Biotron Limited · ASX:BIT
Biotron — IAS 2013 Towards an HIV Cure Symposium
13 slides from Biotron's conference presentation, July 2013
Slide 1: BIT225, a Novel Inhibitor of HIV-1 Release from HIV-1 Reservoirs of the Myeloid Lineage
BIT225, a Novel Inhibitor of HIV-1 Release from HIV-1 Reservoirs of the Myeloid Lineage John Wilkinson*1, Carolyn Luscombe1, Gary Ewart1, Stephen Kerr2, Nattaya Tanliang3, Winai Ratanasuwan3, Robert Murphy4, and Michelle Miller1 1Biotron Limited, Sydney, Australia 2HIV-NAT, Bangkok, Thailand 3Sirira
Slide 2: BIT225, a Novel Inhibitor of HIV-1 Release from HIV-1 Reservoirs of the Myeloid Lineage
BIT225, a Novel Inhibitor of HIV-‐1 Release from HIV-‐1 Reservoirs of the Myeloid Lineage -‐ John Wilkinson -‐ Biotron Limited, Australia IAS 2013 Towards an HIV Cure Symposium
Slide 3: BIT225
BIT225 (N-‐[5-‐(1-‐Methyl-‐1H-‐pyrazol-‐4-‐yl)-‐napthalene-‐2-‐ carbonyl]-‐guanidine) • First-‐in-‐class drug targeHng HIV-‐1 within cells of the myeloid lineage (selected as lead from ~250 compound library designed to target Vpu) • AnH-‐HIV-‐1 acHvity in primary human CD14+ MDM assa
Slide 4: Significant HIV-1 Reduction in Human Macrophages in vitro with BIT225
Significant HIV-‐1 ReducHon in Human Macrophages in vitro with BIT225 Chronic Kinetics d14 infection & d21 BIT225 addition 200 HIV-1 Replication RT 150 DMSO Control BIT225 100 +BIT225 50 16 17 19 21 22 23 24 25 26 27 28 Time (days) +HIV-1 Khoury et al., An7microbial Agents and Chemotherapy. 2009
Slide 5: Monocytes and HIV-1 Infection
Monocytes and HIV-‐1 InfecHon • CD14+ monocytes (~30%) are long lived cells with reports that once infected they can disseminate virus for 6 weeks in vitro (Sharova et al EMBO J 2005) • The minor CD16+ subset (5-‐10% of monocytes) are preferenHally infected; higher CCR5 levels (Ellery et al JI 200
Slide 6: A Phase 1b/2a Trial with BIT225
A Phase 1b/2a Trial with BIT225 BIT225-‐004, a Phase 1b/2a, Placebo-‐Controlled, Randomised Study of the Safety, Pharmacokine7cs and An7viral Ac7vity of BIT225 in Pa7ents with Human Immunodeficiency Virus-‐1 Infec7on Robert Murphy, Winai Ratanasuwan and Ruengpung SuIhent ACLIRES and Dept of Medici
Slide 7: BIT225-004: Synopsis
BIT225-‐004: Synopsis Primary objec7ve The safety and tolerability of 400 mg of BIT225 BID compared with placebo in paHents with HIV-‐1 infecHon that are anHretroviral therapy naïve Secondary objec7ves • The pharmacokineHcs of 400 mg of BIT225 administered daily on day 1 & 10 and twice daily on da
Slide 8: BIT225 Antiviral Activity in a Clinical Setting
BIT225 AnHviral AcHvity in a Clinical Sepng In a study of only 10 days with a drug targeHng cells of the myeloid lineage, dramaHc decreases in HIV-‐1 viral load and concomitant increases in CD4+ T cell number are unlikely to be observed. Issues with access to macrophages Aim: To determine the effect
Slide 9: Monocyte Co-Culture Assay
Monocyte Co-‐Culture Assay Placebo (n=7) BIT225 Treated (n=12) 16 16 HIV-‐1 ReplicaHon (pg/200uL) Day 0 Bleed 14 14 Day 5 Bleed Day 10 Bleed 12 12 Day 20 Bleed 10 10 8 8 6 6 4 4 2 2 5 10 15 20 25 5 10 15 20 25 Time in Co-‐culture (days)
Slide 10: Monocyte Co-Culture Assay
Monocyte Co-‐Culture Assay BIT225 Treated: High Viral Load n=6 16 14 Day 0 Bleed HIV-‐1 ReplicaHon (pg/200uL) Day 5 Bleed 12 Day 10 Bleed Day 20 Bleed 10 8 6 4 2 5 10 15 20 25 Time in Co-‐culture (days) Mann-‐Whitney p= 0 v 5 0.25 0.09 0.1 0.05 0.04 0.2 0 v 10 0.25 0.31 0.31 0.42 0.44 0.28 0 v 2
Slide 11: Monocyte Co-Culture Assay
Monocyte Co-‐Culture Assay BIT225 Treated: Low Viral Load n=6 16 14 HIV-‐1 ReplicaHon (pg/200uL) 12 Day 0 Bleed 10 Day 5 Bleed Day 10 Bleed 8 Day 20 Bleed 6 4 2 5 10 15 20 25 Time in co-culture (days)
Slide 12: In Summary
In Summary • This study strengthens our previous findings in vitro and ex vivo, supporHng the role for BIT225 as a novel drug targeHng HIV-‐1 within the myeloid compartment • In those paHents with high HIV-‐1+ viral loads, treatment with BIT225 for 10 days significantly reduced the amount of infecHo
Slide 13: Acknowledgements
Acknowledgements Biotron Limited ACLIRES Dr Michelle Miller Prof Rob Murphy Dr Carolyn Luscombe Dr Sven-‐Iver Lorenzen Dr Gary Ewart Audrey Thomson Siriraj Hospital Bronwyn Williams Trial ParHcipants Craig Witherington A/Prof Winai Ratanasuwan Gabriela Khoury Prof Ruengpung Suuhent Nauaya Tanliang