Transcript Document

Drug Development in HIV
Michael Zaiac
New Product Development
25/11/05
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Contents
 Background-Setting the scene
 Co receptors and HIV
• Co-receptor tropism
• Co-receptors as targets
 Philanthropy
 Summary
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No Sign of Pandemic Abating
Issues
 No vaccines on horizon
 Resistance to ARV drugs increasing
 Western World
- re-invigorate public health campaigns
- new ARV to address resistance & compliance
 Developing World
- ARV to break infection cycle
- healthcare infrastructure & public education
- economic stability
- global political leadership
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Estimated Number of People Living With
HIV, by Region in 2004
Eastern Europe &
Central Asia
North America and Western/Central Europe
1.4 million
1.6 million
210,000 60,000
64,000 23,000
Caribbean
440,000
53,000 36,000
Latin America
1.7 million
240,000 95,000
North Africa & Middle East
540,000
92,000 28,000
Sub-Saharan Africa
25.4 million
Asia
8.2 million
1.2 million 540,000
3.1 million 2.3 million
Oceania
35,000
5000 700
Total living cases: 39.4 million
New cases, 2004: 4.9 million
AIDS Deaths, 2004: 3.1 million
UNAIDS/WHO, 2005
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Goals of Antiretroviral Treatment
1. Prevention of progressive immunodeficiency;
potential maintenance or reconstruction of a normal
immune system
Delayed progression to AIDS and prolongation of life
2. Control of viral replication and mutation; reduce
viral burden
Decreased risk of selection of resistant virus
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Anti-Retroviral Therapy
Explosion in HIV research since 1980 & AZT in 1987
But…HIV challenging target
- obligate parasite, so few viral targets
- high mutation rate & genetic plasticity
> 20 approved agents but only 4 targets
Combination therapy (at least 3 agents) = HAART
introduced in 1995
- reduce propensity to resistance
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Genetic Plasticity
 109 new virions produced daily
 One mutation during every replication cycle per cellular
genome
 Genetic plasticity enables HIV to:
- evade immune system
- develop resistance to ARV
- produce mutants with different ‘fitness’
 Multiple strains co-exist & are archived in patients’
immune cells
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Emergence of HIV Resistance
Plasma HIV RNA
Total plasma HIV RNA
Wild-type (WT) HIV RNA
Mutant HIV RNA
Time Receiving Treatment
Havlir. Ann Int Med 1996:124:984.
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Approved ARV Agents
Class
Drug
Nucleoside/tide Reverse
Transcriptase Inhibitors
Zidovudine, Zalcitabine,
Didanosine/EC, Stavudine/XR,
Combivir, Trizivir, Lamivudine,
Abacavir, Tenofovir
Non-Nucleoside Reverse
Transcriptase Inhibitors
Efavirenz, Delavirdine,
Nevirapine
Fusion Inhibitors
Enfuvirtide
Protease Inhibitors
Saquinavir, Indinavir, Ritonavir,
Nelfinavir, Amprenavir,
Lopinavir/Ritonavir, Atazanavir
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Problems with HAART
 HAART = HIV chronic disease & saves lives
 But… most agents designed for acute disease
 HAART has considerable drawbacks:
- toxicity & side effects
- drug interactions
- high pill burden & inconvenient dosing
 Tox. & inconvenient dosing reduce compliance
 Resistance emerges within 6 months to 5 years
- up to 27% of newly diagnosed HIV is resistant
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Requirements on HIV medicines
Ideal features of an antiretroviral agent:
- low dose
- convenient regimen
- better toleration
- non cross resistant
- new mechanisms & targets
- low COG
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= compliance
& durability
Attrition on the R&D Process
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Medicine
12
Candidate attrition
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No. candidates
animal toxicity,
chemical stability,
superior compound
human PK,
tolerability,
formulation
12
Efficacy, safety,
differentiation,
Dose, c.o.g.
long-term safety
non-approval
4
0
0
1
2
Preclin. Phase I
3
4
5
Phase II
6
Phase III
13
7
8
9 Years
Registration
New medicine development
Medicine Development Costs
Time/Cost of Medicine Development
Launch
£450 million
File
500
400
Cumulative costs £M
£280 million
£200 million
£70 million
Phase III
300
Phase I
200
Phase II
100
£30 million
0
1976
1986
1990
1997
0
2003
1
2
3
4
5
Years
14
6
7
8
9
10
Co receptor
Drug Development
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CCR5 and CXCR4 Co-Receptors:
HIV Binding and Entry
CD4
CXCR4
CCR5
T-Cell Surface
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HIV-1 Envelope Glycoproteins
HIV-1
gp41
gp120
HIV-1
Envelope
Glycoprotein
CD4
CCR5
T-Cell Surface
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Binding of the gp120 Subunit of the HIV-1
Envelope Glycoprotein to CD4
HIV-1
gp41
gp120
CD4
CCR5
T-Cell Surface
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Conformational Change Exposes the
Co-Receptor Binding Site in gp120
HIV-1
gp41
gp120
CD4
CCR5
T-Cell Surface
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Conformational Change Allows gp120 to Bind
to the Co-Receptor
HIV-1
gp41
gp120
CD4
CCR5
T-Cell Surface
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Fusion of HIV and T-Cell Membranes
HIV-1 RNA
HIV-1
HIV-1 Nucleocapsid
T-Cell Surface
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HIV-1 Tropism Assays:
MT-2 Cell Assay
 Indirect measure of co-receptor use
- Depends on the presence of X4 or R5/X4 isolates
 Uses viral stocks from stimulated patient lymphocytes
• Results are reader dependent and involve the interpretation of
typical cytopathic changes
 Limitations
• HIV derived from stimulated lymphocytes may differ from that of
plasma virus
• Qualitative nature of the assay result
• Detection of CXCR4 only
Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
DAIDS Virology Manual for HIV Laboratories. 1997. Publication NIH-97-3828.
U.S. Department of Health and Human Services, Washington, DC.
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MT2 cell assay
Syncytium Formation in MT-2 Cells

