Michael Zaiac

1
Drug Development in HIV
Michael Zaiac New Product Development 25/11/05
2
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

4
Estimated Number of People Living With HIV, by
Region in 2004
UNAIDS/WHO, 2005
5
Goals of Antiretroviral Treatment

• 1. Prevention of progressive immunodeficiencypot
  ential maintenance or reconstruction of a normal
  immune system
• 2. Control of viral replication and mutation
  reduceviral burden

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
• ButHIV challenging target
• - obligate parasite, so few viral targets
• - high mutation rate genetic plasticity
• gt 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
Emergence of HIV Resistance
Total plasma HIV RNA
Wild-type (WT) HIV RNA
Mutant HIV RNA
Plasma HIV RNA
Time Receiving Treatment
Havlir. Ann Int Med 1996124984.
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Approved ARV Agents
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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

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

12
Attrition on the RD Process
1 Medicine
13
Candidate attrition
25
animal toxicity, chemical stability, superior
compound
human PK, tolerability, formulation
12
No. candidates
Efficacy, safety, differentiation, Dose, c.o.g.
long-term safety
non-approval
4
0
Preclin. Phase I Phase II
Phase III Registration
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New medicine development
Medicine Development Costs
Time/Cost of Medicine Development
Launch
450 million
File
500
400
280 million
Phase III
300
200 million
Cumulative costs M
Phase I
200
Phase II
70 million
100
30 million
0
Years
15
Co receptor Drug Development
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CCR5 and CXCR4 Co-ReceptorsHIV 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 theCo-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
21
Fusion of HIV and T-Cell Membranes
HIV-1 RNA
HIV-1
HIV-1 Nucleocapsid
T-Cell Surface
22
HIV-1 Tropism AssaysMT-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.
200420111-126. 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.
199165356-363. Japour AJ. J Clin Microbiol.
1994322291-2294.
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HIV-1 Tropism AssaysRecombinant 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
• gt500 copies/mL
• May fail to detect X4 when X4 virus constitutes
  lt10 of the viral population
• Sequence variation may result in assay failure

Coakley E, et al. Curr Opin Infect Dis.
2005189-15.
25
HIV entry cell assay
Adapted from Petropoulos CJ et al. Antimicrob
Agents Chemother 200044920-8.
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R5 and X4 VariantsHIV Disease Progression
Absolute Viral Load
R5
X4 Limit of Detection
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry.
200514-16. Moore JP, et al. AIDS Res Hum
Retroviruses. 200420111-126.
27
R5 and X4 VariantsHIV Disease Progression
Absolute Viral Load
R5
X4 Limit of Detection
X4
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry.
200514-16. Moore JP, et al. AIDS Res Hum
Retroviruses. 200420111-126.
28
R5 and X4 VariantsHIV Disease Progression
R5 X4 Infection
Absolute Viral Load
R5
X4
X4 Limit of Detection
Weeks
Years
Time After HIV Transmission
Kuhmann SE, et al. J Viral Entry.
200514-16. Moore JP, et al. AIDS Res Hum
Retroviruses. 200420111-126.
29
R5 and X4 Viruses TargetDifferent Subsets of
CD4 T-Cells
R5 Infection (common, early)
Naïve T-Cells
Relative CD4 Cell Counts
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.
200321265-304. Kuhmann SE, et al. J Viral
Entry. 200514-16.
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R5 and X4 Viruses TargetDifferent Subsets of
CD4 T-Cells
R5 Infection (common, early)
Naïve T-Cells
Relative CD4 Cell Counts
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.
200321265-304. Kuhmann SE, et al. J Viral
Entry. 200514-16.
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Will a CCR5 Antagonist Drive the Emergence of X4
Viruses In Vivo?
Scenario 1
CCR5 Antagonist
R5
Absolute Viral Load
X4 Threshold of Detection
X4
Time (days)
R5 viruses remain suppressed X4 viruses do not
expand
32
Will a CCR5 Antagonist Drive the Emergence of X4
Viruses In Vivo?
Scenario 1
CCR5 Antagonist
R5
Absolute Viral Load
X4 Threshold of Detection
X4
Time (days)
R5 viruses remain suppressed X4 viruses do not
expand
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Scenario 3Partial Expansion of the X4 Virus Pool
Scenario 3
CCR5 Antagonist
R5
X4
Absolute Viral Load
X4 Threshold of Detection
Time (days)
R5 viruses remain suppressed Sustained, partial
expansion of X4 virus pool
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Prevalence ofHIV Co-Receptor Usage
Prevalence of Usage () Prevalence of Usage () Prevalence of Usage ()
R5 X4 R5 X4
Fätkenheuer (n116)1 94 0 6
Brumme (n979)2 82 lt1 18
Moyle (n563)3 85 lt1 15
Demarest (n299)4 88 0 12
Whitcomb (n612)5 62 4 34

1Fätkenheuer G, et al. Nat Med.
2005111170-1172. 2Brumme ZL, et al. J Infect
Dis. 2005192466-474. 3Moyle GJ, et al. J Infect
Dis. 2005191866-872. 4Demarest J, et al. 44th
ICAAC. Washington, DC, 2004. Abstract
H-1136. 5Whitcomb JM, et al. 10th CROI. Boston,
2003. Abstract 557.
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CCR5 Use by Baseline CD4 and HIV RNA
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CCR5- a drugable target?
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?32 inhibition of coreceptor-mediated entry
Huang Y, et al. Nature Med 1996
212401243.Michael NL, et al. Nature Med 1997
311601162.Eugen-Olsen J, et al. AIDS 1997
11305310.
Lui R, et al. Cell 1996 86367377.Samson M, et
al. Nature 1996 382722725.Dean M, et al.
Science 1996 27318561862.
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Drug development
Designer Drugs
SAR
HIV inhibition
High-throughputin vitro testing
Normalfunction
CCR5
CXCR4
crystallography
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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

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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 a1-4
• 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 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. 2003107431-438. 2Philpo
tt S, et al. J Clin Invest. 2001107451-458. 3Equ
ils O, et al. J Infect Dis. 2000182751-757. 4Van
Rij RP, et al. J Virol. 2000763054-3058. 5Demar
est J, et al. 44th ICAAC. Washington, DC, 2004.
Abstract H-1136. 6Sheppard HW, et al. AIDS.
200229307-313.
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Data summary
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CCR5 AntagonistsPotential 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?

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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
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Diflucan Partnership Program

• Donation of Diflucan (fluconazole) and training
  of health care providers
• 22 countries (915facilities) 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 first of, we
hope, many other successful public/private
partnerships initiated by parties who have
demonstrated that they care enough to act. Dr.
Manto Tshabalala-Msimang, Minister of Health,
South Africa
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(No Transcript)
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International Trachoma Initiative

• Public-private partnership focused on
  eliminating blinding trachoma
• The worlds 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

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

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A Leading Corporate Giver
700
Product Giving
600
Cash Giving
500
400
( Millions)
300
200
100
0
Merck
Pfizer
BMS
JJ
Microsoft
Wal-
IBM
Altria
Ford
Intel
Mart
Motor
Source Chronicle of Philanthropy, 7/24/2003