Pure Speculation

Vertex released the data from their pivotal phase 3 combination trial today (VX-809 + VX-770), and reported "positive outcomes."  There has already been a huge amount of discussion about it on social media, so here is my opinion...

First of all, let's be clear about these results--they are modest improvements. This combination does not offer the same MAGNITUDE of results that Kalydeco did for G551D patients (but neither researchers nor the CFF expected it to).   Vertex knew prior to the trial, what the FDA would consider "statistically significant" improvements.  With the combo's relatively lackluster results in phase 2, everyone seemed to predict that the numbers from phase 3 would be "a close call," or just BARELY reach that significant threshold.  As hard as I have tried to pry for inside info on this trial, I was never able to get anyone "in the know" to give the combo better than a 50% chance of reaching the necessary trial endpoints.  I have been on the edge of my seat to see the data--not because I thought it would mirror data from the Kalydeco trial, but because I simply hoped it would be GOOD ENOUGH for FDA approval (and that is yet to be seen!).  It would be wonderful if every drug that came to market from this point forward were as effective as Kalydeco is for G551D, but I don't think that is a realistic expectation.  A reduction in pulmonary exacerbations by approximately 1/3 in the combo trial treatment group seems pretty significant to me, and a reason to celebrate this news!  My hope is that combo serves to stabilize/improve lung function for many with CF while BETTER drugs work their way to market!  Even if this is not the perfect drug, it may be a way to--
1) Buy some precious time for thousands of CFers by stabilizing or improving lung function,
2) Increase media focus on curing CF,
3) Keep fundraising momentum going, and
4) Maintain hope within the CF community about future advancements.  

Once the new drug application is submitted (Vertex says "last quarter of this year"), the FDA ruling should come very quickly thanks to the newly designated "breakthrough" status this combo holds.  Breakthrough is the most expedited review the FDA offers, and only a few drugs have been approved.  Recently, Novartis' cancer drug Zykadia was granted Breakthrough status, and on the market about 6 weeks later! Vertex has a good working relationship with the FDA. In other words, if the FDA approves this drug, a ruling could happen FAST--maybe even by the end of this year!

If the FDA approves the drug for marketing, it will almost certainly be labeled exclusively for homozygous DF508 patients.  I am really curious to see where they set their price point for this drug.  In an investor conference call I listened about 2 years ago, Vertex claimed they "set the price of Kalydeco based on the estimated benefit of this drug, for the limited population size."  So...does that mean that they are going to lower the price for the combo because the population group is much larger??  I doubt it.  Call me a naysayer, but when I see that $30K pricetag attached to Brady's Kalydeco statement each month, and see the access battles that have been waged abroad, I have little faith that they won't try to wring every last penny out of this drug also.  I worry how INSURERS are going to react to when 15,000 CF patients want access to drugs in the "ultra-expensive" category.  A large % of the CF population is on Medicaid, which comes back to taxpayer dollars.  There could be some push back for coverage--especially if it only has modest benefits, or ethical questions raised about who pays for these pricey advancements.  We are entering uncharted territory. This is why it is more important than ever to be an advocate for CF! 

I'm sure that some people are disappointed by the small increase in lung function reported in the Vertex data today.  Of course, everyone wishes that number was larger.  I maintain that these results are basically what was expected with the increasing knowledge of the DF508 specific CFTR dysfunction, and data from earlier phase trials.  Looking forward, I've already seen plenty of evidence that "second generation" combinations (many of which have already been tested in the laboratory), are several years away, but represent the huge clinical benefits we all hope for in this new treatment era.  In a nutshell, here is why--

There are a couple of problem sites within the folded structure of DF508 CFTR.  

VX-809 addresses one of those problems, which enables a small amount of CFTR to pass through "quality control" (endoplasmic reticulum) in the cell and make it to the cell surface--where Kalydeco acts on the protein to "open the gate" and allow Chloride ions to pass through.  Even further benefit might be seen if we could stabilize the protein at the surface, and prevent premature unraveling.  

Researchers discovered a ceiling of benefit when correcting only one site, and found that adding a second corrector compound to the mix to treat the other problem area, GREATLY increased the amount of CFTR that was able to reach the cell surface--where Kalydeco did it's job like a champ and opened that gate for a large amount of Chloride to flow through.

 

Sorry this one is blurry!
It shows that a 3 drug combo restored about 58% CFTR function in the lab.

These "second generation" combos are the ones that are going to give a lot of double deltas the magnitude of results they are hoping for...but for now, I'm going to celebrate a LITTLE BIT of improvement for SOME people with CF!  This is progress!

In the near future, we will also hear more about the VX-661/VX-770 combination. In some ways, VX-661 is known to be a superior corrector compound to VX-809. VX-809 is not highly compatible with VX-770 (The presence of VX-809 degrades the action of VX-770.  To get an effective dosage of VX-770, they had to pump up the initial dosage to 250 mg.--100 mg. more than the standard dosage for Kalydeco monotherapy.  Anytime you increase drug dosages, you run the risk of increased problems with metabolism by liver and kidneys, or other side effects).  VX-661 does not have this type of interaction with VX-770, and just seems to work better in general.  This two drug combo would still be considered "first generation," but could at least represent an option for some folks sooner than a second generation combo.

From this year's Volunteer Leadership Conference

The bar was set extremely high when our first venture into gene modification resulted in Kalydeco.  The announcement today may not live up to those expectations, but I would be thrilled to see the FDA approve this combo and give 50% of the CF population an opportunity to at least TRY a genetic modifying compound to see whether (or not), it works for them.  I AM CELEBRATING a step forward today! Cheers to The CFF!  Vertex Pharmaceuticals!  And all the individuals and families that donated time and/or money to make this possible!