Replies to post #63342 on Biotech Values

[DewDiligence]

VRTX – The fact that the interim PROVE-3 numbers for patients who had relapses in the first line are immensely better than the numbers for patients who had non-responses or breakthroughs has the effect of fragmenting the second-line setting and making it harder to handicap what the FDA will request from VRTX.

My numbers in #msg-26290780 were based on the presumption that the different subgroups of second-line patients would not see huge differences from one another. If these subgroups do in fact show huge differences from one another in the final PROVE-3 results, as now seems likely, the FDA may be inclined to hold off an NDA review until phase-3 is completed, hoping that the phase-3 data help to sort out the inter-subgroup differences.

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[DewDiligence]

Telaprevir PROVE-3 Results to be Presented at EASL

PROVE-3 was a phase-2b trial of genotype-1 patents in the second-line setting. Patients were randomized 1:1:1 to the following arms:

• "12+12" arm: 12 weeks of Telaprevir+SoC followed by 12 weeks of SoC alone.

• "24+24" arm: 24 weeks of Telaprevir+SoC followed by 24 weeks of SoC alone.

• Control arm: 48 weeks of SoC.

(A fourth trial arm testing Telaprevir + peg-interferon without ribavirin produced poor results and will not be discussed further in this post.)

Patients were stratified among the trial arms according to the treatment outcome in the first-line setting; the subgroups consisted of:

• Relapse: Patients who had undetectable virus at the end of first-line treatment but relapsed after treatment stopped. (This is the subgroup most amenable to second-line treatment.)

• Viral breakthrough: Patients who had undetectable virus at some point during first-line treatment but had detectable virus at the end of first-line treatment. (This is the small subgroup of patients who succumbed to a viral mutation that was resistant to SoC therapy.)

• Non-response: Patients who never achieved undetectable virus during first-line treatment. (This is the subgroup least amenable to second-line treatment.)

Here are the SVR data as reported by VRTX in
http://www.abstractserver.com/easl2009/planner/sp.php?go=abstract&action=abstract_iplanner&absno=2670&

 
                   All      ------By Outcome in First Line------ 
                 Patients    Relapse   Breakthrough Non-response 
 "12+12" arm   51% (n=115)  69% (n=42)   57% (n=7)   39% (n=66) 
 "24+24" arm   52% (n=113)  76% (n=41)   50% (n=8)   38% (n=64) 
 control arm   14% (n=114)  20% (n=42)   40% (n=5)    9% (n=68) 

What can we say about these data? Several things:

1. The overall results are blowout great (but we already suspected they would be from the interim data reported in June 2008: #msg-29896176).

2. There was essentially no difference between the "12+12" arm and the "24+24" arm. (Both arms were superior to the control arm with a p-value
<0.001.)

3. Because the "12+12" arm performed as well as the "24+24" arm, the regimen eventually approved by the FDA is likely to be "12+12" for patients who experience a "durable RVR" (undetectable virus at week 4 and week 12) and "24+24" for patients who do not experience a durable RVR. (This "split" regimen in which treatment duration depends on RVR seems to be where all treatment PI-based protocols are heading in both the first- and second-line settings.)

4. Only one patient out of 60 in the "12+12" arm who achieved an SVR12 at the interim data reported in June 2008 relapsed between EoT+12 and EoT+24. (VRTX did not report SVR12 data for the "24+24" arm, which would be irrelevant anyhow.)

5. Non-responders in the first line were clearly harder to retreat than relapsers, which is exactly what one would expect. There were too few patients with viral breakthrough in the first line to say anything definitive about them. (Intuitively, they ought to be intermediate between non-responders and relapsers in amenability to retreatment).

6. The $64,000 question: Are these results good enough for the FDA to approve Telaprevir in the second-line setting without waiting for data from phase-3? If it were up to me, the answer would be Yes, but I have no idea what the FDA will actually do.