BIOTRON LIMITED

Phase 2a Trial of BIT225, HCV-p7 Inhibitor, in Combination with Pegylated Interferon-alfa-2b and Ribavirin in HCV Genotype-1 Treatment Naive Subjects

Carolyn Luscombe PhD cluscombe@biotron.com.au

BIT225 • New investigational oral drug for treating HCV infection

• First in class; targets p7 protein

• p7 critical role in production of infectious HCV in infected cells

• Small hydrophobic protein (63 aa’s); Viroporin (Ion channel activity)

A number of possible roles in viral replication:

viral uncoating like influenza M2 (Amantadine)

Viral assembly and release like HIV-1 Vpu and alphavirus 6K

Synergistic in vitro with IFN/RBV

Synergistic in vitro with polymerase inhibitors (CMA and CMC)

NB Replicon assay not suitable for p7 drugs

Confidential

NH

O NH

NH2

N N

HCV p7 most

Confidential

HCV ASSEMBLY Upon replication of the viral RNA (1), the newly synthesized genome is delivered by NS5A to the core protein residing at the surface of lipid droplets (2). The presence of RNA likely triggers initial assembly of high-order capsid-like core complexes (3), however, only the membrane scaffold provided during budding, which is initiated by p7 and the glycoproteins, allows completion of capsid assembly (4). Gentzsch et al 2013 PLOS Path

BIT225 and Hepatitis C • Three completed trials:

• BIT225-001 – Phase 1a, placebo-controlled, randomized, single dose, dose escalating study in healthy volunteers (48 subjects)

• BIT225-003 – Phase 1b, placebo-controlled, randomized, 7-day, repeat dose study in HCV+ subjects (35 and 200 mg BID; 18 subjects)

• BIT225-005 – Phase 2a, placebo-controlled, randomized, 28-day, repeat dose study in combination with IFN/RBV in HCV+ subjects (200 and 400 mg BID; 24 subjects)

• BIT225-006 – Phase 2, open-label, 28-day, repeat dose study in combination with IFN/RBV in HIV/HCV co-infected subjects (300mg BID; 12 subjects); IN PROGRESS

Michelle Miller, CEO; +61 412 313329; mmiller@biotron.com.au

BIT225-005: Demographics and Baseline Data

400mg 200mg Placebo

BIT225-005: Adverse Events

Confidential

Adverse Events Impacting Dosing

All resolved and patients continued trial

Michelle Miller, CEO; +61 412 313329; mmiller@biotron.com.au

BIT225-005: Clinical Results – Early Response

BIT225-005: Clinical Results – 48 week data

• Clear demonstration that this first in class, direct-acting antiviral drug has good antiviral activity in treatment-naïve genotype 1a and 1b patients

• 21 of 23 subjects were homozygous CC at rs12979860 and homozygous TT at rs8099917; One subject from each of the 400 mg BIT225 and placebo groups were heterozygous for both alleles

• Generally well tolerated at the doses selected in trial

• Confirmed preclinical efficacy studies

• Potential for less frequent dosing in future trials

Treatment Median log reduction

at 35 days

% Complete EVR

(<50IU/ml at 12 weeks)

% ETVR (<50IU/ml at 48 weeks)

400 mg BIT225 + SOC -4.957 86 100

200 mg BIT225 + SOC -4.351 88 88

Placebo + SOC -3.649 63 75

BIT225-005: Clinical Results – PK data

BIT225-005: E2-P7-NS2 Sequencing analysis

Population sequencing of E2, P7 and NS2:

- Day -14 pretreatment and day 28 plasma samples

- Compared to consensus sequences of HCV 1a & 1b

- Several changes were identified

- No unique mutations selected in the BIT225 treatment cohorts compared to placebo

- Suggests the differences were not significant over that of the usual HCV quasi-species.

Domain: p7 protein HCV_REF_GT_1a_--_AF009606-H77-AA lcl|1 A L E N L V I L N A A S L A G T H G L V S F L V F F C F A W Y L K G R W V P G A V Y A F Y G M W P L L L L L L A L P Q R A Y A [ 809]

123-D14-AA_|GT1a|-400mg lcl|17 . . . . . . L . . . . . . T . M . . . . . . . . . . . . . . . . . . K . . . . V A . . . . . . . . F . . . . . . . . H . . . . [ 809]123-D28-AA_|GT1a|-400mg lcl|18 . . . . . . L . . . . . . T . M . . . A . . . . . . . . . . . . . . K . . . . V A . . . . . . . . F . . . . . . . . H . . . . [ 809]

121-D14-AA_|GT1a|-400mg lcl|21 . . . . . . M . . . . . . . . . . . . . . . . . . . . L . . . . . . K . . . . . . . . L . . . . . . . . . . . . . . . . . . . [ 809]121-D28-AA_|GT1a|-400mg lcl|22 . . . . . . M . . . . . . . . . . . . . . . . . . . . L . . . . . . K . . . . . . . . L . . . . . . . . . . M . . . . . . . . [ 809]

