michael zaiac new product development 25/11/05

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Michael ZaiacNew Product Development

25/11/05

Drug Development in HIV

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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

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North Africa & Middle EastNorth Africa & Middle East540,000

92,000 28,000

Sub-Saharan AfricaSub-Saharan Africa25.4 million

3.1 million 2.3 million

Eastern Europe & Eastern Europe & Central AsiaCentral Asia 1.4 million 210,000 60,000

OceaniaOceania35,000

5000 700

North America and Western/Central EuropeNorth America and Western/Central Europe1.6 million

64,000 23,000

CaribbeanCaribbean440,000

53,000 36,000

AsiaAsia8.2 million

1.2 million 540,000

New cases, 2004: 4.9 million AIDS Deaths, 2004: 3.1 millionTotal living cases: 39.4 million

Latin AmericaLatin America1.7 million

240,000 95,000

UNAIDS/WHO, 2005

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

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1. Prevention of progressive immunodeficiency;potential maintenance or reconstruction of a normal immune system

2. Control of viral replication and mutation; reduceviral burden

Goals of Antiretroviral Treatment

Delayed progression to AIDS and prolongation of life

Decreased risk of selection of resistant virus

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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

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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

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Total plasma HIV RNAWild-type (WT) HIV RNAMutant HIV RNA

Havlir. Ann Int Med 1996:124:984.

Time Receiving Treatment

Pla

sma

HIV

RN

A

Emergence of HIV Resistance

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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

EnfuvirtideFusion Inhibitors

Protease Inhibitors Saquinavir, Indinavir, Ritonavir,

Nelfinavir, Amprenavir, Lopinavir/Ritonavir, Atazanavir

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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

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Requirements on HIV medicines

Ideal features of an antiretroviral agent:

- low dose

- convenient regimen

- better toleration

- non cross resistant

- new mechanisms & targets

- low COG

= compliance & durability

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Attrition on the R&D Process

1Medicine

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Candidate attrition

0

4

12

25N

o.

can

did

ates

0 1 2 3 4 5 6 7 8 9 YearsPreclin. Phase I Phase II Phase III Registration

animal toxicity,chemical stability,superior compound

animal toxicity,chemical stability,superior compound

Efficacy, safety,differentiation,Dose, c.o.g.

Efficacy, safety,differentiation,Dose, c.o.g.

human PK,tolerability,formulation

human PK,tolerability,formulation

long-term safetylong-term safetynon-approvalnon-approval

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New medicine development

1976 1986 1990 1997 2003

£30 million

£70 million

£200 million

£280 million

Medicine Development Costs Time/Cost of Medicine Development

Phase IPhase I

Phase IIPhase II

Phase IIIPhase III

FileFile

LaunchLaunch

Years

Cu

mu

lati

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ost

s £M

0

100

200

300

400

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0 1 2 3 4 5 6 7 8 9 10

£450 million

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Co receptor Drug Development

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CCR5 and CXCR4 Co-Receptors:HIV Binding and Entry

CCR5

CXCR4

T-Cell Surface

CD4

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HIV-1 Envelope Glycoproteins

CD4

CCR5

gp120

gp41

T-Cell Surface

HIV-1

HIV-1 HIV-1 Envelope Envelope

Glycoprotein Glycoprotein

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Binding of the gp120 Subunit of the HIV-1 Envelope Glycoprotein to CD4

HIV-1

T-Cell Surface

CD4

CCR5

gp120

gp41

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Conformational Change Exposes theCo-Receptor Binding Site in gp120

HIV-1

T-Cell Surface

CD4

CCR5

gp120

gp41

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Conformational Change Allows gp120 to Bind to the Co-Receptor

HIV-1

T-Cell Surface

CD4

CCR5

gp120

gp41

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Fusion of HIV and T-Cell Membranes

HIV-1

T-Cell Surface

HIV-1 Nucleocapsid

HIV-1 RNA

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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.

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MT2 cell assay

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.

Syncytium Formation in MT-2 Cells

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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 failureCoakley E, et al. Curr Opin Infect Dis. 2005;18:9-15.

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HIV entry cell assay

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

Transfection

HIV envexpression

vector++++

HIV genomicluc vector

CD4 +CCR5 +

CD4 +CXCR4 +

Infection

Pseudovirus

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R5 and X4 Variants:HIV Disease ProgressionR5 and X4 Variants:HIV Disease Progression

Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.Moore JP, et al. AIDS Res Hum Retroviruses. 2004;20:111-126.

Ab

so

lute

Vir

al L

oa

dA

bs

olu

te V

ira

l Lo

ad

Time After HIV Transmission Weeks Years

X4 Limit of Detection

R5

R5 Infection

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Ab

so

lute

Vir

al L

oa

dA

bs

olu

te V

ira

l Lo

ad



R5

R5 Infection

X4

R5 Infection

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Ab

so

lute

Vir

al L

oa

dA

bs

olu

te V

ira

l Lo

ad



R5

R5 InfectionX4X4

R5 + X4 InfectionR5 Infection

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R5 and X4 Viruses TargetDifferent Subsets of CD4+ T-Cells

Douek DC, et al. Douek DC, et al. Ann Rev Immunol. Ann Rev Immunol. 2003;21:265-304.2003;21:265-304.Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.

