TMC435350 in Collaboration with Tibotec

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TMC435350 - in Collaboration with Tibotec
Professor Bertil Samuelsson, VP Discovery and
Research
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HCV PI Competitive Landscape
Ph I
Ph Ib/IIa
Ph IIb
Ph III
Pre-clin
VX-950 JJ/Vertex
TMC435 JJ/ Medivir
MK
Vertex-500
ITMN-191 Roche/ITMN
Protease Inhibitors
Abbott
SCH 503034 SGP
BMS?
BILN
Phenomix
Schering?
MK7009
Combination with PEG-IFN
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Hepatitis C Medivir/JJ Program
NS3/4A Key protease for virus replication

• Process
• Partnership with Tibotec / Johnson Johnson
  since November 2004
• Phase Ia/b completed
• Start of phase IIa November 2007
• Patents
• Extensive and non-limiting IP published July 2005
• Licensing agreement
• Upfront milestones of EUR 68.5m royalties on
  sales
• FTE Funding for 2,5 years
• All development costs covered by JNJ
• Rights to receive pharmaceutical product for
  Nordic countries from JNJ at pre-defined point in
  development
• Nordic rights retained by Medivir

Enzyme inhibiting compound
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TMC435350 - Clinical Trial Status

• Phase Ia completed
• Safety, tolerability and PK of SAD and MAD in
  healthy volunteers
• Phase Ib completed
• Safety, tolerability, viral kinetics and PK in
  HCV patients (G1)
• Phase IIa has started

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Potency in Liver Cells - Replicon Cell system
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TMC435350 The Phase Ia Trial Design
6 3 (active placebo) HVs in each group (SAD
and MAD)
SAD Doses up to 600 mg were well tolerated
without reaching dose-limiting toxicity MAD All
doses well tolerated
Abstract for the American Association for the
Study of Liver Diseases (AASLD) in Boston,
Massachusetts, USA, November 2-6, 2007
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Phase Ia Single Dosing (SAD) - A Once-daily Drug

• Summary Results
• Readily absorbed
• Excellent plasma exposure
• Tmax of 4-6 h
• Plasma elimination half-life of 12 h
• Data support
• once daily dosing

Plasma concentrations of TMC435350 after single
dosing
gt 400-fold the EC50
gt 7-fold the EC50

• TMC435350 has a replicon EC50 value of 8 nM
  (6 ng/mL)
• At all doses (from 50 mg to 600 mg) Ctrough
  for TMC435350 was in large excess of the EC50
  value

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Five Days Multiple Dosing - TMC435350 once-daily
(QD) gives high exposure over 24h
24 h after last dose
5 Days once-daily (qd) repeated dosing
Last dose
Multiple dosing PK excellent exposure of
TMC435350 achieved! 200 mg, once daily, delivers
plasma C24h (Ctrough ) of 1650 ng/mL
which corresponds to gt 250-fold the replicon
EC50 value of TMC435350 (8 nM)
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TMC435350 - Gives high efficacy margin ata low
dose

• Drug plasma Cthrough AND replicon EC50 values

When protein-binding is taken into account, the
efficacy difference between TMC435350 and
telaprevir increases substantially further
TMC435350 Expected to provide good efficacy at a
low dose and with once-daily administration
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TMC435350 Phase Ia Trial Summary

• TMC435350 was found to be safe and well tolerated
  at all doses
• The PK profile supports once-daily dosing
• No food effect
• The plasma levels of TMC435350 24 hours after day
  5 dosing are substantially in excess of the
  replicon EC50 value for both the 100 mg and 200
  mg once-daily (qd) doses
• Only minor (grade 1) adverse events
• Bowel movement
• Flatulence/diarrhea
• Paraesthesia
• Photosensitivity

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TMC435350 Phase Ib Completed

• Evaluation of safety, tolerability, viral
  kinetics (suppression of virus replication) and
  PK in HCV patients following a once-daily
  administration of TMC435350
• Subjects
• patients chronically infected with the
  difficult-to-treat hepatitis C virus (HCV) G1
• Duration of treatment
• 5 days
• Dosing regimen
• 200 mg of TMC435350 once-daily (QD)
• Results
• The viral load reduction met the target set for
  the trial
• Detailed results from the phase Ib trial will be
  presented at the upcoming EASL meeting in Milano
  in April 23-27 2008

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Phase IIa Clinical Trial Design (I)

• Phase IIa Clinical Trial, OPERA-1, started in
  November 2007 and first patient dosing expected
  in December 2007/ January 2008
• Phase IIa clinical trial conducted at several
  centers in Europe including 130 HCV patients
• Four different doses of TMC435350 will be
  evaluated 25 mg, 75 mg, 200 mg and 400 mg given
  once-daily
• 96 treatment-naïve and 24 treatment-experienced
  patients with chronic G1 HCV infection will be
  included
• In addition, 10 HCV infected treatment-experienced
  patients having participated in trial
  TMC435350-TiDP16-C101 will be included in an
  open-label panel

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Phase IIa Clinical Trial Design (N130), OPERA-1,
C201
Panel A
25mg 435 (N9)
435 PEG-IFN RBV
PEG-IFN RBV
Panel A
75mg 435 (N9)
435 PEG-IFN RBV
PEG-IFN RBV
Panel A
PBO (N6)
PBO PEG-IFN RBV
PEG-IFN RBV
48 patients
Panel B
25mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
Panel B
75mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
Panel B
PBO PEG-IFN RBV (N6)
PEG-IFN RBV
200mg 435 (N9)
435 PEG-IFN RBV
PEG-IFN RBV
Panel A
PBO (N3)
PBO PEG-IFN RBV
PEG-IFN RBV
Panel A
24 patients
200mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
Panel B
PBO PEG-IFN RBV (N3)
PEG-IFN RBV
Panel B
Panel A B treatment-naïves
1 wk
3 wks
24 or 48 wks
4 wks
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Phase IIa Clinical Trial Design (N130), OPERA-1,
C201
400mg 435 (N9)
435 PEG-IFN RBV
PEG-IFN RBV
Panel A
PBO (N3)
PBO PEG-IFN RBV
PEG-IFN RBV
Panel A
24 patients
400mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
Panel B
PBO PEG-IFN RBV (N3)
PEG-IFN RBV
Panel B
Panel C
200mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
400mg 435 PEG-IFN RBV (N9)
PEG-IFN RBV
Panel C
34 patients
PBO PEG-IFN RBV (N6)
PEG-IFN RBV
Panel C
400mg 435 PEG-IFN RBV (N10)
PEG-IFN RBV
Panel D
Panel A B treatment-naïves Panel C D
treatment-experienced (prior non-responders or
relapsers to IFN-based therapy)
1 wk
3 wks
24 or 48 wks
4 wks
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Phase IIa Clinical Trial Outcomes

• The OPERA-1 trial will assess the number of
  patients that achieve RVR (undetectable virus at
  week 4)
• The OPERA-1 trial will be able to assess number
  of patients achieving SVR (after 4 weeks of combo
  therapy plus 24 or 48 weeks of IFN plus RBV)
• The Phase IIa RVR data will guide the design of
  the phase IIb trial (OPERA-2)
• Conclusion There is a place for another HCV PI!
• High potency low drug load
• Once-daily good compliance resulting in
  increased efficacy
• Large forgiveness factor higher efficacy
• Less side effects possible from shorter
  duration of treatment
• More treatment options exclude ribavarin from
  therapy