1. UK-CAB: Entry inhibitors and Immunology 3 June 2005
start by introducing myself and thank Ian for the chance to come and talk today.
My name is Simon Collins and I work for the organisation HIV i-Base. This is a small group of mainly HIV-positive people who previously were involved in running the AIDS Treatment Project.
Been HIV+ since late 1980s
Part of a group that was very badly affected
Involvement initially on a personal and individual level - how to negotiate healthcare system
Since 1996 as part of community activist/advocate level - new world
S.Collins HIV i-Base THT talk - 23 March 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)
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

3. Maturation and budding inhibitors
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
Integrase inhibitors
S.Collins HIV i-Base THT talk - 23 March 2005

4. New Treatments DRUG COMPANY CLASS ABS no
Tipranavir Boehringer PI , 560, 617, 654
TMC Tibotec PI LB
UIC NCI PI
GW GSK PI
AG Pfizer PI
BMS BMS Attachment 544
Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663
TAK Takeda CCR5 Inhibitor 541, 542
GW GSK CCR5 Inhibitor 77, 543, 664
CMPD Merck CCR5 Inhibitor 128
AMD Anormed CXCR4 Inhibitor
Compound Tibotec NcRTI
Amdoxovir Frontier Sci NRTI , 554
TMC Tibotec NNRTI , 556
BILR 355BS Boehringer NNRTI , 558
Capravirine Pfizer NNRTI
KMMP NCI RNAase H
L Merck Integrase Inhibitor 161, 725
FZ BioAlliance Integrase Inhibitor
PA Panacos Maturation Inhibitor 159, 551
Mike Youle: NATAP.org
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

5. New Treatments DRUG COMPANY CLASS ABS no
Tipranavir Boehringer PI , 560, 617, 654
TMC Tibotec PI LB
UIC NCI PI
GW GSK PI
AG Pfizer PI
BMS BMS Attachment 544
Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663
TAK Takeda CCR5 Inhibitor 541, 542
GW GSK CCR5 Inhibitor 77, 543, 664
CMPD Merck CCR5 Inhibitor 128
AMD Anormed CXCR4 Inhibitor
Compound Tibotec NcRTI
Amdoxovir Frontier Sci NRTI , 554
TMC Tibotec NNRTI , 556
BILR 355BS Boehringer NNRTI , 558
Capravirine Pfizer NNRTI
KMMP NCI RNAase H
L Merck Integrase Inhibitor 161, 725
FZ BioAlliance Integrase Inhibitor
PA Panacos Maturation Inhibitor 159, 551
Mike Youle: NATAP.org
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

6. New Treatments Breakdown by development phase or class
• Every conference may have 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, pts
• Phase 3 - large scale ‘registrational’ studies, is the drug effective and safe in patients
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

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)
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

8. Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

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
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

10. Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

11. New Treatments: Entry Inhibitors
DRUG COMPANY CLASS ABS no
BMS BMS Attachment 544
Maraviroc (UK427,857) Pfizer CCR5 Inhibitor 96, 663
TAK Takeda CCR5 Inhibitor 541, 542
GW GSK CCR5 Inhibitor 77, 543, 664
CMPD Merck CCR5 Inhibitor 128
AMD Anormed CXCR4 Inhibitor 545
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

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 (GSK)
• Similar log drop (dose mg); CROI showed 50% receptor occupancy after 5 days post drug; LPV/r ok but not GSK PI.
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

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 need to use other active agents
1. Beatty G, et al. Abstract Deeks S, et al. Abstract 680.
S.Collins HIV i-Base THT talk - 23 March 2005

14. New Treatments: other targets
DRUG COMPANY CLASS ABS no
KMMP NCI RNAase H
L Merck Integrase Inhibitor 161, 725
FZ BioAlliance Integrase Inhibitor
PA Panacos Maturation Inhib 159, 551
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

15. L (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 ( )]
• Rebound occurred at varying rates over the next 24 days. This drug has been put of hold due to non-human toxicity.
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005

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
Being +ve led is still relatively recent event - for charities in the UK, for HIV sector
Treatment - main focus - and again relatively new - seen as expert area
S.Collins HIV i-Base THT talk - 23 March 2005