R5 Infection(common, early)

R5 viruses target memory T-cells(eg, GALT)

Naïve T-cells become targets once activated to the memory phenotype

Rel

ati

ve

CD

4 C

ell

Co

un

ts

Time (y)

Memory T-Cells

Naïve T-Cells

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R5 and X4 Viruses TargetDifferent Subsets of CD4+ T-Cells

Douek DC, et al. Douek DC, et al. Ann Rev Immunol. Ann Rev Immunol. 2003;21:265-304.2003;21:265-304.Kuhmann SE, et al. J Viral Entry. 2005;1:4-16.

R5 Infection(common, early)

R5 viruses target memory T-cells(eg, GALT)

Naïve T-cells become targets once activated to the memory phenotype

Rel

ati

ve

CD

4 C

ell

Co

un

ts

Time (y)

Memory T-Cells

Naïve T-Cells

X4 InfectionX4 Infection(very rare)(very rare)

X4 viruses target naive T-cellsX4 viruses target naive T-cells(eg, thymus)(eg, thymus)

CXCR4 expression on some memory CXCR4 expression on some memory cells makes them targetscells makes them targets

Rel

ati

ve

CD

4 C

ell

Co

un

tsR

ela

tiv

e C

D4

Cel

l C

ou

nts

Time (y)Time (y)

NaïveNaïve T-CellsT-Cells

MemoryMemory T-CellsT-Cells

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Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo?

Scenario 1Scenario 1

R5 viruses remain suppressedR5 viruses remain suppressed

X4 viruses do not expandX4 viruses do not expand

Ab

solu

te V

iral

Lo

adA

bso

lute

Vir

al L

oad

Time (days)Time (days)

CCR5CCR5AntagonistAntagonist

X4 ThresholdX4 Thresholdof Detectionof Detection

R5R5

X4X4

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Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo?



X4 viruses do not expandX4 viruses do not expand

Ab

solu

te V

iral

Lo

adA

bso

lute

Vir

al L

oad




R5R5

X4X4



Sustained, possible reciprocal Sustained, possible reciprocal expansion of X4 virus poolexpansion of X4 virus pool

Vir

al L

oad

Vir

al L

oad




R5R5X4X4

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Scenario 3:Partial Expansion of the X4 Virus Pool


Sustained, partial expansionSustained, partial expansionof X4 virus poolof X4 virus pool

Ab

solu

te V

iral

Lo

adA

bso

lute

Vir

al L

oad




R5R5

X4X4


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Prevalence ofHIV Co-Receptor Usage

Prevalence of Usage (%)

R5 X4 R5 + X4

Fätkenheuer (n=116)1 94 0 6

Brumme (n=979)2 82 <1 18

Moyle (n=563)3 85 <1 15

Demarest (n=299)4 88 0 12

Whitcomb (n=612)5 62 4 34

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.

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CCR5- a drugable target?

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Δ32 inhibition of coreceptor-mediated entry

Δ32 CCR5 WT CCR5

< 20% ~ 80%< 1.5%

Delayed progression Normal progression(Essentially) no progression

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.

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.

0 2 4 6 8 10 18 200

20

40

60

80

% A

IDS

fre

e

Years since seroconversion

100

12 14 16

n = 39

n = 110

Genotype +/+

Genotype +/∆32

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Drug development

crystallography

SAR Designer Drugs

High-throughputin vitro testing

HIV inhibition

NormalfunctionCCR5 CXCR4

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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

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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

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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 326

• 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.

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Data summary

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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

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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 (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 Diflucan Partnership is “the first of, we hope, many “the first of, we hope, many other successful public/other successful public/private partnerships initiated private partnerships initiated by parties who have by parties who have demonstrated that they care demonstrated that they care enough to act.”enough to act.”

—— Dr. Manto Tshabalala-Msimang,Dr. Manto Tshabalala-Msimang,Minister of Health, South AfricaMinister of Health, South Africa

The Diflucan Partnership is The Diflucan Partnership is “the first of, we hope, many “the first of, we hope, many other successful public/other successful public/private partnerships initiated private partnerships initiated by parties who have by parties who have demonstrated that they care demonstrated that they care enough to act.”enough to act.”

—— Dr. Manto Tshabalala-Msimang,Dr. Manto Tshabalala-Msimang,Minister of Health, South AfricaMinister of Health, South Africa

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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

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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

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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

Source: Chronicle of Philanthropy, 7/24/2003

$0

$100

$200

$300

$400

$500

$600

$700

($ M

illio

ns)

Merck Pfizer BMS J&J Microsoft Wal-Mart

IBM Altria FordMotor

Intel

Product Giving

Cash Giving

michael zaiac new product development 25/11/05

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