Ef
This presentation is the property of its rightful owner.
Sponsored Links
1 / 18

Disclosure Information PowerPoint PPT Presentation


  • 78 Views
  • Uploaded on
  • Presentation posted in: General

Ef ficacy and Safety of TMC435 in Combination With Peginterferon a -2a and Ribavirin in Treatment-naïve Genotype-1 HCV Patients: 24-Week Interim Results from the PILLAR Study.

Download Presentation

Disclosure Information

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Disclosure information

Efficacy and Safety of TMC435 in Combination With Peginterferon a-2a and Ribavirin in Treatment-naïve Genotype-1 HCV Patients:

24-Week Interim Results from the PILLAR Study

M.W. Fried,1 M. Buti,2 G.J. Dore,3 P. Ferenci,4I. Jacobson,5 P. Marcellin,6S. Zeuzem,7O. Lenz,8 M. Peeters,8 V. Sekar,9G. De Smedt8

1University of North Carolina at Chapel Hill, North Carolina, USA;2Hospital Vall d'Hebron and Ciberehd, Barcelona, Spain; 3St Vincent's Hospital, Sydney, Australia and National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; 4Allgemeines Krankenhaus der Stadt Wien, Wien, Austria ; 5Weill Cornell Medical College, New York, USA; 6Hopital Beaujon, Clichy, Paris, France; 7Klinikum der Johann-Wolfgang-Goethe-Universität - Med. Klinik I, Frankfurt, Germany; 8Tibotec, Beerse, Belgium; 9Tibotec Inc., Titusville, New Jersey, USA


Disclosure information

Disclosure Information

  • Michael Fried Grants/Research Support, Consultant (Roche, Merck, Human Genome Sciences, Vertex, Tibotec, Bristol Myers Squibb, Anadys, Conatus, Schering, Pharmasset, Glaxo, Novartis), Stock/Shareholder (Pharmasset)

  • Maria ButiAdvisory Board and Speaker (MSD, Gilead, BMS)

  • Greg Dore Advisory Committee, Grant/Research Support, Teaching and Speaking, Travel Scholarship (Roche, Merck, Bristol-Myer Squibb, Gilead)

  • Peter Ferenci Advisory Committee and Review Panels, Unrestricted Grant/Research Support, Teaching and Speaking, Consulting, Patent Held (Roche, Vertex/Tibotec, Madaus-Rottapharm, Boehringer Ingelheim, MSD/previously SPI)

  • Ira JacobsonGrant/Research Support, Member of Speaker’s Bureau, Consultant/Advisor (Schering/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome Sciences, Bristol Myers Squibb, Pfizer, Zymogenetics, Abbott, sanofi-aventis)

  • Patrick Marcellin Grant, Investigator, Speaker, and Expert (Roche, Schering Plough, Gilead, BMS, Vertex, Novartis, Pharmasset, Tibotec, MSD, Boehringer Ingelheim, Biolex, Intermune, Zymogenetics)

  • Stefan Zeuzem Consultancy, Member of Speaker’s Bureau (Abbott, BMS, Gilead, Merck, Pfizer, Roche, Tibotec, Vertex)

  • Oliver Lenz Employed by Tibotec

  • Monika Peeters Employed by Tibotec

  • Vanitha Sekar Employed by Tibotec

  • Goedele De Smedt Employed by Tibotec


Disclosure information

  • PILLAR (Study TMC435-C205): Objectives & Endpoints

  • Objective

    • To assess efficacy and safety of protease inhibitor TMC435 once-daily in combination with PegIFN/RBV* in treatment-naïvepatientsinfectedwith HCV genotype-1

  • Study design

    • Ongoing international, Phase IIb, randomized, double-blind, placebo-controlled clinical trial

  • Primary endpoint

    • Sustained virologic response at Week 72

  • Key secondary endpoints

    • Antiviral activity throughout study

    • Viral breakthrough and relapse rates

    • Safety and tolerability

    • Pharmacokinetics

      Results of a planned Week 24 interim analysis are reported today

*PegIFN/RBV, peginterferon -2a (180 g/wk) + ribavirin (1000–1200 mg/day); HCV, hepatitis C virus


