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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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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

  • 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


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

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

  • 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

  • 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


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.


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

  • 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


= 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


Attrition on the R&D Process

1

Medicine


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


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


Co receptor Drug Development


CCR5 and CXCR4 Co-Receptors:HIV Binding and Entry

CD4

CXCR4

CCR5

T-Cell Surface


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

HIV-1

gp41

gp120

CD4

CCR5

T-Cell Surface


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

HIV-1

gp41

gp120

CD4

CCR5

T-Cell Surface


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

  • 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

    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

    • 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.


    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 Infection

    R5 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 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 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 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.


    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?

    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 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

    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 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.


    CCR5- a drugable target?


    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

    Designer Drugs

    SAR

    HIV inhibition

    High-throughputin vitro testing

    Normalfunction

    CCR5

    CXCR4

    crystallography


    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

    SCH-CQT

    AMD-3100cardiac abnormalities but stem cell mobilization

    ALX 404 Cno oral formulation

    TAK 779toxicity at injection sites

    Aplavirochepatic side effects


    Using CCR 5 antagonists

    Tropism shift


    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.


    Data summary


    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

    • 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

    • Noninferiority proven

    • New class Unknown risks

    • Laboratory issues

    • ‘Superiority’ proven

    • Salvage – as part of last viable regimen

    • NRTI sparing

    • Substitution studies


    Pfizer philanthropy


    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

    • 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

    • $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

    • “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

    $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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