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1
Michael ZaiacNew Product Development
25/11/05
Drug Development in HIV
2
Contents
Background-Setting the scene
Co receptors and HIV
• Co-receptor tropism
• Co-receptors as targets
Philanthropy
Summary
3
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
4
North Africa & Middle EastNorth Africa & Middle East540,000
92,000 28,000
Sub-Saharan AfricaSub-Saharan Africa25.4 million
3.1 million 2.3 million
Eastern Europe & Eastern Europe & Central AsiaCentral Asia 1.4 million 210,000 60,000
OceaniaOceania35,000
5000 700
North America and Western/Central EuropeNorth America and Western/Central Europe1.6 million
64,000 23,000
CaribbeanCaribbean440,000
53,000 36,000
AsiaAsia8.2 million
1.2 million 540,000
New cases, 2004: 4.9 million AIDS Deaths, 2004: 3.1 millionTotal living cases: 39.4 million
Latin AmericaLatin America1.7 million
240,000 95,000
UNAIDS/WHO, 2005
Estimated Number of People Living With HIV, by Region in 2004
5
1. Prevention of progressive immunodeficiency;potential maintenance or reconstruction of a normal immune system
2. Control of viral replication and mutation; reduceviral burden
Goals of Antiretroviral Treatment
Delayed progression to AIDS and prolongation of life
Decreased risk of selection of resistant virus
6
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
7
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
8
Total plasma HIV RNAWild-type (WT) HIV RNAMutant HIV RNA
Havlir. Ann Int Med 1996:124:984.
Time Receiving Treatment
Pla
sma
HIV
RN
A
Emergence of HIV Resistance
9
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
EnfuvirtideFusion Inhibitors
Protease Inhibitors Saquinavir, Indinavir, Ritonavir,
Nelfinavir, Amprenavir, Lopinavir/Ritonavir, Atazanavir
10
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
11
Requirements on HIV medicines
Ideal features of an antiretroviral agent:
- low dose
- convenient regimen
- better toleration
- non cross resistant
- new mechanisms & targets
- low COG
= compliance & durability
12
Attrition on the R&D Process
1Medicine
13
Candidate attrition
0
4
12
25N
o.
can
did
ates
0 1 2 3 4 5 6 7 8 9 YearsPreclin. Phase I Phase II Phase III Registration
animal toxicity,chemical stability,superior compound
animal toxicity,chemical stability,superior compound
Efficacy, safety,differentiation,Dose, c.o.g.
Efficacy, safety,differentiation,Dose, c.o.g.
human PK,tolerability,formulation
human PK,tolerability,formulation
long-term safetylong-term safetynon-approvalnon-approval
14
New medicine development
1976 1986 1990 1997 2003
£30 million
£70 million
£200 million
£280 million
Medicine Development Costs Time/Cost of Medicine Development
Phase IPhase I
Phase IIPhase II
Phase IIIPhase III
FileFile
LaunchLaunch
Years
Cu
mu
lati
ve c
ost
s £M
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
£450 million
15
Co receptor Drug Development
16
CCR5 and CXCR4 Co-Receptors:HIV Binding and Entry
CCR5
CXCR4
T-Cell Surface
CD4
17
HIV-1 Envelope Glycoproteins
CD4
CCR5
gp120
gp41
T-Cell Surface
HIV-1
HIV-1 HIV-1 Envelope Envelope
Glycoprotein Glycoprotein
18
Binding of the gp120 Subunit of the HIV-1 Envelope Glycoprotein to CD4
HIV-1
T-Cell Surface
CD4
CCR5
gp120
gp41
19
Conformational Change Exposes theCo-Receptor Binding Site in gp120
HIV-1
T-Cell Surface
CD4
CCR5
gp120
gp41
20
Conformational Change Allows gp120 to Bind to the Co-Receptor
HIV-1
T-Cell Surface
CD4
CCR5
gp120
gp41
21
Fusion of HIV and T-Cell Membranes
HIV-1
T-Cell Surface
HIV-1 Nucleocapsid
HIV-1 RNA
22
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.
