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Vertex Pharmaceuticals Incorporated Message Board

thirdmeinvestor 46 posts  |  Last Activity: Jul 27, 2014 9:36 PM Member since: Feb 25, 2004
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  • thirdmeinvestor thirdmeinvestor May 1, 2014 2:26 PM Flag

    You don't need six lawers for 150 patients! The job ad has to involve Lumacaftor marketing.

  • Reply to

    I don't get why it is up ah

    by itwillgoup May 1, 2014 6:59 PM
    thirdmeinvestor thirdmeinvestor May 1, 2014 10:30 PM Flag

    When VX-661 and Kalydeco were dosed together, the lung function for 551/508 CFers increased by 4.6% on top of the benefit Kalydeco alone can already deliver. This is another indication that VX-661 can act on 508 allele and make it work. This is also another indication that VX-809 which is similar to VX-661 in action mechanism repairs 508 CFTR and send it to the cell membrane.

  • thirdmeinvestor by thirdmeinvestor May 2, 2014 11:05 AM Flag

    Below is from just one of the firms, Needham.

    Needham notes Vertex reported 1Q14 financial results yesterday and announced positive top-line results from a Phase 2 trial testing VX-661 w/Kalydeco in CF patients w/F508del/G551D mutations. The company reported $99.5M in WW Kalydeco sales, slightly below our $102.5M and consensus $107M estimates. Dosing has been completed in the Phase 3 ivacaftor/lumacaftor trials (TRAFFIC/TRANSPORT).
    They believe top-line results are likely to be available ~Jun 2014. They
    expect a favorable outcome; $95 tgt.

  • thirdmeinvestor by thirdmeinvestor May 3, 2014 1:37 PM Flag

    Projection of outcome of Phase III from Phase II data for Lumacaftor + Ivacaftor Trial

    The VRTX share price has been volatile for a long time. This is caused in large part by different understandings of the Phase II data released two years ago. Optimists see 6% absolute improvement of FEV1 and some pessimists might see only noise.

    Some analysts have been saying that the trial results from Traffic and Transport would be all-or-none event for Vertex. I disagree with such assessment. Market reaction to the outcome release would critically depends on the exact value of %FEV1 improvement and other indicators. The market reaction to 5 - 6% improvement will be positive. If the change is much less than 2.5%, the reaction will not be positive. There are other possibilities between those two. So, it is hardly a [binary] event.

    Let us review the past results for the long term shareholders and newcomers. Controversy surrounds the results. It is almost like the Ph II trial of Sarepta’s Eteplirsen. The improvement appears to be small, and noisy. But, the number of participants in Lumacaftor trial is little larger and the signals from the highest two dose regimens are unmistakably positive. However, the decrease of FEV1 in the 4 wk monotherapy phase of the trial adds to the controversy. I want to focus on this, critically examine the Ph II results, and project the Ph III outcome along with market reactions to possible scenarios.

    My theory about the FEV1 decrease in the Lum monotherapy phase is the following. Lum alone can repair some of misfolded CFTR proteins and send them up to the membranes, but it takes Iva to fully open up the Cl ion gates. A number of the ion gates are open and hydration of the airways could take place in this phase, but not enough to expel the mucous out of the lung. Swelling of the previously dry wall and cloggy airway makes breathing even more difficult. Because of this, dose-dependent decrease was observed for the FEV1 in the 4 wk phase.
    [cont]

  • Reply to

    Binary or Quaternary

    by thirdmeinvestor May 3, 2014 1:37 PM
    thirdmeinvestor thirdmeinvestor May 3, 2014 1:46 PM Flag

    [cont’ from above]
    If the theory on the initial decrease of FEV1 is correct, the true increase of FEV1 is not the amount of recovery from the valley bottom read at Day 28, but the net increase from Day 1. Both time course data sets for 200 mg and 400 mg Lum Qd are noisy and do not show clear trends. However, clearer trends can be found in the data coming from 20 people who received 600 mg of Lum daily and 11 people (cohort 3) who received 400 mg twice daily. The absolute FEV1 change for 600 mg at Day 28 scored an average of -2.7% but scored +3.4% at Day 56. The absolute FEV1 change for the group taking 400 mg twice daily scored an average of -4.4% at Day 28 and scored +2.0% at Day 56. The increases from Day 28 to Day 56 are 6.1% for the 600 mg group, and 6.4 % for the 400 mg Q12h group. These changes include the recovery from 4 wk adverse effects, and the amounts should be subtracted from them. What is also clear is that the time course of both data indicate the absolute FEV1 changes are in upward trends. There are only 31 Lum+Iva dosed 508 homozygotes in the two arms, but they together provide significant data. I would think that when measured from Day 1, FEV1 changes from both dosing regimens can reach the range of 4 - 6% when 24 wk dosing is completed.

    The following is entirely speculative projections, so read them for entertainment purpose only. If the TRAFFIC and TRANSPORT, Phase III trials, readout gives an average of 5 - 6% in the absolute FEV1 change, roughly 8 - 10% in the relative change, with high CFQ-R scores and low pulmonary exacerbation and with a low dropout rate, the market will go berserk. The value of such drug combo belongs to the breakthrough status, and we may see 200 for the share price in early days from announcement. Based on the just announced VX-661 + Ivacaftor trial results this scenario is possible. If the readout is in the range of 4 - 5% (= 7 - 8% relative) and the CFQ-R score is high, market reaction will be still positive. [cont]

  • Reply to

    Binary or Quaternary

    by thirdmeinvestor May 3, 2014 1:37 PM
    thirdmeinvestor thirdmeinvestor May 3, 2014 1:48 PM Flag

    [cont']

    We may see 120 for the share price. If the FEV1 change lies in the range of 2.5 - 4% (4 - 7% relative) but CFQ-R and weight gains are positive, the share price would not rise much, but will reach the 90 area because there is a very good chance that the FDA will grant approval. If the FEV1 change is less than 2.5% and the CFQ-R score and weight gains are mediocre, then the sp might drop initially, but will slowly recover because Phase III trials for VX-661+Iva combo will start soon. CFO said once that VX-661 is 18 months behind Lum. But this last scenario is unlikely based on the Phase II results outlined above and the just-announced 508/551 heterozygote trial.

  • 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.

  • 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.

  • 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%.

  • 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.

  • 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 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 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?

  • 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.

  • 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.

  • 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.]

  • 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.

  • 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 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.

  • 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.
    [cont']

VRTX
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