Drug Development in HIV
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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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Michael zaiac new product development 25 11 05

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


Michael zaiac new product development 25 11 05

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


Michael zaiac new product development 25 11 05

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


Michael zaiac new product development 25 11 05

Attrition on the R&D Process

1

Medicine


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


Co receptor drug development

Co receptor Drug Development


Ccr5 and cxcr4 co receptors hiv binding and entry

CCR5 and CXCR4 Co-Receptors:HIV Binding and Entry

CD4

CXCR4

CCR5

T-Cell Surface


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 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 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.


    Ccr5 a drugable target

    CCR5- a drugable target?


    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-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

    Using CCR 5 antagonists

    Tropism shift


    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.


    Data summary

    Data summary


    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


    Pfizer philanthropy

    Pfizer philanthropy


    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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