23
MT2 cell assay
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.
Syncytium Formation in MT-2 Cells
24
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 failureCoakley E, et al. Curr Opin Infect Dis. 2005;18:9-15.
25
HIV entry cell assay
Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother 2000;44:920-8.
Transfection
HIV envexpression
vector++++
HIV genomicluc vector
CD4 +CCR5 +
CD4 +CXCR4 +
Infection
Pseudovirus
26
R5 and X4 Variants:HIV Disease ProgressionR5 and X4 Variants:HIV Disease Progression
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
Ab
so
lute
Vir
al L
oa
dA
bs
olu
te V
ira
l Lo
ad
Time After HIV Transmission Weeks Years
X4 Limit of Detection
R5
R5 Infection
27
R5 and X4 Variants:HIV Disease ProgressionR5 and X4 Variants:HIV Disease Progression
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
Ab
so
lute
Vir
al L
oa
dA
bs
olu
te V
ira
l Lo
ad
Time After HIV Transmission Weeks Years
X4 Limit of Detection
R5
R5 Infection
X4
R5 Infection
28
R5 and X4 Variants:HIV Disease ProgressionR5 and X4 Variants:HIV Disease Progression
Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.
Ab
so
lute
Vir
al L
oa
dA
bs
olu
te V
ira
l Lo
ad
Time After HIV Transmission Weeks Years
X4 Limit of Detection
R5
R5 InfectionX4X4
R5 + X4 InfectionR5 Infection
29
R5 and X4 Viruses TargetDifferent Subsets of CD4+ T-Cells
Douek DC, et al. Douek DC, et al. Ann Rev Immunol. Ann Rev Immunol. 2003;21:265-304.2003;21:265-304.Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
R5 Infection(common, early)
R5 viruses target memory T-cells(eg, GALT)
Naïve T-cells become targets once activated to the memory phenotype
Rel
ati
ve
CD
4 C
ell
Co
un
ts
Time (y)
Memory T-Cells
Naïve T-Cells
30
R5 and X4 Viruses TargetDifferent Subsets of CD4+ T-Cells
Douek DC, et al. Douek DC, et al. Ann Rev Immunol. Ann Rev Immunol. 2003;21:265-304.2003;21:265-304.Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.
R5 Infection(common, early)
R5 viruses target memory T-cells(eg, GALT)
Naïve T-cells become targets once activated to the memory phenotype
Rel
ati
ve
CD
4 C
ell
Co
un
ts
Time (y)
Memory T-Cells
Naïve T-Cells
X4 InfectionX4 Infection(very rare)(very rare)
X4 viruses target naive T-cellsX4 viruses target naive T-cells(eg, thymus)(eg, thymus)
CXCR4 expression on some memory CXCR4 expression on some memory cells makes them targetscells makes them targets
Rel
ati
ve
CD
4 C
ell
Co
un
tsR
ela
tiv
e C
D4
Cel
l C
ou
nts
Time (y)Time (y)
NaïveNaïve T-CellsT-Cells
MemoryMemory T-CellsT-Cells
31
Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo?
Scenario 1Scenario 1
R5 viruses remain suppressedR5 viruses remain suppressed
X4 viruses do not expandX4 viruses do not expand
Ab
solu
te V
iral
Lo
adA
bso
lute
Vir
al L
oad
Time (days)Time (days)
CCR5CCR5AntagonistAntagonist
X4 ThresholdX4 Thresholdof Detectionof Detection
R5R5
X4X4
32
Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo?
