Transcript Document

UK-CAB:
Entry inhibitors and
Immunology
3 June 2005
S.Collins HIV i-Base
THT talk - 23 March 2005
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)
S.Collins HIV i-Base
THT talk - 23 March 2005
HIV lifecycle
HIV v irus
entry inhibitors
CD4 cell
nukes &
non-nukes
(NNRTIs)
protease inhibitors
Maturation and
budding
inhibitors
Integrase
inhibitors
HIV uses CD4 cells as factories to make hundreds of copies of itself. Different drugs work at different stages of the HIV life cycl
S.Collins HIV i-Base
THT talk - 23 March 2005
New Treatments
DRUG
Tipranavir
TMC114
UIC-020301
GW640385
AG-001859
BMS-488043
Maraviroc (UK427,857)
TAK-652
GW 871340
CMPD 167
AMD3100
Compound -1
Amdoxovir
TMC278
BILR 355BS
Capravirine
KMMP05
L-870810
FZ41
PA-457
COMPANY
Boehringer
Tibotec
NCI
GSK
Pfizer
BMS
Pfizer
Takeda
GSK
Merck
Anormed
Tibotec
Frontier Sci
Tibotec
Boehringer
Pfizer
NCI
Merck
BioAlliance
Panacos
CLASS
PI
PI
PI
PI
PI
Attachment
CCR5 Inhibitor
CCR5 Inhibitor
CCR5 Inhibitor
CCR5 Inhibitor
CXCR4 Inhibitor
NcRTI
NRTI
NNRTI
NNRTI
NNRTI
RNAase H
Integrase Inhibitor
Integrase Inhibitor
Maturation Inhibitor
ABS no
104, 560, 617, 654
164LB
562
563
561
544
96, 663
541, 542
77, 543, 664
128
545
156
553, 554
160, 556
557, 558
555
157
161, 725
547
159, 551
Mike Youle: NATAP.org
S.Collins HIV i-Base
THT talk - 23 March 2005
New Treatments
DRUG
Tipranavir
TMC114
UIC-020301
GW640385
AG-001859
BMS-488043
Maraviroc (UK427,857)
TAK-652
GW 871340
CMPD 167
AMD3100
Compound -1
Amdoxovir
TMC278
BILR 355BS
Capravirine
KMMP05
L-870810
FZ41
PA-457
COMPANY
Boehringer
Tibotec
NCI
GSK
Pfizer
BMS
Pfizer
Takeda
GSK
Merck
Anormed
Tibotec
Frontier Sci
Tibotec
Boehringer
Pfizer
NCI
Merck
BioAlliance
Panacos
CLASS
PI
PI
PI
PI
PI
Attachment
CCR5 Inhibitor
CCR5 Inhibitor
CCR5 Inhibitor
CCR5 Inhibitor
CXCR4 Inhibitor
NcRTI
NRTI
NNRTI
NNRTI
NNRTI
RNAase H
Integrase Inhibitor
Integrase Inhibitor
Maturation Inhibitor
ABS no
104, 560, 617, 654
164LB
562
563
561
544
96, 663
541, 542
77, 543, 664
128
545
156
553, 554
160, 556
557, 558
555
157
161, 725
547
159, 551
Mike Youle: NATAP.org
S.Collins HIV i-Base
THT talk - 23 March 2005
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
S.Collins HIV i-Base
THT talk - 23 March 2005
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)
S.Collins HIV i-Base
THT talk - 23 March 2005
S.Collins HIV i-Base
THT talk - 23 March 2005
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
S.Collins HIV i-Base
THT talk - 23 March 2005
S.Collins HIV i-Base
THT talk - 23 March 2005
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
S.Collins HIV i-Base
THT talk - 23 March 2005
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.
S.Collins HIV i-Base
THT talk - 23 March 2005
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.
S.Collins HIV i-Base
THT talk - 23 March 2005
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
PA-457
Panacos
Maturation Inhib
S.Collins HIV i-Base
547
159, 551
THT talk - 23 March 2005
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.
S.Collins HIV i-Base
THT talk - 23 March 2005
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
S.Collins HIV i-Base
THT talk - 23 March 2005