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Drug Development in HIV Michael Zaiac New Product Development 25/11/05 1 Contents Background-Setting the scene Co receptors and HIV • Co-receptor tropism • Co-receptors as targets Philanthropy Summary 2 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 3 Estimated Number of People Living With HIV, by Region in 2004 Eastern Europe & Central Asia North America and Western/Central Europe 1.4 million 1.6 million 210,000 60,000 64,000 23,000 Caribbean 440,000 53,000 36,000 Latin America 1.7 million 240,000 95,000 North Africa & Middle East 540,000 92,000 28,000 Sub-Saharan Africa 25.4 million Asia 8.2 million 1.2 million 540,000 3.1 million 2.3 million Oceania 35,000 5000 700 Total living cases: 39.4 million New cases, 2004: 4.9 million AIDS Deaths, 2004: 3.1 million UNAIDS/WHO, 2005 4 Goals of Antiretroviral Treatment 1. Prevention of progressive immunodeficiency; potential maintenance or reconstruction of a normal immune system Delayed progression to AIDS and prolongation of life 2. Control of viral replication and mutation; reduce viral burden Decreased risk of selection of resistant virus 5 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 6 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 7 Emergence of HIV Resistance Plasma HIV RNA Total plasma HIV RNA Wild-type (WT) HIV RNA Mutant HIV RNA Time Receiving Treatment Havlir. Ann Int Med 1996:124:984. 8 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 Fusion Inhibitors Enfuvirtide Protease Inhibitors Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir/Ritonavir, Atazanavir 9 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 10 Requirements on HIV medicines Ideal features of an antiretroviral agent: - low dose - convenient regimen - better toleration - non cross resistant - new mechanisms & targets - low COG 11 = compliance & durability Attrition on the R&D Process 1 Medicine 12 Candidate attrition 25 No. candidates animal toxicity, chemical stability, superior compound human PK, tolerability, formulation 12 Efficacy, safety, differentiation, Dose, c.o.g. long-term safety non-approval 4 0 0 1 2 Preclin. Phase I 3 4 5 Phase II 6 Phase III 13 7 8 9 Years Registration New medicine development Medicine Development Costs Time/Cost of Medicine Development Launch £450 million File 500 400 Cumulative costs £M £280 million £200 million £70 million Phase III 300 Phase I 200 Phase II 100 £30 million 0 1976 1986 1990 1997 0 2003 1 2 3 4 5 Years 14 6 7 8 9 10 Co receptor Drug Development 15 CCR5 and CXCR4 Co-Receptors: HIV Binding and Entry CD4 CXCR4 CCR5 T-Cell Surface 16 HIV-1 Envelope Glycoproteins HIV-1 gp41 gp120 HIV-1 Envelope Glycoprotein CD4 CCR5 T-Cell Surface 17 Binding of the gp120 Subunit of the HIV-1 Envelope Glycoprotein to CD4 HIV-1 gp41 gp120 CD4 CCR5 T-Cell Surface 18 Conformational Change Exposes the Co-Receptor Binding Site in gp120 HIV-1 gp41 gp120 CD4 CCR5 T-Cell Surface 19 Conformational Change Allows gp120 to Bind to the Co-Receptor HIV-1 gp41 gp120 CD4 CCR5 T-Cell Surface 20 Fusion of HIV and T-Cell Membranes HIV-1 RNA HIV-1 HIV-1 Nucleocapsid T-Cell Surface 21 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. 22 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. 23 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. 24 HIV entry cell assay CD4 + CXCR4 + HIV env HIV genomic expression luc vector vector + Transfection Infection Pseudovirus CD4 + CCR5 + Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother 2000;44:920-8. 25 R5 and X4 Variants: HIV Disease Progression Absolute Viral Load R5 Infection 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. 26 R5 and X4 Variants: HIV Disease Progression Absolute Viral Load R5 Infection R5 R5 Infection 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. 27 R5 and X4 Variants: HIV Disease Progression Absolute Viral Load R5 Infection R5 + X4 Infection R5 X4 R5 Infection 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. 