Scenario 1Scenario 1
R5 viruses remain suppressedR5 viruses remain suppressed
X4 viruses do not expandX4 viruses do not expand
Ab
solu
te V
iral
Lo
adA
bso
lute
Vir
al L
oad
Time (days)Time (days)
CCR5CCR5AntagonistAntagonist
X4 ThresholdX4 Thresholdof Detectionof Detection
R5R5
X4X4
Scenario 2Scenario 2
R5 viruses remain suppressedR5 viruses remain suppressed
Sustained, possible reciprocal Sustained, possible reciprocal expansion of X4 virus poolexpansion of X4 virus pool
Vir
al L
oad
Vir
al L
oad
Time (days)Time (days)
CCR5CCR5AntagonistAntagonist
X4 ThresholdX4 Thresholdof Detectionof Detection
R5R5X4X4
33
Scenario 3:Partial Expansion of the X4 Virus Pool
R5 viruses remain suppressedR5 viruses remain suppressed
Sustained, partial expansionSustained, partial expansionof X4 virus poolof X4 virus pool
Ab
solu
te V
iral
Lo
adA
bso
lute
Vir
al L
oad
Time (days)Time (days)
CCR5CCR5AntagonistAntagonist
X4 ThresholdX4 Thresholdof Detectionof Detection
R5R5
X4X4
Scenario 3Scenario 3
34
Prevalence ofHIV Co-Receptor Usage
Prevalence of Usage (%)
R5 X4 R5 + X4
Fätkenheuer (n=116)1 94 0 6
Brumme (n=979)2 82 <1 18
Moyle (n=563)3 85 <1 15
Demarest (n=299)4 88 0 12
Whitcomb (n=612)5 62 4 34
1Fätkenheuer G, et al. Nat Med. 2005;11:1170-1172.2Brumme 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.
36
CCR5- a drugable target?
37
Δ32 inhibition of coreceptor-mediated entry
Δ32 CCR5 WT CCR5
< 20% ~ 80%< 1.5%
Delayed progression Normal progression(Essentially) no progression
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.
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.
0 2 4 6 8 10 18 200
20
40
60
80
% A
IDS
fre
e
Years since seroconversion
100
12 14 16
n = 39
n = 110
Genotype +/+
Genotype +/∆32
38
Drug development
crystallography
SAR Designer Drugs
High-throughputin vitro testing
HIV inhibition
NormalfunctionCCR5 CXCR4
39
Unknown effects of entry inhibitors
Normal Function
natural ligand allosteric inhibition by drug
Internalisationof receptor
? Normal function
? Internalisation of receptor
Viral mutations overcome
40
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
41
Tropism shift
Using CCR 5 antagonists
42
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 cohorts5
Acquisition of X4 virus in 8 persons homozygous for 326
• 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;107:431-438.2Philpott 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.
43
Data summary
44
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
45
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?
46
Possible scenarios
Noninferiority proven
New class Unknown risks
Laboratory issues
‘Superiority’ proven
Salvage – as part of last viable regimen
NRTI sparing
Substitution studies
47
Pfizer philanthropy
48
Diflucan Partnership Program
Donation of Diflucan (fluconazole) and training of health care providers
22 countries (915+facilities) in Africa, Asia and Caribbean participating
67,000 patients treated for HIV-related fungal opportunistic infections
More than 18,000 health care professionals trained
The Diflucan Partnership is The Diflucan Partnership is “the first of, we hope, many “the first of, we hope, many other successful public/other successful public/private partnerships initiated private partnerships initiated by parties who have by parties who have demonstrated that they care demonstrated that they care enough to act.”enough to act.”
—— Dr. Manto Tshabalala-Msimang,Dr. Manto Tshabalala-Msimang,Minister of Health, South AfricaMinister of Health, South Africa
The Diflucan Partnership is The Diflucan Partnership is “the first of, we hope, many “the first of, we hope, many other successful public/other successful public/private partnerships initiated private partnerships initiated by parties who have by parties who have demonstrated that they care demonstrated that they care enough to act.”enough to act.”
—— Dr. Manto Tshabalala-Msimang,Dr. Manto Tshabalala-Msimang,Minister of Health, South AfricaMinister of Health, South Africa
49
50
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
51
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
52
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
53
A Leading Corporate Giver
Source: Chronicle of Philanthropy, 7/24/2003
$0
$100
$200
$300
$400
$500
$600
$700
($ M
illio
ns)
Merck Pfizer BMS J&J Microsoft Wal-Mart
IBM Altria FordMotor
Intel
Product Giving
Cash Giving