few mutations that are now listed here as not likely to respond that were eligible for enrollment in the 2012 Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis and Residual CFTR Function. There must be a reason that they were included in this original study. Maybe their response wasn’t as significant, but that doesn’t necessarily equate to lack of clinical efficacy, symptom relief. Most mutations in the splice mutation list are Class I, but some are Class V, and some are listed as unknown class. I have come across 3 separate blogs where people with Class I Spicing mutations have had a significant response to off label use. Their mutations are: 621+1G>T & F508del (2 people) and 1717-1G>A & F508del.

The second hurdle is getting insurance to cover off label. To do this there needs to be journal articles supporting use. I am so thankful that my doctor saw this need and has been working with other doctors to have an article published regarding their experiences with off label use with residual function mutations. I’m not sure where they are in the process of journal publication; but he did mention at my last clinic visit that they submitted their info.to be shared at the NACFC in October of this year. Hopefully other doctors will also see this need and try to get their experiences on off-label use published or at the very least, shared in some way. Even if it means simply corresponding with other CF doctors and telling them of their experiences and the responses seen. This may not help with insurance appeals; but it would perhaps convince another doctor to write a prescription for a patient with a mutation that has shown positive clinical response. There is the possibility that insurance will cover, without any appeals necessary (as was the case with me). I know that this is a very expensive drug and that writing a prescription for it shouldn’t be taken lightly. But I believe for some people there is enough evidence out there to warrant the prescription for a trial period.
I would also encourage people to reach out to the CFF patient resource center. They are able to help with appeals. I have sent them articles that may be helpful for off-label use for residual function mutations. They can’t promote/advertise off-label use, but they can give you information if you specifically ask about off-label use. Also, feel free to PM me and I’ll try to help in any way I can.

 

[Aboveallislove]

jricci,

I absolutely agree with all you say and should have been more clear. The issue as you point out is both scripting and insurance and without proof that it works most insurance will deny (as its contract allows), BUT that doesn't mean folks shouldn't try and that some insurance will cover. In fact, now that Orcambi is approved and cheeper than Kalydeco (although still very $$$$), those heterzgous for df508 might have a chance to try Orcambi off label with the hope that insurance companies see one df508 and green light it. A

nd as you note there has to be a reason the mutations are listing different...just looking at the ones listed as likely benefiting from Orcambi--some are treating as not benefiting and others as residual function.

It is so very important too for the doctors to do case studies to get others access as well...so those off label maybe consider asking your doctor.

I didn't realize the cff would provide the info to the patients. I knew that Vertex would give the info to doctors but how much better for folks to be able to gather it ahead of time.

In the end, the evidence can force an insurance company to cover off label (in U.S. and under the typical policy language), but some insurance companies may cover without questioning and it can't hurt to try!!!

And thanks for posting that info for other trials...that helped with what I had been trying to think through but I didn't know where to get that info!

 

[jricci]

jricci,

I absolutely agree with all you say and should have been more clear. The issue as you point out is both scripting and insurance and without proof that it works most insurance will deny (as its contract allows), BUT that doesn't mean folks shouldn't try and that some insurance will cover. In fact, now that Orcambi is approved and cheeper than Kalydeco (although still very $$$$), those heterzgous for df508 might have a chance to try Orcambi off label with the hope that insurance companies see one df508 and green light it. A

nd as you note there has to be a reason the mutations are listing different...just looking at the ones listed as likely benefiting from Orcambi--some are treating as not benefiting and others as residual function.

It is so very important too for the doctors to do case studies to get others access as well...so those off label maybe consider asking your doctor.

I didn't realize the cff would provide the info to the patients. I knew that Vertex would give the info to doctors but how much better for folks to be able to gather it ahead of time.

In the end, the evidence can force an insurance company to cover off label (in U.S. and under the typical policy language), but some insurance companies may cover without questioning and it can't hurt to try!!!

And thanks for posting that info for other trials...that helped with what I had been trying to think through but I didn't know where to get that info!

Aboveallislove, no worries- you were clear and I’m in agreement with what you said Believe me, I know what an advocate you have been on this forum, doing everything possible to keep people informed and up to date. I was just trying to brainstorm with you about off-label use. I didn’t want people to give up hope because they saw their mutation on the not likely to respond list. I’m by no means an expert in genetics, and a lot of what I read is way above my understanding, but from the research I’ve been doing, it does seem possible that some of the splice mutations may benefit from Kalydeco alone and maybe more so with the combo drugs since they also will be treating df508. Of course, what I’m really hoping for is that there will be a significant number of heterozygotes in the VX-107 study, regardless of what grouping they are in, whose one df508 mutation responds enough that the combo drug 661/Ivacaftor is approved. I'm feeling confident that the results from the residual function study (VX-108) will produce favorable results. I just hope when all is said and done, that all those with evidence of residual function will be included in the expanded label. But this seems unlikely. They'll probably just expand label for those mutations included in study. So this is where off-label use really has to be pursued.
Here’s an interesting site I found that explains splicing mutations. It’s from 2012, so info. regarding trials is outdated, but it gives some good explanations about these mutations. It’s not a published journal article, so I’m not sure about accuracy, but it does back up claims with research references. http://www.cftrsplicing.com/page.php?7

 

[Aboveallislove]

Thanks jricci! I too don't understand the genetics of it...I'm a legal/business-type so I learn the science by following what I do understand...the market and my attempt at logic. And I also think the scientists don't fully understand how CF translates in individuals. For instance, Vertex could never explain why the sc didn't decrease but Orcambi worked! (I have my own theory: I think that the salt imbalance differs by the tissue affected and that there are other modifying genes that impact it and that fixing the CFTR function in a small way might improve the salt transfer in some areas but not others and in some people with different modifying genes (thus also explaining the high and low responders). DS has horrible GI issues, off the chart SC (133), the worst aquagentic wrinkling, but minimal lung involvement...there has to be something different in the salt transfer for him and other ddf508 based on his phenotype....and I think these drugs are similar in that they are affecting the salt transfer but differently by tissue/organ, and with various modifying genes. (Science-types please don't laugh too hard at my inept way of explaining this!!) We'll get there soon!! Second-gen corrector (which when added to 661/Kalydeco will reach heteros), in clinic soon! And 661 study pushing ahead fast!

 

[lovemyboy507]

Hi sorry this maybe a stupid question but R560t is listed as a missense mutation and my understanding is it's a class 2 gating mutation, can someone clear up for me? I assume that either way it isn't helped by either drugs? Thanks !

 

[lovemyboy507]

Apologies ignore my post - worked it out should read the full article on the link!!!