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March 19, 2009 Philippe Breton- Marie Delattre- Hélène Delvert- Juliette Morawiec Monogram Bisociences-Overview 3 Biotechnology company founded in 1995 Based in San Francisco Molecular diagnosis in HIV and Oncology Clinical Reference Laboratory –CLIA Accredited CLIA - Clinical Laboratory Improvement Amendments 4 Regulates all laboratory testing performed on humans in the U.S through CLIA Ensure quality laboratory testing since 1988 Mission 5 “To improve healthcare by advancing individualized medicine through the discovery and commercialization of innovative products to guide and improve the treatment of HIV, cancer and other serious diseases.” Overview 6 382 employees: 70% research employees primarily focus on oncology programs 2008 revenues : 62,193 m$ How it all started…. 7 1995 based in San Francisco Base Business in HIV Dec 2004 : Merged Expansion to Oncology Sept 2005 Opportunites Throughout the Continuum 8 Partners of Choice 9 2000 2002 2005 2008 10 JP Morgan Healthcare Conference, January 2009 Tests Drugs HIV drug resistance Tests NRTI NNRTI Protease Inhibitors Monogram Test PhenoSense HIV ® GeneSeq HIV® PhenoSense GT® Entry(fusion) Inhibitors PhenoSense HIV Entry® Fuzeon® Roche GeneSeq HIV Entry® Integrase Inhibitors Isentriss® Merck GeneSeq HIV Integrase® HIV drug development PhenoSense HIV® Antibody Neutralization PhenoScreen® CCR5 antagonists Maraviroc® Pfizer Trofile® Co-Receptor Tropism Tests for Use in HIV Drug Development Programs vaccine development Tropism Patient 11 Selection Test PhenoSense HIV Integrase® 12 HIV Drug resistance testing How does resistance develop? 13 Selective pressure from drugs or from the immune system. When HIV replication is not fully suppressed Viral load Treatment begins (poor adherence/absorption, varying PK). Drug-susceptible quasispecies Drug-resistant quasispecies Selection of resistant quasispecies Incomplete suppression • Inadequate potency • Inadequate drug levels • Inadequate adherence • Pre-existing resistance Time Transmission of HIV resistance strains Resistance can be contained by an appropriate and careful choice of treatment by monitoring for resistance. Monogram’s Resistance Assays 14 Phenotypic HIV drug resistance assays Quantification of drug concentration needed to inhibit HIV replication Genotypic HIV drug resistance assays Identify whether specific mutations are present Resistance inferred through an algorithm or database analysis From CliniCareOptionsTM, Genotyping vs Phenotyping: Which Test When? Monogram’s Resistance Assays 15 Drug resistance testing for healthcare professionals establish the patient’s HIV drug resistance profile “virogram” to all approved ARV Tests HIV drug resistance Tests Drugs Monogram Test NRTI NNRTI Protease Inhibitors PhenoSense HIV ® Entry(fusion) Inhibitors Fuzeon® Roche Integrase Inhibitors Isentriss® Merck PhenoSense HIV Entry® GeneSeq HIV® PhenoSense GT® GeneSeq HIV Entry® PhenoSense HIV Integrase® GeneSeq HIV Integrase® 16 Drug Development testings PhenoScreen™ HIV Novel Drug Screening 17 A phenotypic screening assay Developed in response to customer demand: “Secondary screening” Economical way Quickly Cost-efficiently Well-characterized library viruses 18 TROFILE ASSAY TM Background :HIV viral entry 19 Viral Entry is mediated by chemokine receptors : CCR5 or CXCR4 What is tropism? 20 Tropism refers to which co-receptor the patient’s virus uses to enter the CD4+ T cell 4 HIV-1 strains: CCR5-tropic CXCR4-tropic Dual (D)-tropic Mixed (M)-tropic CCR5 tropic (R5) CXCR4 tropic (X4) Dual/mixed (D/M) Dual tropic Mixed tropism Blake Max, PharmD, RMR CORE Center, Clinical Assistant Professor, UIC College of Pharmacy CCR5 antagonists : Maraviroc 21 Maraviroc- Selzentry® developed by Pfizer 1st in class, approved August 6, 2007(US) CCR5 antagonist: Blocks the CCR5 chemokine receptor on the CD4+ T cell to prevent entry of the R5 tropic HIV-1 virus. not effective if virus is X4 tropic or Dual/Mixed (D/M) tropic. The patient’s HIV tropism must be determined before prescription! Pfizer chose Trofile assay TM 22 Partnership since 