809 combo study -- full data release

[stranger]

http://nacfcdl.cff.org/Documents/NACFC 2012_Boyle_Phase 2 VX809-ivacaftor results.pdf

Released today at the Cf conference in Orlando. Webcast w vrtx @ 6:30pm ET today (11-Oct) to review. Maybe we will get more concrete info re: Phase 3 yes/no? Study design? Any other mutations to be targeted in study if there is one? If there is a Phase 3, what is the future / role of 661?

If I had to guess, I would reckon that if they role this into a Phase 3, it would be the largest study they have done to date to help out with the safety issue (I believe they hinted at this on one of their analyst calls in either July or September).

Either way, another very significant milestone. It sometimes feels like they are moving too slowly but they are moving...

 

[Aboveallislove]

Already have answers to most of this from Vertex. Phase 3 is a definite for 809 combo. Doing an arm three with higher dosing (that's already on the fda study page) and will depend on what FDA says if they can include that higher dosing in Phase 3. And yes, larger size. Only ddf508 for Phase 3 right now.

 

[musclemania70]

6.1 percent is that it?

 

[bigstar]

Well im not good with numbers but this whole thing sounds very promising! At least some good news!

 

[kyeev]

6.1 percent is that it?

6.1 percent doesn't mean much to someone with maybe 80% FEV1.
But to someone at 30%, it might mean moving off the transplant list and stopping 24/7 oxygen.

I hover between 35% and 40%, so I'll take a 6,1% boost everyday thanks!

Its likely kalydeco slows down disease progression too so you have to look at the long term beneficial effects.

We can't really expect these drugs to repair lung damage.
The best they can do is maximise the effectiveness of the lung tissue thats still intact.

 

[calebf]

I don't think the numbers here tell the full story. The benefit isn't just your FEV1 + 6.1%. FEV1 of course is your clinical endpoint, but CF has a lot of intertwined mechanisms of disease. This drug should increase immunity against bugs, leading to decreased inflammation, decreased exacerbations, thinner mucus secretions, the need for less antibiotics (which deplete necessary resources), replenishment of those resources, improved weight gain, which then leads to higher immunity against bugs and the cycle continues upwards. This drug has the potential to stop the destructive spiral that leads to lung damage and reverse the cycle. I think the greater benefit here is the flattening of the rate of decline over years of FEV1 and quality of life. Even if my FEV1 doesn't improve one percent on a drug that does that I'd take it for the rest of my life.

 

[baseballfrank]

benefits of 809/770 combo drug

That is the thing that is the most exciting to me. My FEV1 is in the low to mid 40's. I don't think that will ever increase much because of the significant lung damage I have. But I can live with that if the new drug eliminates or reduces the amount of mucos my body produces. That will reduce the constant coughing, reduce the frequent infections, and reduce the constant inflammation all of which are my biggest problems. From all I have read I think this is the biggest benefit of the new drug and not improved FEV1. Do you all agree?

 

[musclemania70]

Was anyone at the conference that is posting here?

 

[GenH]

I don't think the numbers here tell the full story. The benefit isn't just your FEV1 + 6.1%. FEV1 of course is your clinical endpoint, but CF has a lot of intertwined mechanisms of disease. This drug should increase immunity against bugs, leading to decreased inflammation, decreased exacerbations, thinner mucus secretions, the need for less antibiotics (which deplete necessary resources), replenishment of those resources, improved weight gain, which then leads to higher immunity against bugs and the cycle continues upwards. This drug has the potential to stop the destructive spiral that leads to lung damage and reverse the cycle. I think the greater benefit here is the flattening of the rate of decline over years of FEV1 and quality of life. Even if my FEV1 doesn't improve one percent on a drug that does that I'd take it for the rest of my life.

I agree, and even at 80% a 6.1% increase and then a slower decline is still very useful. It is not so much the initial improvement (although very nice), it is more the stability, decrease in infection, exacerbations etc that caleb mentioned.

