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Vertex Pharmaceuticals Incorporated Message Board

  • thirdmeinvestor thirdmeinvestor Oct 24, 2009 1:30 PM Flag

    BI 201335 data reexamined

    I have done more research on BI’s drug 201335. I’d like to share the result with this board. Among the four clinical trials listed at Clinicaltrials.gov site, BI 201335 has been tested only in a single large (429 patients) trial (Ph 2) and the remaining three trials have the enrollment of only 140, 22, and 77 patients. The only trial that is explicitly stated to deliver BI as softgel capsule is a dose-escalating trial, has the enrollment of 22, and has begun in Japan last July(obviously, this trial was to find the optimal oral dose). I think that other trials use an injectable form of the drug. In all trials the drug is dosed once daily, which is an advantage over TVR dosing. This convenience is a luxury, however, for an oral dosing because Ribavirin has to be dosed orally twice daily anyway. This Ph 2 trial has dosed both BI and IFN/RBV for 24 wks, unlike TVR which is dosed for 8 or 12 wks in most Ph ii and iii.
    The interim data already given in the AASLD abstract tell us quite a lot about the to-be-reported SVR and safety (because the relapse rate is of the order of 5-10% with protease inhibitor, and a longer dosing of p.i. has not been shown to increase the SVR very much).
    I highlighted the interesting aspects of The BI 201335 data for its efficacy and treatment-induced hyperbilirubinemia by tabulating the data directly out of the abstract.

    _________ UND @ wk 4 __UND @ wk 12__Bilirubin
    --------------------------------------------------- increase [mg/dL]
    QD 240mg_____77.1 %____89.6 %_____1.0 (0.1-8.0)
    QD/LI 240mg___62.1 %____80.0 %____ 1.5 (0.1-9.1)
    QD/LI 120mg___69.6 %____84.1 %_____0.6 (0.2-3.9)
    Placebo______ 4.2 %______42.3 %_____ NA

    UND above means the % of patients who were tested to be virus ‘undetectable’ at the end of dosing the drug for 4 or 12 wks. QD appearing above stands for a single dosing daily, and LI stands for a 3 day “lead-in” of IFN/RBV predosing. The number of patients in each arm from the top row to the bottom above is 144, 145, 69, and 71.
    One could be skeptical about the validity of the entire data on the basis of a significant drop in the UND % of LI 240 mg data compared with no-LI data. [continues on the next]

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    • third,

      good info, thanks.

      Your observation of QD/LI vs. QD alone to question the validity of the whole thing is an excellent point.

      • 1 Reply to gladpick
      • I have more.

        Another surprising aspect is that the data for the arm LI 240mg are lower than those of the arm LI 120mg. One cannot help but wonder why the BI dose is halved and achieved better results ( 69.6% vs. 62.1% at wk 4, and 84.1% vs. 80% at wk 12). How could a much lower BI dose produce a better result at both week 4 and 12? The answer is most likely that the lower dose arm scored a much lower bilirubin level range (see the data Table), and the discontinuation rate was much lower.
        Similar argument can be made to the earlier problem.
        The numbers of patients in the first two arms are 144 and 145 which are not a small number. The UND patients for the no-LI and LI arms are 77.1% x 144 = 111 and 62.1% x 145 = 90, respectively (15% drop) at 4 wk time point, and 128 and 116, respectively at 12 wk (10% drop). The probability for these differences btw the two arms to occur by chance alone is very low; it is not random fluctuations but a real effect. Could the 3 day LI dose cause this? Could the LI dosing for only 3 days cause such unbearable side effects that many patients terminated the treatment on their own? A possible clue for answering these questions is provided by the abstract table. All columns had an asterisk and the footnote to the table says:
        <*Some data not available for all patients at week 4 and 12; ITT:missing=failure>
        The trial in question is stated as being based on intent-to-treat (ITT) and had to count any dropouts as failures.
        It is clear that some data were missing, and the missing data originated most likely from some lost patients or missed tests. Nowhere the abstract states the size of missing patients. It also states that < …18 (5.0%) pts discontinued BI 201335 due to (S)AE of which 1.7% were due to rash. Jaundice was seen in 15.9% of pts in the BI 201335 groups versus 1.4% receiving placebo>. (S)AE stands for severe adverse events.
        The 18 (5%) patients out of all BI arms cannot explain the 15% drop seen the first LI arm with respect to no-LI arm. I hypothesize at this point that the difference of 10% are missing patients who did not even report to the trial center to have their viral and bilirubin level checked. If there were patients who terminated the treatment because of excess yellowing of skin, the trial would not know what their real bilirubin levels were.
        [cont']

 
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