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Vertex Pharmaceuticals Incorporated Message Board

thirdmeinvestor 46 posts  |  Last Activity: 23 hours ago Member since: Feb 25, 2004
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  • thirdmeinvestor thirdmeinvestor Jun 18, 2014 10:47 AM Flag

    Verity, you exactly pointed out the very weak point of Porges' pseudo-science. They believe in molecular stability argument but do not believe in in vitro biology of Van Goor. Biology is a better predictor of clinical outcome than molecular argument is.

  • [[ Underscoring the bullish sentiment in Vertex's favor, Cowen's Eric Schmidt noted his bet that the drug will likely succeed. Schmidt wrote: "The imminent release of results from VX-809's Ph. III trials has the potential to be one of the biggest binary events in biotech during 2014. We think that there is a 60% chance the trials succeed, and a 40% chance they fail (or have mixed results). We expect VRTX's stock to go to $100+ on success, but $40 on failure. We continue to think that VRTX is fairly valued, and remain at Market Perform."]]

    Eric Schmidt is a MIT PhD who studied at the Paul Schimmel's lab.
    Geoffrey Porges holds a Harvard Business School MBA.

  • Reply to

    A post from facebook:

    by gladpick Jun 6, 2014 11:24 AM
    thirdmeinvestor thirdmeinvestor Jun 13, 2014 9:03 PM Flag

    Glad, thank you for posting this. The mother's blog is entirely believable. Presumably, the lung function she was referring to was FEV1, and it changed from the prior 38% to 59% at the first several weeks of open-labeled rollover study, whether or not the daughter had received the real drug or not during the double-blinded trial. This is an absolute change of 21% and a relative change of 21/38 = 55%. Astounding. Some placebo effect might be superposed, but it cannot be all placebo effect because it is too large for placebo effect.

  • thirdmeinvestor thirdmeinvestor May 21, 2014 8:07 PM Flag

    Q, I think that the 400mg bid regimen is superior in efficacy based on pharmacokinetic data. But, the side effects may be greater also.

  • thirdmeinvestor thirdmeinvestor May 21, 2014 8:02 PM Flag

    Verity and Q, you asked good questions. I am expecting (and hoping) an FEV1 improvement of 5-6% for the Ph III trials. The results of Ph II trial for 508 homozygotes on 661/Kalydeco appear to level off after 2 weeks of dosing, but Ph II results of the same groups on 809/Kalydeco appear to continue to rise beyond 4 weeks of combo. And I am also expecting for this long term dosing positive feedback effects coming from clearing of lung airways inflammation due to stronger immunity resulting from metabolic improvements.

    Verity, I think that the 4.6% from the latest trial is on rather high side. If you exclude the placebo effect, the number is likely about 3.5%. Kalydeco alone can improve CFTR from a single 551 allele better than corrector+potentiator combo can a single 508 allele. Kalydeco alone would improve 551 of 551/508 hetero by 10%. So, on the average, the participants improved the lung function by a number like 13.5%, not 4.7ish %, when measured from the base line of taking no drug at all.

  • thirdmeinvestor thirdmeinvestor May 19, 2014 10:46 PM Flag

    [cont' from above]

    Next, in vitro data for F508del/G551D (van Goor et al.) also have shown that VX-809/Kalydeco improves the Cl ion transport beyond that Kalydeco alone could achieve as you would expect from the molecular genetic reasoning. Moreover, there has been a clinical proof: as announced at the earnings conference call, VX-661 had an effect on a single allele of F508del CFTR in the heterozygous CFers. The corrector VX-809 will be active just as much as VX-661.

  • If CFTR modulator or modulators are effective in repairing CFTR from a single allele, then they are effective in repairing the molecules from both alleles of homozygous mutants to raise the chloride transport. This means that the just-announced data on 508/551 heterozygotes supports the success of treatment of homozygotes of the same mutation. I’ll use a jet liner metaphor to explain the above statement.

    A Boeing 737 with a pair of repaired engines can fly better than the same jet with only one repaired engine. If the engine has its full capacity, it does not need the other engine. The plane is designed to fly, land, and take-off with only one normal engine. However, if the repair is suboptimal, two engines help each other to support plane’s normal functions. So, if a jet plane flies on a single engine, it can fly better with twin engines. Similarly, when repaired CFTR proteins from one 508 allele can improve Cl ion transport, then repaired proteins from two alleles can perform even better.

    The above is supported by genetic, in vitro, and clinical evidence. From the molecular genetics point of view, you would expect nothing more or nothing less than the observed effectiveness. Both CFTR genes from the pair chromosomes must have CF mutations to become a CF person (= autosomal recessive). If a single allele is healthy, then the person does not have CF symptoms because the healthy allele produces enough normal CFTR in every cell in the body and supports needed Chloride transport. In heterozygotes of F508del/G551D, G551D is repaired with Kalydeco, but to a subnormal level. So, when F508del is repaired with the combination of VX-661 and Kalydeco, there will be twice as many repaired CFTRs on every cell membranes in the body, and consequently, the effects of CFTRs will be additive. They will improve FEV1 among others.

