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Vertex Pharmaceuticals Incorporated Message Board

  • tek_jansen500 tek_jansen500 Feb 23, 2012 1:35 PM Flag

    Thoughts on today's results

    Results were maybe a little weaker than I might have hoped for (83% of naive patients undetectable at end of treatment).

    But what looks interesting to me is this: no moderate or severe rash with the all oral regimen. Definitely encouraging for a better safety profile. Then they say that the phase 2b will *not* be response-guided. What this suggests to me (and maybe I'm over-interpreting) is that they're going to run the 2b trial at 12 & 18 (& 24, 30?) weeks. They can do this since they're not having to deal with Interferon/Incivek rash, and they can just see how many weeks it takes to maximize cure rate.

    I'm curious to hear what others think.

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    • 6 out of 8 relapsed but 2 out of 8 did not achieved SVR. Giving them time, the last 2 would relapse too.

    • Another way to look at the data is to consider the SVR in null responders for Incivek/Peg/ribavirin from the phase III REALIZE trial. 31% of nulls achieved SVR in this trial. Now, compare this result to the GS-7977/ribavirin trial in nulls where the SVR 4 was 25% (6 out of 8 patients relapsed). I do not know if one can now extrapolate these results to treatment naive HCV patients but, if this is the case, the SVR for GS-7977/ribavirin in these patients should be less than 79%. Why? Because the SVR for treatment naive patients with Incivek/Peg/ribavirin is 79%. Of course, this assumes the success rate for naives vs. nulls should be about the same ratio for the two different drug regimens. I guess we will have to wait for the results of the trials for this question to be answered. That's why they they do trials.

    • PSI-7997 has a 91% SVR12 for GT1 naive with PegInt & Rib:

      If 20% of pool is null then:

      91% * 80%(naive) + 25% * 20%(null) = 78% SVR.

      This is GS-7977 with PegInt & Rib

      Remove PegInt and of course SVR goes below 78%.

    • johnf50@rocketmail.com johnf50 Feb 24, 2012 5:11 PM Flag

      Research the interferon, peginterferon a, peginterferon b, and ribivirin studies pre Merck / Vertex.

      Understand that data... then understand how PSI-7997 works.

      The conclusion is logical IMHO.

      [And the thus far released SVR4 data for GS-7997 / Rib in GT1 null responders is equal in potency to the SVR48 PegInt & Rib null responders.]

      This is contrasting GS-7997 / Rib nulls at 4 weeks to PegInt/Rib Nulls at 48 weeks.

      The extrapolation of 15% is based on PegInt / Rib studies alone and independant of other drugs as simply the delta of effectiveness of what Rib and PegInt achieve independently.

      [What makes you think GSI7977+Rib won't achieve nearly as good an efficacy as 7977+Rib+Peg on treatment-naive patients?]

      (Interferon or PegInt(a) or PegInt(b)) add what % of effectiveness to the Interferon / Rib mix?

      What was the SVR rate of interferon before Rib?

      What was the SVR after Rib?

      What was the SVR after peg?

      After peg(b)?

      What does interferon do?

      What does Rib do?

      What does PSI-7997 do?

      You understand that, and I think you can answer your own question that GS7997 + Rib cannot be greater than GS7997 + Rib + PegInt because theoretically:

      GT1 naive: GS7997 (36%) + Rib (40%) + PegInt (15%) = 91%
      GT1 naive: GS7997 (36%) + Rib (40%) = 76%

      Again... the conclusion is logical.

      And when you figure that there is a 10% range of effectiveness in Rib / PegInt with GT1 naives... where is that 10% range from? Rib? or Interferon? And then add another 15% for the potential for the naives to be nulls...and you can get as low as 50% SVR12 for GT1 naives with GS-7997 / Rib.

    • >PSI-7997 has a 91% SVR12 for GT1 naive with PegInt & Rib:
      >And the thus far released SVR4 data for GS-7997 / Rib in GT1 null responders is equal in potency to the SVR48 PegInt & Rib null responders.