102-D14-AA_|GT1a|-200mg lcl|3 . . . . . . V . . . . . . . . . . . . A . . . . . . . . . . . . . . . . . . . . . . . L . . . . . . . . . . . . . . . . . . . [ 809]102-D28-AA_|GT1a|-200mg lcl|4 . . . . . . V . . . . . . . . . . . . A . . . . . . . . . . . . . . . . . . . . A . . L . . . . . . . . . . . . . . . . . . . [ 809]

103-D14-AA_|GT1a|-Placebo lcl|5 . . . . . . M . . . . . . . . . . . . A . . . . . . . . . . . . . . K . . . . . . . . . . . T . . . . . . . . . . . . . . . . [ 809]103-D28-AA_|GT1a|-Placebo lcl|6 . . . . . . M . . . . . . . . . . . . A . . . . . . . . . . . . . . K . . . . . . . . . . . T . . . . . . . . . . . . . . . . [ 809]

122-D14-AA_|GT1a|-Placebo lcl|15 . . . . . . L . . . . . . . . . . . . A . . . . . . . . . . . . . . . . . . . V A . . L . . . . . . . . . . . . . . . . . . . [ 809]122-D28-AA_|GT1a|-Placebo lcl|16 . . . . . . L . . . . . . . . . . . . A . . . . . . . . . . . . . . . . . . . V A . . . . . . . . . . . . . . . . . . . . . . [ 809]

HCV_REF_GT_1b_--_AJ238799-Con1-AA lcl|2 . . . . . . V . . . . . V . . A . . I L . . . . . . . A . . . I . . . L . . . . A . . L . . V . . . . . . . . . . . P . . . . [ 809]

115-D14-AA_|GT1b|-Placebo lcl|11 . . . . . . . . . . . . . V . M . . . F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]115-D28-AA_|GT1b|-Placebo lcl|12 . . . . . . . . . . . . . V . M . . . F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]

117-D14-AA_|GT1b|-200mg lcl|13 . . . . . . . . . . . . . . . . . . V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]117-D28-AA_|GT1b|-200mg lcl|14 . . . . . . . . . . . . . . . . . . V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]

124-D14-AA_|GT1b|-200mg lcl|19 . . . . . . . . . . . . . . . . . . . F P . . . L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]124-D28-AA_|GT1b|-200mg lcl|20 . . . . . . . . . . . . . . . . . . . F P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]

104-D14-AA_|GT1b|-Placebo lcl|7 . . . . . . . . . . . . . . . . . . . F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]104-D28-AA_|GT1b|-Placebo lcl|8 . . . . . . . . . . . . . . . . . . . F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 809]

108-D14-AA_|GT1b|-Placebo lcl|9 . . . . . . . . . . . . . . . . . . V . . . . . . . . . . . . . . . . . . . . . . . . F . . . . . . . . . . . . . . . . . . . [ 809]108-D28-AA_|GT1b|-Placebo lcl|10 . . . . . . . . . . . . . . . . . . V . . . . . . . . . . . . . . . . . . . . . . . . F . . . . . . . . . . . . . . . . . . . [ 809]

Green highlighting: HCV Genotype 1a reference sequence H77Yellow Highlighting: HCV Genotype 1b reference sequence Con1

Red highlights indicate amino acids that were observed to vary between day -14 and day +28 samples

Conclusions

• BIT225 is a first-in-class, specifically designed, HCV p7 inhibitor.

• The PK data suggest that the dosing regimen generated sufficient drug levels in the plasma, resulting in promising antiviral activity.

• The data also suggests that there is the potential for less frequent dosing in future trials.

• Sequencing studies demonstrated that no BIT225-resistant variants were selected during therapy.

• This study provides proof-of-concept of the validity of this approach to treatment of HCV infection in treatment-naïve genotype 1 subjects.

• A Phase 2b, 12-week dosing trial in HCV+ Gen 1 and 3 subjects with IFN/RBV is scheduled to commence in 4Q13.

Acknowledgements

Gary Ewart, Michelle Miller, John Wilkinson, Biotron Limited, North Ryde, NSW, Australia. Rob Murphy, Northwestern University, Chicago, IL, USA Zhuhui Huang, Southern Research Institute, Fredrick, MD, USA. Gene Morse, Robin Defrancesco, Qing Ma, University of Buffalo, Buffalo, NY, USA. Marion Peters, University of California-San Francisco, San Francisco, C.A, USA Tawesak Tanwandee (PI) and ACLIRES for clinical trial assistance, the staff and trial participants at Sirijaj Hospital, Mahidol University, Bangkok, Thailand.