  • thirdmeinvestor thirdmeinvestor May 12, 2014 3:41 PM Flag

    When treatment of 508/551 heterozygotes is successful, there is a good chance that the treatment of 508 homozygotes will be a success provided a certain condition (this is too long to explain all in detail) is met. The reverse is not true: success of homozygote treatment does not imply success of heterozygote treatment.

  • thirdmeinvestor thirdmeinvestor May 11, 2014 7:57 PM Flag

    There is no question in that they should have had a larger placebo group. Most Kalydeco users were happy with the drug, and perhaps did not respond to the recruitment for this trial. Perhaps CSO did not anticipate the need ahead of time. All Phase II trials in which VX-809 or 661 was used the placebo scored either negative or slightly (about 1% relative FEV1) positive numbers at the end of trials.

  • thirdmeinvestor thirdmeinvestor May 11, 2014 5:10 PM Flag

    If they give out individual data now, then they have nothing to report in the upcoming meeting. Besides, an average of 4 is meaningless particularly when they jump around as placebo effects do. What they want you to know at this time is that the magnitudes of all in the placebo group don't exceed 4.6%. The placebo group was placed to insure that the subjects would not know what they are taking. The placebo effect for this particular trial would not be much different from the placebo effects of all other trials of CF drugs.

    What they don't say but very important for us is that this heterozygous results are indicative of the 508 homozygous trial results.

  • Is the change in FEV1 seen in 661-dosed heterozygotes all a placebo effect? No. CMO answered "it's modest changes". The following is the exchange in Q&A.

    [ Mark J. Schoenebaum - ISI Group Inc., Research Division
    I just wanted to -- on the placebo issue, would you guys be willing to characterize behavior? I know it's only 4, but would you guys be willing to characterize the behavior of the 4 placebo patients? Maybe give us some reassurance that they didn't behave as well as the treated patients or something like that? And then my second question was -- in the data where you removed the drug, were both drugs removed, or was that just 661?
    Jeffrey A. Chodakewitz - Chief Medical Officer and Senior Vice President
    Great. Thanks, Mark. So sure, let me try to give you a little more color. Again, it's 4 patients. I'd say that what we observed in those patients was really that there were modest shifting around. It was variable, as you'd expect, in this disease with 4 patients getting placebo. And it was very typical of what we've seen in general with smaller cohorts of patients receiving placebo. So hopefully, that gives you a little better flavor of that.
    Mark J. Schoenebaum - ISI Group Inc., Research Division
    So modest would not be 4.6% on an absolute basis, I would imagine?
    Jeffrey A. Chodakewitz - Chief Medical Officer and Senior Vice President
    Correct, it's modest changes. So I think that the -- the other piece, in terms of the study design, was really that we started and then stopped the VX-661. KALYDECO, which our patients were receiving in a marketed setting, was continued throughout the study. And in the follow-up period, they just stayed on their KALYDECO.]

  • During the last conf. call Q&A, Dr. Chodakewitz, CMO, said the following (cut from SA transcript).

    [ we've said all along that we want to continue our leadership position in CF, and that's going to come in 2 forms. One is to continue to develop our expanding portfolio of medicines, so not only 809 and 661 but next-gen correctors, which we think are going to be very important in both expanding the region, expanding the benefit. But the other thing is we have a Very Active (my emphasis), as you can imagine, ongoing surveillance program of all of the potential, other assets out there in CF. And we'll continue to watch that and make sure that we're either partnering, acquiring or doing whatever we can to get the best regimens we can in combination with our drugs.]

    I am sure they research the potentials for RNA drugs and gene therapy as well as other forms of treatment.

  • Reply to

    The Antidote: Inside the World of New Pharma

    by papaalien2000 Mar 9, 2014 3:51 PM
    thirdmeinvestor thirdmeinvestor May 7, 2014 2:21 PM Flag

    I bought the book on your recommendation. It is very revealing.

  • thirdmeinvestor thirdmeinvestor May 7, 2014 9:00 AM Flag

    When Gilead bought Pharmasset's drugs, did it think small ? Is that why its market cap is 50% larger than BMY's?

  • thirdmeinvestor thirdmeinvestor May 6, 2014 2:30 PM Flag

    Right, they are interchangeable because we don't know which is better. Eventually one or the other has to be chosen based on the quality of the drugs because it is unlikely that they would be exactly the same in efficacy and safety. VX-809 might be better than 661 in long term safety, but we don't know yet.

  • thirdmeinvestor thirdmeinvestor May 6, 2014 9:24 AM Flag

    If a 2nd gen corrector is successful, the triple can address the need of 90% of all CF case. Even without it, 60% of all CF people will need only the dual combo 661+Kalydeco. Only about 3% will need Kalydeco alone.

  • thirdmeinvestor thirdmeinvestor May 6, 2014 9:23 AM Flag

    If a 2nd gen corrector is successful, the triple can address the need of 90% of all CF case. Even without it, 60% of all CF people will need only the dual combo 661+Kalydeco. Only about 3% will need Kalydeco alone.