2002 for development of Trofile test Trofile used in all Selzentry Clinical trials Trofile used before Prescription Currently the only CLIA-validated tropism assay available Trofile assay mechanism : 23 Bioluminescence detection Patient derived HEK 293 cells ©2007 Monogram Biosciences, Inc 24 Trofile characteristics 25 Accurate, precise, reproducible PCR amplification sensitivity : 95 % when Viral load ≥ 1000 copies/ml The whole of gp160 is used No differentiation between dual-tropic & mixed-tropic viruses Dual/mixed (D/M) Dual tropic Mixed tropism Detection of minor X4 species 26 Original Trofile test could not detect low levels of X4 strains Sensitivity 100% when 10% of population is CXCR4 Sensitivity 83% when 5% of population is CXCR4 Enhanced version in June 2008 : 100% sensitivity of X4 virus as low as 0,3% Clinical validation through retrospective analyses of Vicriviroc phase II and Selzentry phase III trials Trofile major disadvantages 27 Accessibility : only done in San Francisco Time (2-4 weeks) Cost :$2,000 Reimbursed by Medicare/Medicaid… Outside of the US : paid by Pfizer Trofile opportunities : « The Collaboration Agreement » 28 May 2006, expires on December 31, 2009, renewable by Pfizer for five successive one year terms Monogram • making Trofile available within the U.S Pfizer • sales, marketing and regulatory matters outside of the U.S • pays Monogram for each assay • will reimburse Monogram for costs to make the assay available. In 2008 : Trofile revenues due to Selzentry: over $16 million. Trofile opportunities : Entry Inhibitors Pipeline 29 CCR5 antagonists CXCR4 antagonists Vicriviroc Schering Plough phase III* PRO140 Progenics Phase II* SCH 532706 Schering Plough Phase I TBR-652 Tobira Therapeutics Phase I AMD 11070 AnorMED Phase I* *trials with the Trofile assay Threats : other tropism assays 30 Homebrew tests Genotypic tests : quicker, cheaper, easier to realize. Competitors : Virco Phenoscript™(VIRalliance) Sensitrop II (Pathway diagnosis) ViroTech (Invirion) used for SCH 532706 ScheringPlough phase 1 31 Targeted cancer therapeutics 32 designed to block activated protein pathways that are driving : cell proliferation tumor development less effective if : the patient lacks the target protein the target protein is not “activated” there are several activated pathways Patient selection testing 33 which pathways have been activated and are driving cancer cell growth ??? measure cancer drug targets in their activated state focused on the EGFR/HER receptor family Beyond Chemotherapy Signaling Cascades of Angiogenesis Extracellular space Integrin Cell membrane Ligand VEGF receptor C-src Ligand ERBB receptor Farnesyl transferase STAT PI3K Activated tyrosine kinase Akt ras mTOR raf MEK MAP kinase VEGF PDGF- ERK Cytoplasm HIF-1 Nucleus Martin L, et al. J Clin Oncol. 2007;25:2894-2901. © 2009 American Society of clinical Oncology. All rights reserved. clinicaloptions.com/oncology Beyond Chemotherapy The EGFR Superfamily of Receptors HBEGF AR ß cell TGFα EP NRG2 NRG4 NRG3 NRG1 AR ERBB1 EGFR ERBB2 HER2 ERBB3 HER3 ERBB4 HER4 TK TK X TK clinicaloptions.com/oncology Beyond Chemotherapy EGF Binds to Receptor Resulting in Dimerization and Autophosphorylation EGF EGF TK TK EGF TK Increased cell proliferation, inhibition of apoptosis, neoplastic angiogenesis pY TK pY pY pY TK pY pY Activation of intracellular signaling molecules clinicaloptions.com/oncology An example : breast cancer 37 HER2 amplified (HER2+) in 25% of breast cancer high levels of a 185kd glycoprotein with tyrosine kinase activity more agressive different treatment Routine testing of HER2 recommended on newly diagnosed and metastatic breast cancer since 2001 38 JP Morgan Healthcare Conference, January 2009 How VeraTag works? 39 Multi-labeled antibodies are Activation of "molecular scissor" Released VeraTag reporters are directed to different epitopes on liberates singlet oxygen, cleaving quantified by capillary the same or associated protein all tethers within a designated electrophoresis partner range Their 1st test 40 introduced commercially in July 2008 determines patient’s HER2 status : level of HER2 total protein HER2 homodimers Response to Herceptin 41 Strengths 42 very small amounts of tumor samples prepared in a variety of methods formalin fixation paraffin embedded permits the quantitative and accurate measurement of proteins and their activated forms specific, sensitive and reproducible SUPERIOR TO CURRENT TECHNOLOGIES In the future... 