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

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
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.
9
Approved ARV Agents
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

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
14
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
16
CCR5 and CXCR4 Co-ReceptorsHIV Binding and Entry
CD4
CXCR4
CCR5
T-Cell Surface
17
HIV-1 Envelope Glycoproteins
HIV-1
gp41
gp120
HIV-1 Envelope Glycoprotein
CD4
CCR5
T-Cell Surface
18
Binding of the gp120 Subunit of the HIV-1
Envelope Glycoprotein to CD4
HIV-1
gp41
gp120
CD4
CCR5
T-Cell Surface
19
Conformational Change Exposes theCo-Receptor
Binding Site in gp120
HIV-1
gp41
gp120
CD4
CCR5
T-Cell Surface
20
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.
23
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.
24
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.
26
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.
30
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.
31
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
33
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
34
Prevalence ofHIV Co-Receptor Usage
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.
35
CCR5 Use by Baseline CD4 and HIV RNA
36
CCR5- a drugable target?
37
?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.
38
Drug development
Designer Drugs
SAR
HIV inhibition
High-throughputin vitro testing
Normalfunction
CCR5
CXCR4
crystallography
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 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.
43
Data summary
44
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?

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 (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
49
(No Transcript)
50
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

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
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