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Vertex Pharmaceuticals Incorporated Message Board

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  • verityvoila verityvoila May 9, 2012 10:01 PM Flag

    Hypothesis I: f508d defects vary & this explains great combo results

    Reasons justifying continued:
    Study Results:
    1. The interim results from the Phase 2b 809/770 combo study support this hypothesis because the stat. sign. SC improvement occurred only in the 809 phase and yet the FEV improved significantly, but only for about half the population. To me, this indicates that segment of the f508d population does not have a problem with sequencing and/or gating, or that the problem is minimal and can be overcome.
    2. For a small subset of the double-deltas, there was an improvement when dosed solely on 770 (Kalydeco), indicating that subset in fact has protein on the cell surface. The improvement was not maintained, though, so I posit that the folding/sequencing defect prevents the protein from getting to the cell surface quick enough for potentiation. The initial improvement occurred because there was some protein there waiting for potentiation. Logically, this would seem to also explain why a longer (and possibly higher) dosing of 809 would result in such drastic improvement in Phase 2b–because now there is much more protein on the cell surface waiting to be potentiated, or for some, not needing to be potentiated.
    Ancedotally:
    1. Some Cfers on the 661 and 809 combo studies have indicated feeling significantly better on the 809/661 portion of the study, indicating they might not have an issue with gating.
    Implications:
    1. The potential for success in the 661/809 combo study is much higher than originally thought because of the large portion of the f508d population retaining some gating function (i.e. having unlimited credit!)
    2. While it is possible that some double deltas could benefit from 809 mono-therapy, because it is impossible to know which individuals have solely a folding defect (and/or a sequencing defect), combined therapy is the best approach. Also, even those individuals who benefit greatly from 809 or another corrector because they have gating function, the gating function might not be perfect, so a combo make sense.
    3. There will be a need for the third med (what I call a sequencer) to address the portion of f508d Cfers whose protein also cannot fold in the proper sequence. This sequencer will benefit some double-deltas more than others (i.e., the 50%ish who did not have substantial FEV reduction will need this added med the most, while those with >10 will be least impacted, although they might not have perfect sequencing function.

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    • Wow. That was a pretty technical post. I liked the club analogy.

      Wasn't the purpose of the Phase II trails to measure a great improvement in SC? This was not accomplished. Vertex does not want the focus on the primary goal of the research which is where it was focused as a large improvement in SC would be in the right direction.

      Highlighting the FEV ( I can breathe better ) improvement of ~ 5% seems weak to me. I would argue that a good steriod-based inhaler would increase the FEV more, but the test was not measured against all known forms of treatment ( antibiotics, inhalers, etc. ), it was measured against a placebo ( a control created to do absolutely nothing on purpose).

      I am as hopeful as the next person in medical advancements and cures, but these tests are just not there yet. I think you can complicate the argument with deep-lingo science terms that only another geneticist would appreciate, but in the end, you need to create something that is orders of magnitude better than current treatment options. Vertex has not gotten there yet, maybe they will someday.

      I can't buy into the idea that just because we learned how to create a telescope today, tomorrow we will all be traveling the galaxy. I can imagine it, I can hope for it, I can dream about it. But is a telescope really going to help me create a interstellar spaceship or will it just motivate me to want one.

      • 2 Replies to sbob888
      • I too will give you the benefit of the doubt that you really don't understand what you are saying as oppose to trying to mislead others. Dr. White has explained SC and FEV. Let me just add re the "value" of the drug other currently available drugs. Our 2 year old spend 40 minutes a day doing hyper-sal for that 5-7% improvement. And another 10 minutes daily doing Pulmyzyme for another 5-7% improvement. And we spend another 15 minutes cleaning and sterlizing multiple nebulizers. These drugs work to fix the underlying defect AND are 3 pills which take what 1 minute total to take? The value to Cfers is truly amazing.

        Re my scientific lingo. As I’ve often said here, I haven’t had a science class since I was 15 or 16. Anyone who has followed Vertex and the science of CF understands the basics. I wasn't complicating anything, but merely putting it all together and seeking educated insights, which I’ve been blessed to get by several others on this Board who truly are interested in understanding the drugs and how they work, etc., and who have taught me immeasurably in this area.

      • I am not sure if you are sincere with the questions you raise or if you are just trying to confuse less sophisticated investors. I will give you the benefit of the doubt and I will assume you are sincere. First, SC is just a marker and it does not necessarily correlate perfectly with improvements in the condition of CF patients. The main purpose of treatments for CF is to make the patient breathe better, whether or not their sweat is less salty. And that is exactly what the new study shows: significant FEV1 improvements which is what really matters. Why are these new CF drugs so much better than what is already on the market? Because Vertex's drugs treat the underlying cause of the disease, not the manifestations. Other treatments are aimed at dealing with the thick mucus after it is already in the lungs while Vertex's drugs should prevent the thick mucus from forming in the first place. These are revolutionary new drugs for the treatment of CF!

 
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