Prior to the discovery of the role that
CCR5 and CXCR4 play in viral entry,
viruses were characterized by ability
to infect T-cells and cause syncytium
formation
• MT-2 cell lines were used
• MT-2 cells express only CXCR4

Syncytium inducing (SI)
• Changed to CXCR4-using virus

Non-syncytium inducing (NSI)
• Changed to CCR5-using virus
Schuitemaker H, et al. J Virol. 1991;65:356-363.
Japour AJ. J Clin Microbiol. 1994;32:2291-2294.
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HIV-1 Tropism Assays:
Recombinant Phenotypic Assays
 Direct measure of co-receptor use
• Infect engineered cell lines to determine co-receptor
utilization
 Obtained by RT-PCR from patient plasma sample
 Virus stocks pseudotyped with envelope sequences
derived from patient plasma samples
 Limitations
• >500 copies/mL
• May fail to detect X4 when X4 virus constitutes <10% of the
viral population
• Sequence variation may result in assay failure
Coakley E, et al. Curr Opin Infect Dis. 2005;18:9-15.
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HIV entry cell assay
CD4 +
CXCR4 +
HIV env
HIV genomic expression
luc vector
vector
+
Transfection
Infection
Pseudovirus
CD4 +
CCR5 +
Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother 2000;44:920-8.
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R5 and X4 Variants:
HIV Disease Progression
Absolute Viral Load
R5 Infection
R5
X4 Limit of Detection
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
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R5 and X4 Variants:
HIV Disease Progression
Absolute Viral Load
R5 Infection
R5
R5 Infection
X4 Limit of Detection
X4
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
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R5 and X4 Variants:
HIV Disease Progression
Absolute Viral Load
R5 Infection
R5 + X4 Infection
R5
X4
R5 Infection
X4 Limit of Detection
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
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R5 and X4 Viruses Target
Different Subsets of CD4+ T-Cells
R5 Infection
Relative CD4 Cell Counts
(common, early)
Naïve
T-Cells
Memory
T-Cells
Time (y)
R5 viruses target memory T-cells
(eg, GALT)
Naïve T-cells become targets once
activated to the memory phenotype
Douek DC, et al. Ann Rev Immunol. 2003;21:265-304.
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
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R5 Infection
X4 Infection
(common, early)
(very rare)
Relative CD4 Cell Counts
Relative CD4 Cell Counts
R5 and X4 Viruses Target
Different Subsets of CD4+ T-Cells
Naïve
T-Cells
Memory
T-Cells
Time (y)
Memory
T-Cells
Naïve
T-Cells
Time (y)
R5 viruses target memory T-cells
(eg, GALT)
X4 viruses target naive T-cells
(eg, thymus)
Naïve T-cells become targets once
activated to the memory phenotype
CXCR4 expression on some memory
cells makes them targets
Douek DC, et al. Ann Rev Immunol. 2003;21:265-304.
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
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Will a CCR5 Antagonist Drive the Emergence