28 R5 and X4 Viruses Target Different Subsets of CD4+ T-Cells R5 Infection Relative CD4 Cell Counts (common, early) Naïve T-Cells 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. 29 R5 Infection X4 Infection (common, early) (very rare) Relative CD4 Cell Counts Relative CD4 Cell Counts R5 and X4 Viruses Target Different Subsets of CD4+ T-Cells Naïve T-Cells Memory T-Cells Time (y) Memory T-Cells Naïve T-Cells Time (y) R5 viruses target memory T-cells (eg, GALT) X4 viruses target naive T-cells (eg, thymus) Naïve T-cells become targets once activated to the memory phenotype CXCR4 expression on some memory cells makes them targets Douek DC, et al. Ann Rev Immunol. 2003;21:265-304. Kuhmann SE, et al. J Viral Entry. 2005;1:4-16. 30 Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo? Scenario 1 Absolute Viral Load CCR5 Antagonist R5 X4 Threshold of Detection X4 Time (days) R5 viruses remain suppressed X4 viruses do not expand 31 Will a CCR5 Antagonist Drive the Emergence of X4 Viruses In Vivo? Scenario 1 Scenario 2 CCR5 Antagonist R5 R5 Viral Load Absolute Viral Load CCR5 Antagonist X4 X4 Threshold of Detection X4 Threshold of Detection X4 Time (days) Time (days) R5 viruses remain suppressed R5 viruses remain suppressed X4 viruses do not expand Sustained, possible reciprocal expansion of X4 virus pool 32 Scenario 3: Partial Expansion of the X4 Virus Pool Scenario 3 Absolute Viral Load CCR5 Antagonist R5 X4 X4 Threshold of Detection Time (days) R5 viruses remain suppressed Sustained, partial expansion of X4 virus pool 33 Prevalence of HIV Co-Receptor Usage Prevalence of Usage (%) R5 X4 R5 + X4 94 0 6 82 <1 18 85 <1 15 88 0 12 62 4 34 Fätkenheuer (n=116)1 Brumme (n=979)2 Moyle (n=563)3 Demarest (n=299)4 Whitcomb (n=612)5 1Fätkenheuer G, et al. Nat Med. 2005;11:1170-1172. 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. 2Brumme 34 CCR5- a drugable target? 36 Δ32 inhibition of coreceptor-mediated entry Δ32 CCR5 < 1.5% WT CCR5 < 20% ~ 80% Delayed progression (Essentially) no progression Normal progression 100 % AIDS free 80 Genotype +/+ Genotype +/∆32 60 40 n = 39 n = 110 20 0 0 2 4 6 8 10 12 14 16 18 20 Years since seroconversion 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. 37 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 SAR High-throughput in vitro testing CCR5 CXCR4 crystallography 38 Designer Drugs HIV inhibition Normal function Unknown effects of entry inhibitors Normal Function natural ligand allosteric inhibition by drug Internalisation of receptor ? Normal function ? Internalisation of receptor Viral mutations overcome 39 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 40 Tropism shift Using CCR 5 antagonists 41 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 cohorts 5 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. 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. 2Philpott 42 Data summary 43 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 44 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? 45 Possible scenarios Noninferiority proven New class Unknown risks Laboratory issues ‘Superiority’ proven Salvage – as part of last viable regimen NRTI sparing Substitution studies 46 Pfizer philanthropy 47 Diflucan Partnership Program Donation of Diflucan (fluconazole) and training of health care providers 22 countries (915+facilities) in Africa, Asia and Caribbean participating 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.” 67,000 patients treated for HIV-related fungal opportunistic infections More than 18,000 health care professionals trained — Dr. Manto Tshabalala-Msimang, Minister of Health, South Africa 48 49 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 50 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 51 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 52 A Leading Corporate Giver $700 Product Giving $600 Cash Giving ($ Millions) $500 $400 $300 $200 $100 $0 Merck Pfizer BMS J&J Microsoft Source: Chronicle of Philanthropy, 7/24/2003 53 WalMart IBM Altria Ford Motor Intel