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CELERA From a genomic platform to a product-development company

February 9, 2007. CELERA From a genomic platform to a product-development company. Cécile DUVAL Céline DELPLACE Céline LANTOIN Pauline SALADIN. Safe Harbor

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CELERA From a genomic platform to a product-development company

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  1. February 9, 2007 CELERA From a genomic platform to a product-development company Cécile DUVAL Céline DELPLACE Céline LANTOIN Pauline SALADIN

  2. Safe Harbor • This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques de Lille • The opinions expressed are our own and not necessarily those of Celera

  3. THE ACTORS APPLERA CORPORATION Celera Genomics Applied Biosystems www.celera genomics.com

  4. Financial situation in 2006

  5. Plan • Part I : A genomic platform • Part II : Evolution to a product-development company • Part III : Activities & pipeline • Part IV : Partners network • Part V : Careers in Celera • Part VI: Our vision of Celera in coming years

  6. Part IA genomic platform

  7. HUMAN GENOME PROJECT 1988 HUGO: Human Genome Organisation Aim = sequencing the human genome the most rapidly as possible to avoid patents from private companies 1990 Starting signal of the human genome sequencing is given by the USA ⇨HGP: Human Genome Project Co-financing : - NIH National Institutes of Health - Department of energy(DOE) Are joined by France, Germany, Japan and China ec.europa.eu, research, RDT info 27

  8. HUMAN GENOME PROJECT 1992 The U.K. launch into the project Financing: Foundation Wellcome Trust • Problem of organization • Database complex to stock • Sequencing methods: must be faster and cheaper www.genoscope.fr

  9. CELERA HISTORY 1998 Creation of Celera Genomics Foundation: Applera Corporation + Craig Venter Primary mission • sequencing and assembling the human genome within 2001 • budget of 200 to 250 millions $ (-1/10 than HGP’s one) ⇨ database business (one year access = 5millions euros) ⇨ genes which can be useful are patent HGP reaction: draft of the human genome is announced for 2000 thanks to an increase of 60.5 millions $ of the budget ec.europa.eu, research, RDT info 27

  10. CELERA HISTORY 1999 Recapitalization⇨ creation of 2 subsidiary companies Applied Biosystems • Headquater: Foster City, California • Developing and marketing: -instrument-based systems -consumables, software, services ⇨ Tools for genome sequencing Celera Genomics • Headquater: Rockville,Maryland • Genomics and proteomics discovery platforms www.celera genomics.com

  11. CELERA HISTORY 2000 March - Drosophila sequence published by Celera - Common declaration of Bill Clinton and Tony Blair June - Celera announces completion of its first draft of the human genome…but:  probably used HGP database  financial obligation (stocks)  negociation between Celera and HGP failed (2nd competition: sequencing the human proteom!) www.celera genomics.com

  12. CELERA HISTORY Celera announces completion of its first draft of the human genome

  13. CELERA HISTORY 2001 february - publication of Celera’s human genome paper in Science april - Celera completes first assembly of the mouse genome www.celera genomics.com

  14. HGP strategy: « Clone by clone » or « Hierarchical shotgun sequencing » • 1st step : BAC library • Extraction of human genomic DNA • DNA is cut into pieces (150Mb) • Insertion into BAC vectors • Transformed into E.Coli where they are replicated • clones www.genoscope.fr www.bio.davidson.edu Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)

  15. HGP strategy: « Clone by clone » or « Hierarchical shotgun sequencing » • 2nd step : physical map • BAC inserts are isolated and mapped • Search for markers • Determination of the order of each cloned fragment / genome • Physical map www.genoscope.fr www.bio.davidson.edu Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)

  16. HGP strategy: « Clone by clone » or « Hierarchical shotgun sequencing » • 3rd step : Sequencing (shotgun type) • BAC fragments are fragmented randomly into smaller pieces • Each smaller piece is cloned into a plasmid and sequenced on both strands • These sequences are aligned so that identical sequences are overlapping • These contiguous pieces are assembled into finished sequence www.genoscope.fr www.bio.davidson.edu Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)

  17. Celera strategy :« Whole genome shotgun » • One step : • Extraction of human genomic DNA • DNA is cut into smaller pieces (2-10Mb / 150Mb) • Smaller pieces are cloned randomly into a plasmid and sequenced on both strands ⇨ some fragments are « lost » • These fragments are aligned and assembled into finished sequence, based on overlapping sequences ⇨ Elimination of BAC step and physical map

  18. Celera strategy :the limits…  repetitive sequences www.ncbi.nlm.nih.gov

  19. Celera strategy :the limits…  overlap detection Notion of « coverage » = average number of reads representing a given nucleotide in the reconstructed sequence Ex: « 10X coverage » = each base in the final sequence was present, on average, in 10 reads www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)

  20. Celera strategy :the limits…  Matter of linking: some « gaps » can still remain The goal is to select « good » overlapping pairs and lay them out into larger contigs: « contiguous regions » ⇓ We have to order these contigs ⇓ Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)

  21. Which method is better ?

  22. Part II Evolution to a product-development company • Why ? • How? • Targeted Medicine • The New Business Model

  23. Why ? Database business model : Technological platform • Limited markets • Fast but poor near-term profit • Free access to genome sequences