of X4 Viruses In Vivo?
Scenario 1
Absolute Viral Load
CCR5
Antagonist
R5
X4 Threshold
of Detection
X4
Time (days)
R5 viruses remain suppressed
X4 viruses do not expand
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Will a CCR5 Antagonist Drive the Emergence
of X4 Viruses In Vivo?
Scenario 1
Scenario 2
CCR5
Antagonist
R5
R5
Viral Load
Absolute Viral Load
CCR5
Antagonist
X4
X4 Threshold
of Detection
X4 Threshold
of Detection
X4
Time (days)
Time (days)
R5 viruses remain suppressed
R5 viruses remain suppressed
X4 viruses do not expand
Sustained, possible reciprocal
expansion of X4 virus pool
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Scenario 3:
Partial Expansion of the X4 Virus Pool
Scenario 3
Absolute Viral Load
CCR5
Antagonist
R5
X4
X4 Threshold
of Detection
Time (days)
R5 viruses remain suppressed
Sustained, partial expansion
of X4 virus pool
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Prevalence of
HIV Co-Receptor Usage
Prevalence of Usage (%)
R5
X4
R5 + X4
94
0
6
82
<1
18
85
<1
15
88
0
12
62
4
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Fätkenheuer (n=116)1
Brumme (n=979)2
Moyle (n=563)3
Demarest (n=299)4
Whitcomb (n=612)5
1Fätkenheuer
G, et al. Nat Med. 2005;11:1170-1172.
ZL, et al. J Infect Dis. 2005;192:466-474.
3Moyle GJ, et al. J Infect Dis. 2005;191:866-872.
4Demarest J, et al. 44th ICAAC. Washington, DC, 2004. Abstract H-1136.
5Whitcomb JM, et al. 10th CROI. Boston, 2003. Abstract 557.
2Brumme
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CCR5- a drugable target?
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Δ32 inhibition of coreceptor-mediated entry
Δ32 CCR5
< 1.5%
WT CCR5
< 20%
~ 80%
Delayed progression
(Essentially) no progression
Normal progression
100
% AIDS free
80
Genotype +/+
Genotype +/∆32
60
40
n = 39
n = 110
20
0
0
2
4
6
8
10
12
14
16
18
20
Years since seroconversion
Lui R, et al. Cell 1996; 86:367–377.
Samson M, et al. Nature 1996; 382:722–725.
Dean M, et al. Science 1996; 273:1856–1862.
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Huang Y, et al. Nature Med 1996; 2:1240–1243.
Michael NL, et al. Nature Med 1997; 3:1160–1162.
Eugen-Olsen J, et al. AIDS 1997; 11:305–310.
Drug development
SAR
High-throughput
in vitro testing
CCR5
CXCR4
crystallography
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Designer Drugs
HIV inhibition
Normal
function
Unknown effects of entry inhibitors
Normal Function
natural ligand
allosteric inhibition by drug
Internalisation
of receptor
? Normal function
? Internalisation
of receptor
Viral mutations
overcome
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some Co-receptor antagonists have fallen by the
wayside
SCH-C
QT
AMD-3100
cardiac abnormalities but stem
cell mobilization
ALX 404 C
no oral formulation
TAK 779
toxicity at injection sites
Aplaviroc
hepatic side effects
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Tropism shift
Using CCR 5 antagonists
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Impact of Current Antiretroviral Agents on R5
and X4 Virus Dynamics

