Tuesday, June 24, 2014

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! 


  1. This is something I too am cautiously optimistic about.

    If I have learned anything about vertex it is this...

    1. They report good results
    2. The stock price shoots up
    3. Several high level execs cash out their stocks and make billions
    4. Vertex releases additional data reporting the findings are not quite as good as they first thought.
    5. The stock price drops down again.

    I am not trying to sound ungrateful, but I had a lofty view and faith in those who control the path of cf through fundraising, foundations, drug trials etc.

    But the more the curtain is pulled back, I don't always like what is revealed. I wish I could remain blissfully unaware, but it is not my nature.

    The CFF has a big investment in Vertex, so they profit too, but the $75 million the CFF gave to vertex came from you and me and all of us that work hard at fundraising.

    Did the CFF pass the savings on to the patients by asking Vertex to price the drug lower? Not even close.

    Will the CFF go to bat for the patients on the new drug combo to ask vertex to lower the cost of the drug? I guess we will see.

    Money talks. CFF wants the highest return on their stock too, so it is not in the best interest of CFF to ask for a lower price. Can you say conflict of interest?

    Sorry to be negative.

    1. I really appreciate your comments, and I agree with you that we are taking about a lot of money at stake here. In response to the CFF's role--they are just like any other investor at Vertex, and own a small percentage of the rights to Kalydeco. The CFF would LOVE to get these drugs at lower prices, but they have absolutely no sway when Vertex is setting the price. The CFF took a risk with Vertex when we made the investment with them, just hoping that they would find ANYTHING, and they found Kalydeco and brought it to my doorstep. Do I wish it was cheaper? Of COURSE! But it wouldn't exist if the CFF hadn't been willing to work within the system. Also, the money that the CFF receives in royalties from Kalydeco is invested back into research in an attempt to avoid conflicts of interest. Personally, I would rather have this happen than have them sell their rights, and just give 100% of the profits to Vertex every month. Vertex's saving grace is the patient assistance program--Vertex GPS, which has been truly phenomenal to work with. They have committed to get every FDA APPROVED patient access to Kalydeco, and we pay a $15 co-pay each month--nothing more. The issue then turns to patients who want access and might actually benefit, but who aren't yet listed on the FDA approved label. They are left out. I can't tell you what a knot I get in my stomach thinking about all the ways pitfalls we might encounter as we lead the way toward personalized (expensive) genetic medicine. Thanks for reading the blog and commenting!

  2. @political Jules

    Patients don't tend to pay (at least not directly) for their drugs. Their insurers do or, in countries with socialized medicine, their taxes do. The CFF benefit from drug sales with royalties, which they do not spend on yachts... they put it straight back into CF drug development programmes, investing in multiple companies beside Vertex. I don't see the conflict of interest here. In simple terms:
    1. CFF part-funds drug development (or it doesn't happen at all). CF patients win when drugs result.
    2. If drugs are high-priced, the CFF gets big royalties... which they put into *more* drug research for CF. CF patients win, again.

  3. Thanks for such a positive article Rebecca. In a sea of negativity it was refreshing.. At a time I should be celebrating this victory ,I feel like the air has been let out of my balloon. I too worry about the pricing, but agree if large amounts of money are not pumped back into research we will reach a halt to the exciting things on the drawing board. One last word, as a nurse of 38 years, this is history people! I have seen medicine move quickly but this is Penicillin exciting, something that has never been done before.. a miracle if you will. As with the discovery of penicillin, lives will be saved. And as with penicillin, some will tolerate and benefit from the drug, while others will suffer severe side effects and will not be able to take it. Science will move on to finding alternative better drugs.. I consider my life blessed that my granddaughter was born at a time when we are actually seeing real hope! Thank you for all the time and work you do to bring us the facts and thank you for being our cheerleader during this exciting time.. you could have walked away from all this when your son received his drug. You have touched my heart that you have been so happy about this victory. Thank you!
    Beverly Tayler

    1. Thank you for your kind words and perspective Beverly. I will never walk away from my family...and that is what the CF community is to me!

  4. Thanks for the great blog, again.
    As you noted, VX-809 degrades the action of VX-770. In fact, in-vitro experiments, VX-809 corrects up to 50% of mutant F508del. However, these in-vivo results tell us that only around 5-20% is corrected and potentiated. What will be interesting after approval is whether patients combine the genistein/curcumin potentiator with vx809 and ivacaftor and see much larger improvements. Genistein/curcumin have shown similar potentiating effects in patients with gating mutations (one sweat chloride test drop of 59 mmol/L!) and some unpublished work on organelles showed that its affects are additive to ivacaftor. So, if one limiting factor is the potentiation of corrected F508del, then genistein/curcumin treatment could lead to potentially kalydeco-like improvements in some of the F508del community. Read more on curcumin/genistein at www.potentiate.info.