VX-445: What's It All About?
I posted two weeks back on Instagram, that there was big news in the CF community about the positive results shared from the third phase of clinical trials for a new triple combination drug. This post is SO delayed, SORRY!! (I actually began writing this post right away, but it didn't feel right so I couldn't bring myself to hit the publish button. Anyway, I needed to step away and come back to write a bit more clearly for those not as close to CF and the drugs available for treatment.)
Shortly after Sienna was born, Kalydeco finished up trials and became approved for CF patients with a very specific gene mutation (G551D). It was the first corrector to become available to the CF population and was a huge milestone and win in our community. And to see this with a newly diagnosed child - we had HOPE.
Now years later, we also have Orkambi and Symdeko available for individuals with two copies of a specific gene (F508Del also referred to as DDF508 or "double deltas" because there are two copies).
One of my biggest worries with all of these correctors coming out, is that they are targeted towards specific gene mutations - which makes sense, as mutations can differ the way the CFTR gene functions and therefore the correction needed to function properly varies. Some mutations create no functional CFTR protein, some create the CFTR protein but don't allow it to get to the cell surface, some create the CFTR protein and can get to the cell surface, but then the channel gate doesn't open to let it out, and so on. There are actually five classifications of genes and you can find a helpful infographic on the CFF website.
But did you know there are over 2,000 known CF gene mutations?! And as you can see now, knowing the mutations of a CF patient is pretty important if you want access to these correctors and new therapies. We knew Sienna carried the most common gene mutation, F508Del, from the results of her newborn screen. But it took several weeks of investigation from a blood test to tell us she also carries an insanely rare mutation of unknown significance, Ex22Dup (a duplication on Exon 22). The rare mutation, is a catch 22. It seemingly presents mildly, but there is no data on it which means there's no focus on creating a corrector for it. It doesn't even make the CF gene mutation database.
So knowing that, all our hope really hinges on the success of a corrector for F508Del. Because if you can restore function of one mutation, that makes a HUGE impact. VX-445 is a new drug in the Vertex Pharmaceutical pipeline, that when paired with Symdeko (currently on the market) it has shown positive restoration of CFTR function for individuals with at least one copy of the F508Del gene mutation. That's Sienna!
That summarizes our excitement over this news for those of you wanting the semi-abridged version! Read on if you want more medical/scientific jargon discussing VX-445 and other correctors. :)
Now to understand the "triple combo", let me give a quick rundown on the other correctors. Because as a triple combo, it's really just layering on to other correctors available.
First, I find it helpful knowing the pharmaceutical name for each drug.
Ivacaftor = Kalydeco
Tezacaftor + Ivacaftor = Symdeko
Lumacaftor + Ivacaftor = Orkambi
VX-445 + Symdeko (Tezacaftor + Ivacaftor) = new triple combo, unnamed
Kalydeco is the first corrector to become available for those with specific residual function mutations. It's targeted towards people with what we call a "gating mutation", meaning the CFTR protein is being created and released to the cell surface, but the channel gate doesn't open; hence "gating". Kalydeco restores function by opening the channel gate.
Symdeko is currently targeted towards individuals with two copies of F508Del (also called double deltas) or one copy of F508Del plus a second specific gene mutation that showed a positive response to the use of Symdeko. Symdeko is the second corrector to be released for the double deltas, showing improvement over the first corrector released, Orkambi. Both Symdeko and Orkambi are a double combo corrector - meaning they use Tezacaftor/Lumacaftor to unfold the CFTR protein and allow it to move to the cell surface, and then the Kalydeco to open the channel gate.
VX-445 is taken in addition to Symdeko, creating that triple combo. This corrector is expected to help NINETY PERCENT of the CF population, being as the majority of CF patients carry at least one copy of the F508Del gene. When VX-445 is paired with Symdeko, it helps the CFTR protein unfold and get to the cell surface.
With all this talk of VX-445, I should mention that Vertex has another drug seeing success in clinical trials as a triple combo, so we are also watching VX-651.
2020 will be a big year in the CF community. I'm dreaming of the day we have a corrector in our hand; even if not a cure, it's getting us so.much.closer.
