S'Collins HIV iBase THT talk 23 March 2005

1
UK-CABEntry 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
• QAs 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

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

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 lt5 pure X4)

8

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

10

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 benefit1
• STI vs immediate salvage 53 vs 36 lt 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 gt50 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 drug1
  placebo) as 10 days of monotherapy
• 200mg (n7) or 400mg (n17) twice daily
• Baseline CD4 460 and viral load of 4.6log.
• Median viral load -1.7log 6/16 lt400copies/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 n6) naïve or of-treatment for gt4
  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 gt0.3
  log.
• Return to baseline was inhibited for at least 20
  days in the 250mg dose arm