  24. Why ? Annual Report 2002

  25. Why ? Annual Report 2002

  26. Why ? Database business model : Technological platform • Limited markets • Fast but poor near-term profit • Free access to genome sequences 1. Celera Diagnostics 2. Axys Pharmaceuticals New business model : Product-development company • Bigger markets • More important revenues • Easier access to alliances

  27. How ?1. Celera Diagnostics Presentation • Creation : april 2001 • 50/50 joint-venture between Celera Genomics and Applied Biosystems • Director : Kathy Ordonez • Strategic Alliance with Abbott Laboratories (development and distribution)

  28. How ?1. Celera Diagnostics Activities • Industrial-scale study variations : SNPs (Database : 150000 specimens, 30000 SNPs) • Genotyping, gene expression • New genetic markers • Genetic tests, In Vitro Diagnostic products • Therapeutic targets (targeted medicine) Diseases • Auto-immune diseases • Cardiovascular diseases • Alzheimer’s disease • Infectious diseases • Cancers

  29. How ? 2. Axys Pharmaceuticals Presentation • Acquisition : november 2001 • Drug discovery and development company Activities • Programs and expertise in medicinal chemistry, in biology, screening and structure-based design (protease inhibitors) • Pipeline of preclinical small molecules • Chronic diseases • Chemical libraries and facilities • Most of the drugs in development in Celera’s pipeline are from Axys’ program at the acquisition

  30. Targeted Medicine

  31. Targeted medicine = Pharmacogenomics Molecular diagnostic tests DISEASE Genomic SNPs Therapeutic targets

  32. Targeted medicine : Why? Consequences on therapeutics • Improving current response rates1: • Alzheimer’s Disease : 30% • Osteoporosis : 48% • HCV : 47% • Rheumatoid arthritis : 50% • Cancer : 25% • Recent Targeted Medicine Example: Gleevec for CML : 60%2 • Avoiding adverse drug reactions3: • 2 million ADRs / 2.8 billion prescriptions (>100,000 deaths) • cost : ~$1.3 billion • Reuse of drugs in eligible population 1 Spear, Heath-Chiozzi and Huff, Trends in Mol Med 7, 201 (2001). 2 N Engl J Med, 348 (11),1048 (2003). 3 Lazarou et al., JAMA, 279, 15 (1998).

  33. Development cost Development cost Time Time Targeted medicine = Pharmacogenomics Consequences on development • Stratified population => smaller and more consistent clinical trial population =>improvement • Sooner marketing • LESS COSTS www.celera.com

  34. New business model History • January 2002 : Dr. J. Craig Venter • steps down as President of Celera Genomics • April 2002 : Kathy Ordoñez appointed President of • Celera Genomics New mission : « To build a valuable portfolio of preclinical and clinical therapeutics » • December 2002 : announcement of Celera Genomics’ new strategy

  35. New business model Genome sequences Products + Axys Pharmaceuticals Celera Genomics Knowledge Partners R&D Cash Cash Celera Diagnostics Applied Biosystems Small molecules Antibodies Out licensing Thèse Zoé Verhasselt

  36. Part IIIActivities & pipeline Celera genomics Celera diagnostic

  37. Celera genomics • Chemical molecules acquired with Axys • Proteomic and genomic research

  38. Pipeline in 2005 Axys

  39. An exemple of a small molecule acquired with Axys Histone desacetylase inhibitors (HDACi)

  40. HDACi: histone desacetylase inhibitors Lysine

  41. Targets of HDAC: histones HAT HDAC Lysine: NH3+ Lysine: NH-CO-CH3 Transcriptional repression Transcriptional activation Cancer HDAC inhibitors Chromatin Remodeling and Leukemia: New Therapeutic Paradigms By Robert L. Redner, JianxiangWang, and Johnson M. Liu

  42. Apoptosis Anticancer activities of histone deacetylase inhibitors Jessica E. Bolden, Melissa J. Peart and Ricky W. Johnstone

  43. Some competitors • Companies: • Merck • Schering AG • Methylgene • Novartis • Etc…

  44. Results from proteomic and genomic research Generalities Some examples

  45. Clinical genomic and proteomic Differences between sequence of genes Differences of gene expression: RNA Differences of proteins

  46. Celera genomics: structural genomic Sequence of gene Sequence of RNA Sequence of protein Structure of protein Find the function of the protein Discover new ligands

  47. New markers of cancer • Differentially expressed proteins found in multiple cancers provide clues to disease development Target selection Collaboration with Medarex to discover fully human antibodies for the potential treatment of multiple indications cancer

  48. New markers of autoimmune disease • Identification of SNP in a cytoplasmic tyrosine phosphatase gene (PTPN22) associated with certain autoimmune conditions Lead optimization of chemicals that target the protein coding by this SNP.

  49. Celera diagnostic Diagnostic tools Diseases markers

  50. Genetic and Infectious diseases • Cystic fibrosis: mutation identification • HCV: genotyping, viral load, and progression (HCV liver fibrosis GenotypR™) • HIV: genotyping (Viroseq™) and viral load of HIV 1 • Etc…

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