Disclosure information

  • PILLAR: Study Design

Planned interim analysis

All available data included

N=ITT

Pbo & PegIFN/RBV

TMC435 75 mg & PegIFN/RBV

TMC12/PR24 75 mg

N=78

Post-therapy FU

TMC24/PR24 75 mg

N=75

TMC435 75 mg & PegIFN/RBV

Post-therapy FU

Pbo & PegIFN/RBV

TMC435 150 mg & PegIFN/RBV

TMC12/PR24 150 mg

N=77

Post-therapy FU

TMC24/PR24 150 mg

N=79

Post-therapy FU

TMC435 150 mg & PegIFN/RBV

Pbo24/PR48

N=77

Post-therapy FU

PegIFN/RBV

Pbo & PegIFN/RBV

Week

0

12

72

24

48

  • Response-guided treatment duration in TMC435 arms

  • End treatment at Week 24, if

    • HCV RNA <25 IU/mL detectable or undetectable at Week 4, and

    • HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20

  • All other patients continued Peg/RBV for up to 48 weeks

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; FU, follow-up; ITT, intent to treat; Pbo, placebo; RNA, ribonucleic acid; TMC, TMC435


Disclosure information

  • PILLAR: Demographics and Baseline Disease Characteristics

*As determined by NS5B sequence-based assay

† Patients with cirrhosis (F4) were not eligible

‡ Polymorphism on chromosome 19 s12979860, data available for patients who consented only (67.9%)

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; no. of subjects completing therapy at Week 24 was according to response-guided treatment algorithm


Disclosure information

TMC12/PR24 75 mg

TMC24/PR24 75 mg

TMC12/PR24 150 mg

TMC24/PR24 150 mg

Pbo24/PR48

  • PILLAR Week 24 Analysis: Mean Change in Plasma HCV RNA From Baseline

0

-1

-2

-3

Mean (+/- SE) change in plasma HCV RNA (log10 IU/mL) from baseline

-4

-5

-6

-7

0

4

8

12

16

20

24

Week

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error


Disclosure information

  • PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12

Week 12

Week 4

100

***

***

***

***

***

***

***

***

80

60

Proportion of patients (%)

40

20

0

Pbo24/PR48 (n=74)

TMC12/PR24 75 mg (n=77)

TMC24/PR24 75 mg (n=75)

TMC12/PR24 150 mg (n=76)

TMC24/PR24 150 mg (n=75)

Pbo24/PR48 (n=75)

TMC12/PR24 75 mg (n=78)

TMC24/PR24 75 mg (n=73)

TMC12/PR24 150 mg (n=77)

TMC24/PR24 150 mg (n=77)

>25 IU/mL

<25 IU/mL undetectable

<25 IU/mLdetectable

HCVRNA

***TMC435 vs placebo: p≤0.001; TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2


Disclosure information

  • PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Week 24

Week 24

100

80

60

Proportion of patients (%)

40

20

0

TMC12/PR24 75 mg (n=77)

TMC24/PR24 75 mg (n=72)

TMC12/PR24 150 mg (n=69)

TMC24/PR24 150 mg (n=73)

Pbo24/PR48 (n=73)

>25 IU/mL

<25 IU/mL undetectable

<25 IU/mLdetectable

HCVRNA

TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2


Disclosure information

  • PILLAR Week 24 Analysis: Proportion of Patients Achieving Undetectable HCV RNA After Planned End of Treatment

  • Between 79% and 86% of patients in TMC435 arms ended therapy at Week 24 as per protocol-defined response criteria

* Denominator based on number of patients that stopped treatment for any reason by Week 24 and reached specified timepoint

TMC12/PR24, TMC435 for 12 weeks in addition to PegIFN/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to PegIFN/RBV for 24 weeks; SVR, sustained virologic response; †not yet defined in the placebo group in this Week 24 analysis as planned end of treatment has not been reached


Disclosure information

  • PILLAR Week 24 Analysis: Viral Breakthrough

50

40

30

Proportion of patients with viral breakthrough,* cumulative (%)