I was not at the conference but I listened in detail to the latest vertex investor presentation. They said Kalydeco and VX809 are both metabolised by the same system so VX809 can reduce the level of Kalydeco. This is why the dose is higher (250mg compared to 150mg for G551D). At least 400mg of VX809 is needed to ‘saturate’ the system and to get a stable exposure level (basically to get a high enough long term dose). There was a consistent PFT response in the trial when a stable exposure of Kalydeco and VX809 was observed. The amount of VX809 and Kalydeco is also influenced by an individual’s absorption, which varies and can be affected by poor digestion.

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Hopefully this means that if the amount in the body is high enough for long enough, it is likely there will be a better PFT response. This image shows 55% improved at least 5% and 25% improved more than 10%, hopefully improving the exposure would help the other 45% get to the 5% improvement point.

It was also mentioned that many people in the trial were on inhaled antibiotics, and their ‘off’ month was the second period where Kalydeco was added. The 6.1% improvement was seen despite many stopping the antibiotics.

Finally it was mentioned that a second generation of medications is being developed, in the lab this increases the CFTR function of DDF508 cells from 25% with VX809/Kalydeco to 50%.

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[Aboveallislove]

GenH: At the actual CF Conference the second generation correctors (i.e., several correctors working together) are suppose to increase to 70-80% CFTR function. 809 is just the start to keep us going until 661 and then second generation!

 

[GenH]

GenH: At the actual CF Conference the second generation correctors (i.e., several correctors working together) are suppose to increase to 70-80% CFTR function. 809 is just the start to keep us going until 661 and then second generation!

Did they say they had actually acheived 70-80% or was that what they hoped to get? I'm just surprised because they only mentioned 50% in the investor conference, I would have thought if the % was higher they would have mentioned it (unless youre talking about meds from other companies, then I would understand why vertex was not discussing them )

 

[Aboveallislove]

This is from my friends who attended at the CF Conference and at those presentations Vertex said they had achieved in vitro 70-80% with the "combination" of correctors, i.e. many correctors working at different points of the folding process etc. I listned to the investor conference and what I heard was that Kalydeco does 50% improvement on CFTR and that 809/770 with tweaked dosing is 30% and that the future correctors have an improvement like Kalydeco. I interpretted that to be 50% also, but then the 70-80% was discussed at the actual conference. I'm hoping Vertex clarifies at another investor conference!

 

[GenH]

Yes it makes sense that adding more correctors could increase the % further. Exciting that they have acheived this in a lab, lets hope this translates soon in to an improvement in humans!

I was reading the EMA report on Kalydeco today and noticed that there were many trials on animals and also many phase 1 dosing trials before we even heard about the phase 2 and 3 trials. I now have a much greater appreciation of the time frame and why it takes time to go from the lab to a phase 2 trial!

 

[Aboveallislove]

I missed it but I read someone else say that at the investor conference that the additional correctors were getting ready for "clinic." I'm hoping that means clinical studies!!

 

[GenH]

I missed it but I read someone else say that at the investor conference that the additional correctors were getting ready for "clinic." I'm hoping that means clinical studies!!

They might mean the phase 1 human trials. I'm guessing they will need quite a few phase 1 trials looking at safety and dosing before the longer phase 2 trials (especially with multiple meds).

 

[bigstar]

I'm very optimistic and hopefull that in a more long term perspective we will see even greater results! I mean that it was just a 52 days study... Even IVs take a 21 days period or more to work. And of course sometimes you see the benefits later on: feeling better, having a better appetite, your pfts raise, your weight goes up, your cough drops. It takes some time for your body to adjust. So im very very anxious to see how the next phase proceeds!

 

[GenH]

Yes in the vertex investor presentation they did mention that the pfts were still increasing when the trial ended. It was only 28 days of the combination medications so it will be interesting to see the long term results.

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