Vertex Conference Live Now--triple combo gets up to 75% function

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Aboveallislove

Super Moderator
I'm in tears watching the slides. The 3 drugs combo gets in vitro CFTR function to 75% function. Orkambi only to 25%. Kalydeco...that miracle for 551...only got CFTR function to 50%. And for heterozygotes to almost 50%, which again is what Kalydeco did for 551!
vrtx.com has link if you want to watch, listen
 
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triples15

Super Moderator
Thanks for keeping us updated Love! I just checked out the slides on the Vertex website. It's truly amazing stuff going on here, things I really thought I'd never see in my lifetime.....
 
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Heather

Guest
What's the difference between residual function and minimal function mutations? My daughter has d508 and r1162x - a stop mutation. Does she fit into either of these categories? It's been wonderful to see all of the recent progress with meds but it's getting tougher to cheer from the sideline.
 
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Aboveallislove

Super Moderator
Heather...these slides mean that the three drug combo could get your daughter to 50% cftr function. Slide 11 is the key. And 50% cftr function is what kalyd co did for 551...this is amazing for all with one another or two with df508. But still make re work to get this set without df508 and some research in those areas is promising to.
 
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Aboveallislove

Super Moderator
Residual function means some protein on cell surface and would benefit from kalydeco alone. Minimal function are those that don't make protein I believe...most class 1...ones that don't benefit from kalydeco or orkambi.
 
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AllthebestforLiam

New member
Thanks for sharing this Aboveall!!
Would a nonsense mutation (class1) really fall into the group of "minimal function"? I fear it would rather fall out of this Vertex study, being "no function" rather than "minimal function " - don't you think? Don't get me wrong, I'd be beyond happy if Vertex believed they could get a nonsense mutation+DF508 to 50% CFTR function - in fact I'd go and open a bottle of champagne if they did..
 
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Gammaw

Super Moderator
Similar concern here Liam. I'm trying to determine Vertex's definition of minimal function. Class I does not produce any CFTR. Class II produces little. But they aren't talking about minimal production, they are talking about minimal function. Clearly Class II is in the mix, since that is the class to which f508d belongs.......I believe at one point Vertex was "redefining" the classes, so I would really like to hear their definition for minimal and residual function.
 
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Aboveallislove

Super Moderator
My understanding of how they use the term "minimal function" is that it doesn't benefit from VX809/VX661 or VX770 either alone or together. I don't think they are using it in a scientific way, more as a short hand for those who cannot benefit enough for approval with Kalydeco or Orcambi. Not sure if that helps, but what they are trying to say simply, I think is that we're testing for those who have df508 on one allele and on the other a gene that is not a residual function one (listed in the recent press release), and not a gating mutation. I think there is a wide array of those within the minimal function which benefit differently, from some with class 1 and no protein to some with class 2 and might actually benefit like df508, but that they aren't testing those separately and they are keeping them all in the same bucket as minimal function.
 
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Aboveallislove

Super Moderator
Just read it more closely: I do not think they are excluding those with "NO FUNCTION". I think they just mean df508 and another gene not believed to respond. The theory is that they can fix df508 enough that it doesn't matter if the other gene does nothing. Kinda like Kalydeco fixed 551 no matter what was on the other allele.
 
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Aboveallislove

Super Moderator
The studies for 661 on going now for those "unlikely to benefit for Kalydeco or VX661" list the mutations that fit within that category.
https://tools.cff.org/Display/dsp_C...S=&BCepacia=&PLT=0&Therapy=&Char=&Keyword=661

So I think the "minimal function" is a short hand for investors to understand what they mean. Two points: 1) those listed would qualify for the study and likely on-label for the triple combo. 2) The 50% for heterozygotes had to use tissue from a specific "minimal function"...what that was might determine if it is 50% or 30% or 60% as there are so many of those mutations and all respond slightly differently.

Does this make sense?
 
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Aboveallislove

Super Moderator
Heather and Liam's mom: It looks like both of your precious ones have df508 and r1162X? If I'm right, my understanding is that the triple would get their CFTR genes to function at 50% normal. The link above lists those that Vertex is currently testing 661 for with Kalydeco. Vertex would use the same criteria for a triple for the "minimal function" genes. The studies actually calls it "non responsive" which I like better because I think Vertex isn't saying it has minimal function (as opposed to none), but saying it isn't responding to other drugs, so we need to get enough correction on the other allele which has 1 copy of df508. Slide 11 shows what the tissue did in vitro when given different drugs. Vertex has two next gen ones that get it up to around 50% of normal. THAT IS WHAT KALYDECO DOES! I really can't express how amazing slide 11 is. ...last year Vertex had shown the improvement and for ddf508 it wasn't quite to 50% and for df508+non responsive it was only 33%. They've found correctors that get that much higher and those will be in healthy volunteers in a study starting next month and then in CFers second half of next year.
 
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Aboveallislove

Super Moderator
This link has older slides which show the previous impact of adding a third corrector. It also shows the impact of kalydeco on g551 and two corrector on 551. For those with df508 and a gating or residual function mutation this means the triple will likely get you to 90-100% normal and vertex said that was its plan....one drug for all with df508 that is a tripple. And kalydeco for those with gating or residual function but. It df508. And then the benefit will very from 90-100 for gating and residual function, 75% of normal for ddf508, and 50ish for df508.
https://sixtyfiverosesblog.wordpres...x-second-generation-correctors-latest-graphs/

Compare those slides wth slide 11 from Vrtx.com which I also screen shot and put in an album which I think you can see from the feed here.
 
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ToriMom

Guest
Hmmmmm on the CF link it says the study is recruiting in many locations, but the clinical trials.org link says only two are recruiting. I guess I need to call the centers. Thanks for this hopeful information!

Michelle
 
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Heather

Guest
Aboveallislove, thanks so much for taking the time to explain these slides to me. I was beginning to loose hope-seemed nothing was working on the stop mutations. My daughters young so time is on our side, but it feels great to know that good results are starting to come in.
 
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