20

7.8%

6.4%

10

3.9%

2.7%

2.5%

0

TMC24/PR24 75 mg

TMC12/PR24 150 mg

TMC24/PR24 150 mg

Pbo24/PR48

TMC12/PR24 75 mg

Weeks 1-12

Weeks 1-4

Weeks 1-24

*Viral breakthrough: confirmed increase of >1 log from nadir or >100 IU/mL if undetectable; TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks


Disclosure information

  • PILLAR Week 24 Analysis: Mean Change in HCV RNA from Baseline According to IL28B Genotype*

Placebo

0

-2

CC

CT

TT

-4

-6

Mean (+/- SE) change in plasma HCV RNA (log10 IU/mL) from baseline

0

4

8

12

16

20

24

Week

All TMC435 75 mg

All TMC435 150 mg

0

0

-2

-2

-4

-4

-6

-6

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Week

Week

*Data shown for patients who consented only (67.9%); CC/TT/CT, polymorphism on chromosome 19 s12979860


Disclosure information

  • PILLAR Week 24 Analysis: Adverse Events

*Reported in ≥25% of subjects in the ‘All TMC435’ group (all dose groups combined)

† Rash (any type) combines all reported types of rash

‡ Reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks


Disclosure information

  • PILLAR Week 24 Analysis: Laboratory

  • Parameters, Bilirubin Over Time

  • Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150 mg dose arms

Pbo24/PR48

TMC 75 mg

TMC 150 mg

30

25

Upper limit of normal

20

Mean (+/- SE) values of bilirubin (μmol/L)

15

10

Lower limit of normal

5

0

0

1

2

4

6

8

12

16

20

24

Week

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1


Disclosure information

  • PILLAR Week 24 Analysis: Laboratory

  • Parameters, Bilirubin Over Time

  • Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150 mg dose arms

TMC12/PR24 75 mg

TMC24/PR24 75 mg

TMC12/PR24 150 mg

TMC24/PR24 150 mg

Pbo24/PR48

TMC 75 mg

TMC 150 mg

30

25

Upper limit of normal

20

Mean (+/- SE) values of bilirubin (μmol/L)

15

10

Lower limit of normal

5

0

0

1

2

4

6

8

12

16

20

24

Week

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1


Disclosure information

  • PILLAR Week 24 Analysis: Laboratory Parameters, Bilirubin, ALT, and ALP Over Time (TMC12/PR24 150 mg)

Upper limit of normal

Mean (+/- SE) values of bilirubin (μmol/L)

20

10

90

Mean (+/- SE) values of ALT (IU/mL)

60

Upper limit of normal

30

Upper limit of normal

140

120

100

Mean (+/- SE) values of ALP (IU/mL)

80

60

40

20

0

1

2

4

6

8

12

16

20

24

Week

TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); ALT, alanine aminotransferase; ALP, alkaline phosphatase ; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1


Disclosure information

  • PILLAR Week 24 Analysis: Efficacy Summary

  • TMC435 administered once-dailywith PegIFN/RBV over 12 or 24 weeks demonstrated potent antiviral activity

    • At Weeks 4 and 12, HCV RNA was <25 IU/mL (undetectable) for the majority of patients in TMC435 groups

    • The majority of patients in TMC435 groups met the criteria to stop treatment at Week 24

  • In patients who completed therapy at or before Week 24, response rates remained high 12 weeks after planned end of therapy

    • Addition of TMC435 to PegIFN/RBV increased response rates in all IL28B genotypes


Disclosure information

  • PILLAR Week 24 Analysis: Safety Summary

  • No clinically relevant difference in safety and tolerability between TMC435 and placebo groups

  • Frequency of rash, gastrointestinal events, and anemia were similar to placebo group

  • Mild and reversible increases in bilirubin concentration observed with 150 mg dose

  • ALT concentration decreased in all treatment groups

  • Discontinuation in TMC435 groups was low and similar to placebo group

  • Planning of Phase III studies of TMC435 is underway


Disclosure information

  • Acknowledgements

Gregory Fanning, Richard Hoetelmans, Ronald Kalmeijer,Eric Lefebvre, Karen Manson, Gaston Picchio, Setareh Seyedkazemi, and Brian Woodfall (Tibotec) have also contributed to development of the presentation, and editorial assistance was provided by Bethan Lowder at Complete Medical Communications.