      So the billion dollar question is, "When you deduct PegInt from the mix... does that SVR% go up or down?"

      Clearly it goes down. And it goes down at least 15% from the 91% SVR12 data with PegInt / Rib.

      Why are you extrapolating the data in null responders to claim that GS7977+Rib will show a 15% drop in efficacy in treatment-naive patients?

      That doesn't seem to add up. Do you have any links to backup this claim?

      What makes you think GSI7977+Rib won't achieve nearly as good an efficacy as 7977+Rib+Peg on treatment-naive patients?

    • johnf50@rocketmail.com johnf50 Feb 24, 2012 3:51 PM Flag

      PegInt & Rib has an SVR48 of 33% to 42% in GT1 and 80% in GT2-4.

      http://www.lancet.com/journals/lancet/article/PIIS0140-6736(01)06102-5/abstract

      PegInt & Rib has an SVR48 of 14% in null responders.

      http://gastrojournal.org/article/S0016-5085(09)00102-4/abstract

      PSI-7997 has a 91% SVR12 for GT1 naive with PegInt & Rib:

      http://investor.pharmasset.com/releasedetail.cfm?ReleaseID=603298

      And the thus far released SVR4 data for GS-7997 / Rib in GT1 null responders is equal in potency to the SVR48 PegInt & Rib null responders.

      So the billion dollar question is, "When you deduct PegInt from the mix... does that SVR% go up or down?"

      Clearly it goes down. And it goes down at least 15% from the 91% SVR12 data with PegInt / Rib.

      GS-7997 / Rib will not be shown as effective of an all oral treatment as VX-222/Rib/Telaprevir in GT1 naives.

      GS-7997 / Rib will likely show an SVR12 of 76% or less.

      Pharmasset did a very good job selling the effacy of their drug on GT2 - 3 with the implication that it was as effective on GT1. Gilead has been following suit... but the ride is about to be over when the rollercoaster hits an 11 billion dollar hole.

    • Comparing GS-7977/ribavirin 4 week RVR (100 percent) vs. Incivek/VX-222/ribavirin 12 week end of treatment response of 83 percent in treatment naive HCV is problematic. Obviously, the most important numbers are the SVR for extended periods.

    • >Any large pool of treatment-naive patients contains a substantial portion of potential old-SOC null responders.
      There is a difference between potential null-responders and null responders who have taken interferon treatment. In the post-treatment scenario, the virus has mutated and shown resistance to a treatment regimen. So achieving cure might be more difficult.


      >There will be relapsers in the 7977 + riba trial if they select patients randomly.
      While GILD issued PR about relapsers in null-responders, there was no PR regarding any relapse in the treatment-naive arm. Remember that VRTX has not picked ANY genotype 1a null-responders in this trial.

      I will wait until the final results from GILD are out before putting money on VRTX.

    • The rates of UND at EOT could have been 96% for Arm E and 92% for Arm F if adverse events were managed better. The disappointing part of the data is the low rates for satisfying the stopping rule; only 11 out of 46 (24%) achieved the UND at both week 2 AND week 8. No doubt this rule must be too restrictive. Some may achieve the SVR without the UND at both week 2 and 8 without the help from P/R. They may have more data they don't disclose yet. That is why they want to remove this rule for the all oral Phase IIb.

      One possibility is that the response guided therapy may be replaced with a new genetic testing (which gets cheaper and cheaper everyday). I have a paper written by a Japanese group which found a new sequence near IL28B, which is a marker to tell success of Incivek based triple therapy. It is possible that Vertex may have their own genetic marker to tell the success of INC/222/Riba all oral. Patients who have unfavorable indication could receive P/R together with Inc/222 from the beginning.

      You have a right idea in seeing possible lengthening of the treatment duration. Another possibility is to increase the 222 dosing back to 750 mg from 400 mg.

 
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