In 3 cohorts, patients on HAART who were X4 or X4/R5 tropic
•
•
•
•

showed a:1-4
Preferential suppression of X4
Shift from X4 to R5
Loss of X4 from T-cell reservoirs in some cases
Treatment experience associated with greater risk of X4 in some cohorts 5
Acquisition of X4 virus in 8 persons homozygous for D326
•
•
•
•
•
Rapid initial CD4 decline
Established wide variation in viral load “set point”
Rapid progression not invariable
Suggested behavior of X4 virus less pathogenic than in late stage
Is X4 cause or effect of progression?
1Skrabel
K, et al. AIDS. 2003;107:431-438.
S, et al. J Clin Invest. 2001;107:451-458.
3Equils O, et al. J Infect Dis. 2000;182:751-757.
4Van Rij RP, et al. J Virol. 2000;76:3054-3058.
5Demarest J, et al. 44th ICAAC. Washington, DC, 2004. Abstract H-1136.
6Sheppard HW, et al. AIDS. 2002;29:307-313.
2Philpott
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Data summary
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CCR5 Antagonists:
Potential Advantages
 Inhibit entry of HIV-1 into host cells
 Activity against viral strains resistant to current agents
 Human protein target versus viral gene target
 Extracellular mechanism of action
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Challenges in CCR5 Antagonist Use
 Utility may be related to disease stage, rather than
treatment experience
• Higher prevalence of X4 virus in patients with advanced
disease
• Trends toward later initiation of therapy may limit utility of
CCR5 antagonists
 Clinical trials underway to address:
• Long-term safety of CCR5 inhibition
• Frequency/risk/implications of X4 emergence/unmasking
• Risk/benefit in patients with mixed infection
 Possible need for laboratory monitoring of viral tropism?
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Possible scenarios


Noninferiority proven
New class
Unknown risks

Laboratory issues

‘Superiority’ proven

Salvage – as part of last viable regimen

NRTI sparing

Substitution studies
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Pfizer philanthropy
47
Diflucan Partnership Program
 Donation of Diflucan (fluconazole)
and training of health care providers
 22 countries (915+facilities) in
Africa, Asia and Caribbean
participating
The Diflucan Partnership is
“the first of, we hope, many
other successful public/
private partnerships initiated
by parties who have
demonstrated that they care
enough to act.”
 67,000 patients treated for
HIV-related fungal opportunistic
infections
 More than 18,000 health care
professionals trained
— Dr. Manto Tshabalala-Msimang,
Minister of Health, South Africa
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International Trachoma Initiative
 Public-private partnership focused
on eliminating blinding trachoma
• The world’s leading cause of
preventable blindness
 ITI now in place in 9 countries
in Africa and Asia
• 90% reduction in prevalence
in Morocco
• 50% in Tanzania
• 75% in Vietnam
 Donated $225 million worth
of Zithromax
 10 million antibiotic
treatments to date
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Infectious Diseases Institute
$11 million commitment to fund
regional Center of Excellence for
HIV/AIDS treatment and training at
Makerere University in Kampala
Extensive, one-month HIV training
program for 150 physicians each
year in Uganda and the region
Care and treatment for more than
50,000 patients annually
Construction of facility completed
March 2004
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Pfizer Global Health Fellows
“Peace Corps” for Pfizer employees
Up to 6-month overseas
assignments for employees to work
with NGOs fighting HIV/AIDS in
developing countries
Many NGO partners
18 Global Health Fellows selected to
serve in 2003
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A Leading Corporate Giver
$700
Product Giving
$600
Cash Giving
($ Millions)
$500
$400
$300
$200
$100
$0
Merck
Pfizer
BMS
J&J
Microsoft
Source: Chronicle of Philanthropy, 7/24/2003
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WalMart
IBM
Altria
Ford
Motor
Intel