  • The patients and their families

  • The PILLAR investigators and their study staff

  • New Zealand

  • Ed Gane, Auckland

  • Catherine Stedman, Christchurch

  • Graeme Dickson, Hamilton

  • Norway

  • Trond Bruun, Bergen

  • Bent von der Lippe, Kirkeveien

  • Zbigniev Konopski, Trondheimsveien

  • Kjell Block Hellum, Sykehusveien

  • Jon Florholmen, Tromso

  • Poland

  • Robert Flisiak, Bialystok

  • Andrzej Horban, Warszawa

  • Waldemar Halota, Bydgoszcz

  • Wieslaw Kryczka, Kielce

  • Maciej Jablkowski, Lodz

  • Ewa Janczewska-Kazek, Czeladz

  • Russia

  • Alexey A. Yakovlev, Saint-Petersburg

  • Vladimir V. Rafalskiy, Smolensk

  • Evgeny E. Voronin, Saint-Petersburg

  • N Zakharova, Saint-Petersburg

  • Igor G. Nikitin, Moscow

  • Pavel O. Bogomolov, Moscow

  • Vladimir T. Ivashkin, Moscow

  • Vyacheslav G. Morozov, Samara

  • Olga V. Korochkina, Nizhny

  • Novgorod

  • Spain

  • Maria Buti, Barcelona

  • Moises Diago, Valencia

  • Ricardo Moreno-Otero, Madrid

  • Manuel Romero, Sevilla

  • Jose Luis Calleja, Madrid

  • Germany

  • Keikawus Arasteh, Berlin

  • Thomas Berg. Berlin

  • Peter Buggisch, Hamburg

  • Hartwig Klinker, Würzburg

  • Andreas Trein, Stuttgart

  • Tobias Goeser, Köln

  • Stefan Mauss, Düsseldorf

  • Dr. Jens Rasenack, Freiburg

  • Stefan Zeuzem, Frankfurt

  • Hans-Jürgen Stellbrink, Hamburg

  • USA

  • Daniel Pambianco, Charlottesville

  • Edwin DeJesus, Orlando

  • Kyle Etzkron, Jacksonville

  • Michael Fried, Chapel Hill

  • Andrei Gasic, Longview

  • Nigel Girgrah, New Orleans

  • Ira M. Jacobson, New York

  • Donald M. Jensen, Chicago

  • Mark E. Jonas, Cincinnati

  • Fred Poordad, Los Angeles

  • Coleman Smith, Plymouth

  • Jawahar Taunk, Palm Harbor

  • Lawrence Wruble, Germantown

  • Ziad Younes, Germantown

  • Canada

  • Pierre Cote, Montreal

  • Gideon Hirschfield, Toronto

  • Maged Peter Ghali, Montreal

  • Sam Lee, Calgary

  • Morris Sherman, Toronto

  • Australia

  • Greg Dore, Darlinghurst

  • Paul Desmond, Fitzroy

  • Stuart Roberts, Melbourne

  • Jacob George, Westmead

  • Graeme Macdonald, Woolloongabba

  • Alice Lee, Concord

  • Austria

  • Peter Ferenci, Wien

  • Hermann Laferl, Wien

  • Michael Gschwantler, Wien

  • Belgium

  • F. Nevens, Leuven

  • Y. Horsmans, Bruxelles

  • C. Moreno, Bruxelles

  • H. Van Vlierberghe, Ghent

  • P. Michielsen, Edegem

  • H. Orlent, Brugge

  • H. Reynaert, Bruxelles

  • J. Decaestecker, Roeselare

  • Denmark

  • Jan Gerstoft, Copenhagen

  • Alex Lund Laursen, Aarhus

  • Lars Mathiesen, Hvidovre

  • Axel Møller, Kolding

  • Peer Brehm Christensen, Odense

  • France

  • Yves Benhamou, Paris

  • Christian Trepo, Lyon

  • Jean Pierre Bronowicki, Vandoeuvre Les Nancy

  • Christophe Hezode, Creteil

  • Patrick Marcellin , Clichy

  • Jean-didier Grange, Paris

  • Jean Pierre Zarski, Grenoble

  • Albert Tran, Nice


  • Login