43 additionnal assays to identify Herceptin resistance HER1, HER3, HER2:HER3, p95 expansion of clinical applications assays on HER1 and HER3 now available for clinical development 44 45 Let’s have a look at the shares… 46 Financial assessment: revenues 47 80 m$ 70 62.193 60 48.252 47.958 50 43.229 40 33.379 30 25.261 18.273 20 7.466 10 0 0.102 1.069 Total Revenue 36.801 Revenues in 2008 from customers 48 Costs & Expenses 49 146.914 m$ 140 120 Aclara purshase 100 83.744 71.461 73.924 80 61.785 60 45.25 47.261 32.268 40 39.008 18.215 20 3.316 8.26 0 Total costs & expenses Linear (trend line without aclara purshase) Repartition of costs & expenses 50 160000 140000 44,8% 120000 39,6% 100000 38,3% 80000 60000 40000 20000 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 % revenues in R&D cost of product revenue R&D General&administrative Sales&Marketing aclara purshase 2008 Financial assessment 51 m$ 140 Aclara purshase 120 100 80 60 40 20 0 Total Revenue Total costs & expenses Linear (trend line without aclara purshase) Operating loss 52 120000 100000 80000 60000 40000 20000 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Forecast 53 An increase of revenue But not yet profitability… Investments 54 A good opportunity Buy now and make money! 2.60$ to 5.60$ (according to Thompson) SWOT 55 Strengths Science driven R&D : VeraTag technology Leader in HIV test (Trofile) Many partnerships Present throughout the continuum SWOT 56 Strengths Weaknesses Science driven Lost of money every year R&D : VeraTag technology Bad reputation with shareholders Leader in HIV test (Trofile) Low cash flow Many partnerships Present throughout the continuum Presence limited to the U.S SWOT 57 Strengths Weaknesses Science driven Lost of money every year R&D : VeraTag technology Bad reputation with shareholders Leader in HIV test (Trofile) Low cash flow Many partnerships Present throughout the continuum Opportunities Development of personalized medicine VeraTag technology : a universal platform Oncology market growth CCR5 antagonists pipeline The Pfizer Note Presence limited to the U.S « The Pfizer Note » 58 Pfizer invests 25 million$ in Monogram through a Senior Secured Convertible Note note will bear interest at 3%, payable : quarterly in cash or Pfizer's option into Monogram Common Stock will be due on May 19, 2010, unless converted earlier. Advantages for both Monogram and Pfizer!! SWOT 59 Strengths Weaknesses Science driven Lost of money every year R&D : VeraTag technology Bad reputation with shareholders Leader in HIV test (Trofile) Low cash flow Many partnerships Presence limited to the U.S Present throughout the continuum Opportunities Threats Development of personalized medicine VeraTag technology : a universal platform Not enough money to continue development Financial crisis Oncology market growth CCR5 antagonists pipeline The Pfizer Note Competitors Patent litigations : Roche and Bayer Facilities not GMP compliant IVDMIAs Regulation The FDA and IVDMIAs 60 IVDMIAs In Vitro Diagnostic Multivariate Index Assays FDA published its guidance in September 2006 Require premarket review by FDA Must demonstrate analytic and clinical performance of test The FDA and IVDMIAs 61 FDA has taken a bite into the lab developed test marketplace! It states 3 criteria meant to distinguish the assays from other laboratory-developed tests: the use of clinical data, an algorithm, and a result that requires the test developer help to interpret. Our opinion on Monogram’s future 62 Pivotal years ahead of them Succeed into a profitable Diagnostic Business Model? Bought by Pfizer? THANK YOU FOR YOUR ATTENTION! ANY QUESTIONS? 63 Determination of tropism :Trofile assay TM 64 Isolate patient’s RNA RT envcDNA PCR ampliation Env senquence Expression vector