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Drug Development in HIV. Michael Zaiac New Product Development 25/11/05. Contents. Background-Setting the scene Co receptors and HIV Co-receptor tropism Co-receptors as targets Philanthropy Summary. No Sign of Pandemic Abating. Issues No vaccines on horizon

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slide1
Drug Development in HIV

Michael Zaiac

New Product Development

25/11/05

contents
Contents
  • Background-Setting the scene
  • Co receptors and HIV
    • Co-receptor tropism
    • Co-receptors as targets
  • Philanthropy
  • Summary
no sign of pandemic abating
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

slide4
Eastern Europe &

Central Asia

1.4 million

210,00060,000

North America and Western/Central Europe

1.6 million

64,000 23,000

North Africa & Middle East

540,000

92,00028,000

Asia

8.2 million

1.2 million540,000

Caribbean

440,000

53,000 36,000

Sub-Saharan Africa

25.4 million

3.1 million2.3 million

Latin America

1.7 million

240,00095,000

Oceania

35,000

5000700

Total living cases: 39.4 million

New cases, 2004: 4.9 million AIDS Deaths, 2004: 3.1 million

Estimated Number of People Living With HIV, by Region in 2004

UNAIDS/WHO, 2005

goals of antiretroviral treatment
Goals of Antiretroviral Treatment

1. Prevention of progressive immunodeficiency;potential 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

anti retroviral therapy
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

genetic plasticity
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
slide8
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 1996:124:984.

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

Enfuvirtide

Fusion Inhibitors

Protease Inhibitors

Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir/Ritonavir, Atazanavir

Approved ARV Agents
problems with haart
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

requirements on hiv medicines
= compliance

& durability

Requirements on HIV medicines

Ideal features of an antiretroviral agent:

- low dose

- convenient regimen

- better toleration

- non cross resistant

- new mechanisms & targets

- low COG

candidate attrition
Years

0

1

2

3

4

5

6

7

8

9

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

new medicine development
0

1

2

3

4

5

6

7

8

9

10

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

hiv 1 envelope glycoproteins
HIV-1 Envelope Glycoproteins

HIV-1

gp41

gp120

HIV-1

Envelope

Glycoprotein

CD4

CCR5

T-Cell Surface

binding of the gp120 subunit of the hiv 1 envelope glycoprotein to cd4
Binding of the gp120 Subunit of the HIV-1 Envelope Glycoprotein to CD4

HIV-1

gp41

gp120

CD4

CCR5

T-Cell Surface

conformational change exposes the co receptor binding site in gp120
Conformational Change Exposes theCo-Receptor Binding Site in gp120

HIV-1

gp41

gp120

CD4

CCR5

T-Cell Surface

conformational change allows gp120 to bind to the co receptor
Conformational Change Allows gp120 to Bind to the Co-Receptor

HIV-1

gp41

gp120

CD4

CCR5

T-Cell Surface

fusion of hiv and t cell membranes
Fusion of HIV and T-Cell Membranes

HIV-1 RNA

HIV-1

HIV-1 Nucleocapsid

T-Cell Surface

hiv 1 tropism assays mt 2 cell assay
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.

mt2 cell assay
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.

hiv 1 tropism assays recombinant phenotypic assays
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.

hiv entry cell assay
CD4 +

CXCR4 +

HIV env

expression

vector

HIV genomic

luc vector

+

Infection

Transfection

Pseudovirus

CD4 +

CCR5 +

HIV entry cell assay

Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother 2000;44:920-8.

r5 and x4 variants hiv disease progression
R5 InfectionR5 and X4 Variants:HIV Disease Progression

Absolute Viral Load

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.

r5 and x4 variants hiv disease progression1
R5 Infection

R5 Infection

R5 and X4 Variants:HIV Disease Progression

Absolute Viral Load

R5

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.

r5 and x4 variants hiv disease progression2
R5 Infection

R5 Infection

R5 and X4 Variants:HIV 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. 2005;1:4-16.

Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.

r5 and x4 viruses target different subsets of cd4 t cells
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. 2003;21:265-304.

Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.

r5 and x4 viruses target different subsets of cd4 t cells1
X4 Infection

(very rare)

Memory

T-Cells

Relative CD4 Cell Counts

Naïve

T-Cells

Time (y)

X4 viruses target naive T-cells

(eg, thymus)

CXCR4 expression on some memory cells makes them targets

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. 2003;21:265-304.

Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.

will a ccr5 antagonist drive the emergence of x4 viruses in vivo
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

will a ccr5 antagonist drive the emergence of x4 viruses in vivo1
Scenario 2

CCR5

Antagonist

R5

X4

Viral Load

X4 Threshold

of Detection

Time (days)

R5 viruses remain suppressed

Sustained, possible reciprocal expansion of X4 virus pool

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

scenario 3 partial expansion of the x4 virus pool
Scenario 3:Partial 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

prevalence of hiv co receptor usage
Prevalence ofHIV Co-Receptor Usage

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.

32 inhibition of coreceptor mediated entry
Δ32 CCR5

WT CCR5

< 1.5%

< 20%

~ 80%

Delayed progression

Normal progression

(Essentially) no progression

100

80

Genotype +/+

Genotype +/∆32

60

% AIDS free

40

n = 39

20

n = 110

0

0

2

4

6

8

10

12

14

16

18

20

Years since seroconversion

Δ32 inhibition of coreceptor-mediated entry

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.

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
Drug development

Designer Drugs

SAR

HIV inhibition

High-throughputin vitro testing

Normalfunction

CCR5

CXCR4

crystallography

unknown effects of entry inhibitors
Unknown effects of entry inhibitors

Normal Function

natural ligand

allosteric inhibition by drug

Internalisationof receptor

? Normal function

? Internalisation

of receptor

Viral mutations overcome

some co receptor antagonists have fallen by the wayside
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

impact of current antiretroviral agents on r5 and x4 virus dynamics
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 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.

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.

ccr5 antagonists potential advantages
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
challenges in ccr5 antagonist use
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?
possible scenarios
Possible scenarios
  • Noninferiority proven
  • New class Unknown risks
  • Laboratory issues
  • ‘Superiority’ proven
  • Salvage – as part of last viable regimen
  • NRTI sparing
  • Substitution studies
diflucan partnership program
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 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

international trachoma initiative
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
infectious diseases institute
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
pfizer global health fellows
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
a leading corporate giver
A Leading Corporate Giver

$700

Product Giving

$600

Cash Giving

$500

$400

($ Millions)

$300

$200

$100

$0

Merck

Pfizer

BMS

J&J

Microsoft

Wal-

IBM

Altria

Ford

Intel

Mart

Motor

Source: Chronicle of Philanthropy, 7/24/2003

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