UK-CAB: Entry inhibitors and Immunology 3 June 2005

1. UK-CAB:Entry inhibitors and Immunology3 June 2005

2. Overview • Introductions, i-Base and UK-CAB • Issues from CROI relating to new treatment • How to stay up to date • How to sort and select information • Other interesting stuff • Q&As throughout (please)

3. Maturation and budding inhibitors Integrase inhibitors

4. New Treatments DRUG COMPANY CLASS ABS no Tipranavir Boehringer PI 104, 560, 617, 654 TMC114 Tibotec PI 164LB UIC-020301 NCI PI 562 GW640385 GSK PI 563 AG-001859 Pfizer PI 561 BMS-488043 BMS Attachment 544 Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663 TAK-652 Takeda CCR5 Inhibitor 541, 542 GW 871340 GSK CCR5 Inhibitor 77, 543, 664 CMPD 167 Merck CCR5 Inhibitor 128 AMD3100 Anormed CXCR4 Inhibitor 545 Compound -1 Tibotec NcRTI 156 Amdoxovir Frontier Sci NRTI 553, 554 TMC278 Tibotec NNRTI 160, 556 BILR 355BS Boehringer NNRTI 557, 558 Capravirine Pfizer NNRTI 555 KMMP05 NCI RNAase H 157 L-870810 Merck Integrase Inhibitor 161, 725 FZ41 BioAlliance Integrase Inhibitor 547 PA-457 Panacos Maturation Inhibitor 159, 551 Mike Youle: NATAP.org

5. New Treatments DRUG COMPANY CLASS ABS no Tipranavir Boehringer PI 104, 560, 617, 654 TMC114 Tibotec PI 164LB UIC-020301 NCI PI 562 GW640385 GSK PI 563 AG-001859 Pfizer PI 561 BMS-488043 BMS Attachment 544 Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663 TAK-652 Takeda CCR5 Inhibitor 541, 542 GW 871340 GSK CCR5 Inhibitor 77, 543, 664 CMPD 167 Merck CCR5 Inhibitor 128 AMD3100 Anormed CXCR4 Inhibitor 545 Compound -1 Tibotec NcRTI 156 Amdoxovir Frontier Sci NRTI 553, 554 TMC278 Tibotec NNRTI 160, 556 BILR 355BS Boehringer NNRTI 557, 558 Capravirine Pfizer NNRTI 555 KMMP05 NCI RNAase H 157 L-870810 Merck Integrase Inhibitor 161, 725 FZ41 BioAlliance Integrase Inhibitor 547 PA-457 Panacos Maturation Inhibitor 159, 551 Mike Youle: NATAP.org

6. New Treatments Breakdown by development phase or class • Every conference may have 20-30 new targets and compounds discussed in pre-clinical and in vitro studies - very difficult to generate real interest or to pick which will come through. Always the subject of PR • Phase 2 - activity in +ve, often dose ranging, 2-300 pts • Phase 3 - large scale ‘registrational’ studies, is the drug effective and safe in 2-3000 patients

7. New Treatments: Entry Inhibitors • Work at binding site - preventing the virus from joining and entering a CD4 cell • Virus uses two main co-receptors on the CD4 cell: CCR5 and CXCR4 - called CCR5-blockers or CCR5-antagonists • Safety for R5 is that people naturally with deletions of CCR5 are protected form HIV infection, and this appears to have no biological disadvantage. May not be true for X4 though (ie mouse data suggest not) • Generally R5 in early and chronic infection • Switch to X4 in late infection (but even then 30-50% pts are mixed X4 and R5 and <5% pure X4)

9. New Treatments: Entry Inhibitors • 2 log range of sensitivities against different HIV-1 isolates • therefore very differing levels of activity within individuals • Need sensitive tests to identify baseline receptors However • several mutations are required to block R5 or X4 virus • receptor switching may be rare • mice and primates use in microbicides research

11. New Treatments: Entry Inhibitors DRUG COMPANY CLASS ABS no BMS-488043 BMS Attachment 544 Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663 TAK-652 Takeda CCR5 Inhibitor 541, 542 GW 871340 GSK CCR5 Inhibitor 77, 543, 664 CMPD 167 Merck CCR5 Inhibitor 128 AMD3100 Anormed CXCR4 Inhibitor 545

12. New Treatments: Entry Inhibitors Maraviroc (UK427,857) (Pfizer) • at 10 days around 1.5 log drops; PK interactions studies (50% reduction in 427 with EFV and 200% with LPV/r). Slight change may overcome resistance, ?PR GW 871340 (GSK) • Similar log drop (dose 200-600mg); CROI showed 50% receptor occupancy after 5 days post drug; LPV/r ok but not GSK PI.

13. T-20 Resistance • T-20 - first entry inhibitor - sc injection, possible needle-free • STI prior to T-20 showed little benefit[1] • STI vs immediate salvage: 53% vs 36% < 75 copies/mL at Week 24 (P = ns) and similar trend at Week 48 • PSS, but not T-20 susceptibility, predicted treatment response • Low genetic barrier to T-20 resistance • Resistance to T-20 at first rebound, including one case in one week • Rapid viral rebound to baseline levels • T-20 stopped in 22 patients >50 c/ml [2] • Only average +0.2 log rebound • Phenotypic susceptibility by wk16 in most subjects • No benefit of continuing T-20 - need to use other active agents 1. Beatty G, et al. Abstract 581. 2. Deeks S, et al. Abstract 680.

14. New Treatments: other targets DRUG COMPANY CLASS ABS no KMMP05 NCI RNAase H 157 L-870810 Merck Integrase Inhibitor 161, 725 FZ41 BioAlliance Integrase Inhibitor 547 PA-457 Panacos Maturation Inhib 159, 551

15. L-870810 (Merck) • double blind placebo controlled (4 drug:1 placebo) as 10 days of monotherapy • 200mg (n=7) or 400mg (n=17) twice daily • Baseline CD4 460 and viral load of 4.6log. • Median viral load -1.7log [6/16 <400copies/mL; • T4 rise +89 cells (+30-+148)] • Rebound occurred at varying rates over the next 24 days. This drug has been put of hold due to non-human toxicity.

16. PA-457 (Panacos) • first maturation inhibitor • data from a double blind, placebo controlled single dose study of 75mg, 150mg and 250mg and placebo (all n=6); naïve or of-treatment for >4 weeks; two subjects had MDR • Dose related response with median reduction at the highest dose of -0.51log and a greatest decline of -0.73log. 8/12 in higher doses >0.3 log. • Return to baseline was inhibited for at least 20 days in the 250mg dose arm