Deatils of Prove 2 from AASLD

PROVE2 Study Shows High SVR Rates With Combination Treatment With Telaprevir, Peginterferon alfa-2a, and Ribavirin in Treatment-Naive Patients Infected With HCV Genotype 1

Posting Date: November 07, 2007

    * Interim analysis of PROVE2 (study VX05-950-104EU): randomized, placebo-controlled, phase II study

Summary of Key Conclusions

    * Combination therapy for 12 weeks with telaprevir, peginterferon alfa-2a, and ribavirin produced better virologic responses at Weeks 4 and 12 compared with standard peginterferon alfa-2a/ribavirin combination therapy in treatment-naive patients with chronic HCV genotype 1 infection
          o Virologic response rates reduced when ribavirin excluded from combination
    * High sustained virologic response (SVR) rates observed among patients treated with telaprevir/peginterferon alfa-2a/ribavirin combination therapy for 12 weeks
          o Best SVR and relapse rates observed when telaprevir/peginterferon alfa-2a/ribavirin given for 12 weeks and then followed by additional 12 weeks of peginterferon alfa-2a/ribavirin
    * Skin and gastrointestinal events most common adverse events associated with telaprevir, consistent with previous data

Background

    * Telaprevir an investigational oral inhibitor of HCV NS3/4A protease
          o Produced consistent, rapid virologic suppression during initial clinical studies
    * PROVE2 designed to assess efficacy and safety of telaprevir in combination with peginterferon alfa-2a/ribavirin in treatment-naive individuals chronically infected with HCV genotype 1
          o Rapid virologic effects of telaprevir may lead to higher SVR rates and possibly shorter duration of treatment
    * Current study reported results of a planned, interim, on-treatment efficacy, and safety analysis of PROVE2

Schematic of Study Design

Eligibility

    * Inclusion criteria
          o HCV genotype 1
          o Treatment naive
    * Exclusion criteria
          o Cirrhosis (METAVIR F4 or equivalent)

Baseline Characteristics

    * Baseline characteristics well balanced across treatment groups

Characteristic


Control Arm
(n = 82)


24-Week Arm
(n = 81)


12-Week Arm
(n = 82)


No RBV Arm
(n = 78)

Median age, yrs (range)


45
(18-63)


45
(19-65)


44
(21-65)


45
(20-64)

Male, %


56


67


60


55

White, %


93


93


93


99

Median weight, kg (range)


73
(46-101)


72
(45-115)


68
(45-105)


70
(45-108)

HCV subtype, %













    * 1a



44


40


45


51

    * 1b



56


60


54


49

Median HCV RNA, log10 IU/mL (range)


6.4
(4.8-7.4)


6.6
(4.0-7.7)


6.5
(3.4-7.3)


6.4
(3.9-7.3)

METAVIR score F2-F3, %


28


35


35


26
Description of Current Analysis

    * N = 323 treatment-naive, chronic HCV genotype 1–infected individuals from 30 treatment sites in 4 countries (Austria, France, Germany, United Kingdom)
    * Current interim analysis performed at Week 36
          o Peginterferon alfa/ribavirin control arm still ongoing
    * Definitions
          o Undetectable HCV RNA:  1 log10 IU/mL increase in HCV RNA above nadir or > 100 IU/mL increase in patients who achieved undetectable HCV RNA
    * Intent-to-treat analysis

Main Findings

    * Low rates of treatment discontinuation in all arms, although slightly higher rates in arms that received telaprevir
          o Treatment discontinuation primarily driven by adverse events during initial 12 weeks of telaprevir therapy (in 23 of 31 patients)

Patient Disposition, n (%)


Control Arm
(n = 82)


24-Week Arm
(n = 81)


12-Week Arm
(n = 82)


No RBV Arm
(n = 78)

Discontinuation before Week 12


4 (5)


12 (15)


11 (13)


8 (10)

Completion of treatment duration


Ongoing


61 (75)


71 (87)


70 (90)

    * Telaprevir produced high initial virologic response rates that maintained through Week 12
          o Impressive SVR rates observed to date in 24- and 12-week arms

Outcome, %


Control Arm
(n = 82)


24-Week Arm
(n = 81)


12-Week Arm
(n = 82)


No RBV Arm
(n = 78)

Undetectable HCV RNA













    * Week 4



13


69*


80*


51*

    * Week 12



41


73*


79*


62*

SVR†


Ongoing


65


59


29

*P < .001 vs control arm.
†SVR at 12 weeks posttreatment for 24-week arm; SVR at 24 weeks posttreatment for 12-week and no ribavirin arms.

    * Among patients who completed assigned treatment, relapse rates twice as high in 12-week arm compared with 24-week arm (28% vs 14%, respectively)
          o Low relapse rates observed among patients who achieved rapid virologic response

Outcome, n/N (%)


24-Week Arm


12-Week Arm

Virologic relapse


8/57 (14)


18/63 (28)

    * Among individuals who achieved rapid virologic response



5/47 (11)


12/55 (22)

    * Among individuals who did not achieve rapid virologic response



3/10 (30)


6/8 (75)

    * Rates of virologic breakthrough very low among control arm and 12- and 24-week arms
          o Rates of virologic breakthrough
                + Control arm: 1%
                + 12-/24-week arms: 2%
                + No ribavirin arm: 24%
          o High rate of breakthrough in no ribavirin arm emphasizes importance of ribavirin at providing optimal virologic suppression among patients receiving telaprevir and peginterferon alfa-2a
    * Telaprevir generally well tolerated
          o Most common adverse events associated with treatment included asthenia, pruritus, nausea, rash, headache, and flu-like symptoms
                + Asthenia, headache, and flu-like symptoms comparable in telaprevir-treated arms vs peginterferon alfa-2a/ribavirin control arm
    * Select adverse events (eg, skin, gastrointestinal events, and insomnia) occurred more frequently with telaprevir, particularly among patients receiving ribavirin, than in control arm

All Grade Adverse Event, %


Control Arm
(n = 81)


12-/24-Week Arms
(n = 163)


No RBV Arm
(n = 78)

Pruritus


24


56


58

Nausea


32


48


28

Rash, all types


26


47


40

Insomnia


15


26


15

Dyspnea


11


23


9

    * Certain grade 3 events observed only among patients who received telaprevir
          o Depression, dyspnea, nausea, pruritus, and rash

Adverse Event, %


Control Arm
(n = 81)


12-/24-Week Arms
(n = 163)


No RBV Arm
(n = 78)

Depression


--


< 1


3

Dyspnea


--


1


--

Nausea


--


< 1


--

Pruritus


--


1


1

Rash


--


6


4

    * Maculopapular rash resolved following treatment discontinuation
    * Telaprevir had no effect on neutrophil or platelet counts
          o Hemoglobin reductions observed in telaprevir-treated patients in 12-week and 24-week arms, but predominantly only grade 1-2 in severity

Reference

Zeuzem S, Hezode C, Ferenci P, et al. PROVE2: phase II study of VX950 (telaprevir) in combination with peginterferon alfa2a with or without ribavirin in subjects with chronic hepatitis C, first interim analysis. Program and abstracts of the 58th Annual Meeting of the American Association for the Study of Liver Diseases; November 2-6, 2007; Boston, Massachusetts. Abstract 80.

[3txsofar]

Apologies for the prior post.  Here is the link:

http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Boston%202007/Tracks/Investigational%20HCV/Capsules/80.aspx