  • The management has been stating that a second generation corrector will be selected near the year end. Central to this objective has been to treat heterozygous F508del CFers using a triple combo of Kalydeco, VX-661(or 809) and the second gen corrector. However, if this triple combo is successful, its use will not be limited to heterozygous 508 mutations as outlined below.
    Listed below are all possible use of VX-661 in combination with Kalydeco, but with or without a second generation corrector.
    1) To replace VX-809/Kalydeco after 2 years of use for homozygous 508 CF group. VX-661 has the advantage over 809 in tissue distribution, a favorable drug-drug interaction profile with Kalydeco, hence requires the low dose(150mg) Kalydeco. 2) To provide benefits to CFers who have F508del in one CFTR allele and a gating mutation or residual function mutation on the other CFTR allele. The proteins generated from the first allele are repaired by VX-661 and the proteins generated by the latter allele will be repaired by Kalydeco. According to an abstract for the NACF Conference 2013 held in October, 72.2% of G551D CFers have 508 mutation on the other allele (this came from a different context). So, nearly ¾ of 551 and other groups with non-551 gating mutations and with residual function mutations will enjoy the benefit beyond the benefit Kalydeco alone can provide. The percentage of CFers who would benefit from Kalydeco + VX-661 combo is 10% x 72% = about 7% of all CFers. Clearly it is a luxury to use a second gen corrector for this group. 3) To combine with a 2nd generation corrector to treat group with non-gating-heterozygous F508del mutations. These 2nd generation correctors are like buns in the oven, as the CFO put it in a CC. None of them are fully baked yet, but if they become ready, triple combo will be tested against these heterozygous mutations. 4) To combine with a 2nd generation corrector to treat homozygous F508del CFers. They can increase FEV1 by 10%.

  • Reply to

    Binary or Quaternary

    by thirdmeinvestor May 3, 2014 1:37 PM
    thirdmeinvestor thirdmeinvestor May 4, 2014 11:32 AM Flag

    There is another indication that 4.6% FEV1 enhancement is not boosted by placebo effects. G551D mutation is easier to repair than F508del mutation with VX-661/770. This means that 508/551 heterozygotes should respond better than 508 homozygotes. Actually 4.6% is very close to the 4.8% scored by the 661 100mg arm in the other Phase II trial using VX-661/770. Taking right out of the PR dated April 18 last year, we have:

    .........................Absolute FEV1 change (%)..................Relative FEV1 change (%)
    .................................vs. Placebo...........................................vs. Placebo.....................

    100 mg Qd of 661....... 4.8% ...................................................9.0%..........
    15 508 homozygotes
    150 mg Qd of 661....... 4.5% ...................................................7.5% .........
    16 508 subjects

    The above data say convincingly that efficacy achieved by 661/770 combo so far are all consistent from one another.
    The reason I think that the VX-809/770 can exceed mid-4% area is related to the longer dosing time. Better lung and pancreatic functions improve nutritional and mental well-being which boost immune response which, in turn, further enhance the lung function because infection/inflammation are less a problem. Moreover, in Phase III trials subjects did not have to recover from the side effects of 4 wk monotherapy phase.

  • Reply to

    Binary or Quaternary

    by thirdmeinvestor May 3, 2014 1:37 PM
    thirdmeinvestor thirdmeinvestor May 3, 2014 6:36 PM Flag

    My record shows that Flynn, in 2007-8 at Lazard Capital, called Strong Sell twice with a price target of 15. Then, called a Strong Buy rating of 95 target price several years later. He is not worthy of being an analyst.

    Because CF has the autosomal recessive trait, both of two alleles of CFTR have to have mutated genes. Repair of 551 allele with Kalydeco improved FEV1 by 10%. Repair of both alleles of G551D homozygotes using Kalydeco improved by 16% after one year of treatment (anecdotal but quoted from a NEJM letter). Furthermore, it has been clearly demonstrated in clinical trials that F508del homozygotes are easier to treat than heterozygotes using either 809/770 or 661/770 combination. Molecular genetics also supports the notion that both allele have to contribute to the disease and to treatment.

    As I wrote before, when VX-661(or VX-809 theoretically) and Kalydeco were dosed together, the lung function for 551/508 heterozygotes increased by 4.6% on top of the benefit Kalydeco alone can already deliver. Kalydeco alone can produce proteins from repaired 551 allele, but the other 508 allele is not functional. But VX-661 can act on 508 allele and make it work. So, both alleles are effectively repaired by using 661/770 combo, and the clinical effect is better than 770 alone can achieve. This also suggests that VX-809 which is similar to VX-661 in action mechanism repairs 508 CFTR homozygotes and send the proteins to the cell membrane.

    The reason the management did not have data for placebo is because they are somewhat scattered and the an average is meaningless because it is not statistically significant. Placebo effects are highly variable from an individual to another, and a high statistical significance of the figure 4.6% indicates that placebo effect is not superimposed.

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