As always, we thank all those that dedicate their time, their money, and/or their voice to CF research. None of this would be possible today without all of you.
Shortly after Sienna was born, Kalydeco finished up trials and became approved for CF patients with a very specific gene mutation (G551D). It was the first corrector to become available to the CF population and was a huge milestone and win in our community. And to see this with a newly diagnosed child - we had HOPE.
 |
| "Breathe" |
Now years later, we also have Orkambi and Symdeko available for individuals with two copies of a specific gene (F508Del also referred to as DDF508 or "double deltas" because there are two copies).
One of my biggest worries with all of these correctors coming out, is that they are targeted towards specific gene mutations - which makes sense, as mutations can differ the way the CFTR gene functions and therefore the correction needed to function properly varies. Some mutations create no functional CFTR protein, some create the CFTR protein but don't allow it to get to the cell surface, some create the CFTR protein and can get to the cell surface, but then the channel gate doesn't open to let it out, and so on. There are actually five classifications of genes and you can find a helpful infographic on the CFF website.
But did you know there are over 2,000 known CF gene mutations?! And as you can see now, knowing the mutations of a CF patient is pretty important if you want access to these correctors and new therapies. We knew Sienna carried the most common gene mutation, F508Del, from the results of her newborn screen. But it took several weeks of investigation from a blood test to tell us she also carries an insanely rare mutation of unknown significance, Ex22Dup (a duplication on Exon 22). The rare mutation, is a catch 22. It seemingly presents mildly, but there is no data on it which means there's no focus on creating a corrector for it. It doesn't even make the CF gene mutation database.
So knowing that, all our hope really hinges on the success of a corrector for F508Del. Because if you can restore function of one mutation, that makes a HUGE impact. VX-445 is a new drug in the Vertex Pharmaceutical pipeline, that when paired with Symdeko (currently on the market) it has shown positive restoration of CFTR function for individuals with at least one copy of the F508Del gene mutation. That's Sienna!
 |
| Shakies, Nebby, and Sisterly Love |
That summarizes our excitement over this news for those of you wanting the semi-abridged version! Read on if you want more medical/scientific jargon discussing VX-445 and other correctors. :)
Now to understand the "triple combo", let me give a quick rundown on the other correctors. Because as a triple combo, it's really just layering on to other correctors available.
First, I find it helpful knowing the pharmaceutical name for each drug.
Ivacaftor = Kalydeco
Tezacaftor + Ivacaftor = Symdeko
Lumacaftor + Ivacaftor = Orkambi
VX-445 + Symdeko (Tezacaftor + Ivacaftor) = new triple combo, unnamed
Kalydeco is the first corrector to become available for those with specific residual function mutations. It's targeted towards people with what we call a "gating mutation", meaning the CFTR protein is being created and released to the cell surface, but the channel gate doesn't open; hence "gating". Kalydeco restores function by opening the channel gate.
Symdeko is currently targeted towards individuals with two copies of F508Del (also called double deltas) or one copy of F508Del plus a second specific gene mutation that showed a positive response to the use of Symdeko. Symdeko is the second corrector to be released for the double deltas, showing improvement over the first corrector released, Orkambi. Both Symdeko and Orkambi are a double combo corrector - meaning they use Tezacaftor/Lumacaftor to unfold the CFTR protein and allow it to move to the cell surface, and then the Kalydeco to open the channel gate.
VX-445 is taken in addition to Symdeko, creating that triple combo. This corrector is expected to help NINETY PERCENT of the CF population, being as the majority of CF patients carry at least one copy of the F508Del gene. When VX-445 is paired with Symdeko, it helps the CFTR protein unfold and get to the cell surface.
With all this talk of VX-445, I should mention that Vertex has another drug seeing success in clinical trials as a triple combo, so we are also watching VX-651.
2020 will be a big year in the CF community. I'm dreaming of the day we have a corrector in our hand; even if not a cure, it's getting us so.much.closer.
As always, we thank all those that dedicate their time, their money, and/or their voice to CF research. None of this would be possible today without all of you.
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