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ELISSI 2005Expo Life Science Svizzera Italiana
15 Settembre 2005 Mendrisio
Life sciences: business of complexity
Welcome!AFTI - ASIRB – ATC - Biopolo
Gianni SoldatiPresident ASIRB
Grazie agli sponsorsPrincipali
Sponsors
Mappatura dell’evento
Luca BolligerDirector Biopolo Ticino
ELISSI: Innovation along the value chain -1-The technological map of the event
‚Framework‘
Research MarketDevelopment
DNA: an economist's perspective P
Vaccines HCV P
Cerbios SA B
Gimac Srl B
Microsphere SA B
AM Instruments Srl B
Cro Alliance SA B
Solvias AG B+P
Fedegari Autoclavi SA B
Mondobiotech SA B+P
Alchemy Srl B
Evolva bio Ltd P
Nikem Srl P
Esbatech AG P
Areta International Srl P
COFFEE
B = Booth/StandP = Presenting/Presentazione
ELISSI: Innovation along the value chain -2-The technological map of the event
‚Framework‘
Research MarketDevelopment
MWG Biotech AG B
Mettler-Toledo AG B
PALL AG B
PQE Srl B
SWISS STEM CELLS BANK SA B
VWR International AG B
Hoffmann-La Roche Ltd P
Merck & Co Ltd P
Cardinal Health Ltd P
Fondazione Cardiocentro B Hospital
SWX AG B+P Finance
Biovalley P Cluster
Promozione Economica del Cantone Ticino B Economic
promotion
UK trade agency P Tech transfer
B = Booth/StandP = Presenting/Presentazione
Ticino: ideal platform for internationally competing companies
Arnoldo CoduriEconomics and Finance Department of Canton Tessin
Promozione economica del Cantone TicinoViale Stefano Franscini 17, CH-6501 Bellinzona
Tel. +41 (0)91 814 35 41, Fax +41 (0)91 814 44 [email protected]
ELISSI l September 15th, 2005
Key figuresArea 2812 km2
Population 317000Workforce 157000
Cross-border commuters 35000Small-medium enterprises 15’000
> 50 employees: 390Yearly GDP 15 billion CHF
GDP pro capita: 40’700.- CHF Primary Sector 1% of GDPIndustry 25%Service 74%
ELISSI l September 15th, 2005
24.6 75.4
0% 20% 40% 60% 80% 100%
Food & GroceryOthers
Offset & Pr intingConstruction
Watches & PreciousElectronics
PlasticsTextile & Apparels
Chemical & PharmaceuticalMechanics & Machinery
GLOBAL
Switzerland ExportExport
ELISSI l September 15th, 2005
Main economic sectorsFinancial institutions (Banks and Insurance)Corporate services (Consultancy and Advisory)LogisticsConstruction and real estateTourism (500 hotels)High Tech Industry (Electronics, Chemicals & Pharmaceuticals)Textile industries (fashion)
ELISSI l September 15th, 2005
‚Framework‘MarketDevelopment
IRBHuman biology/immunologyAntibodiesStem cellsProtein folding/maturationGenetic control
IOSIOncology therapiesPatient supportClinical trialsClinical research
IDSIASophisticated mathematicsArtificial intelligenceData mining
CSCSAdvanced computingNetworking resourcesResearch in computationalscience
USI/SUPSICommunication EconomicsInformation technologySocial sciencesArchitecture
Canton TicinoEconomic promotionEOCCantonal research
institutes
LogisticsFinancial infrastructureOn the north-south transit axis
Life science financing
Industry More the 100 pharma companiesManufacturing capabilitiesCompetitive and advanced formulationtechnologies National and international marketing capabilitiesGMP/FDA cleared plantEstablished diagnostic labs
Clinical Large number on MD involved in trials3 CROsOpen attitude of MDs to new tech (e.g. telemedicine, eCR)Centralized and comprehensibleFormulation expertise (e.g.inhalation)
Life science value chain in Ticino
Research
ELISSI l September 15th, 2005
Economic Promotion
A public office dedicated to promoting and developing the economy of Canton Ticino
A complete range of services offered to corporate and private initiatives:
Domestic: to local companies and start-upsInternational: to foreign companies willing to relocate activitiesCo-ordination between the economic players as interface between public and private sector
ELISSI l September 15th, 2005
The One-Stop Shop Coaching
Residence and working permits
Housing
Personnel search
Customs aspects
Legal issues
Financial aspects
Fiscality
EconomicPromotion
EntrepreneurPromoter
Efficient and business-friendly public administrationSimplified and accelerated administrative proceduresEasy access to the appropriate decision-making authorities
ELISSI l September 15th, 2005
CopernicoA marketing initiative
Promote the local economy and improve the visibility of Ticino abroadBoost the awareness of investment possibilities in our CantonEncourage the creation of new establishments on the territoryDevelop Ticino as the North-South logistics platform
ELISSI l September 15th, 2005
Ticino’s AssetsStrategically located in the heart of EuropeThird most important Swiss financial centerIntegrated education, research and economyHighly qualified multilingual workforceSocial peace and political stabilityWorld-class mobility and telecommunication infrastructure High quality of life, high level of personal safetyBusiness-friendly PA and a moderate taxation
ELISSI l September 15th, 2005
Come forbusiness, stay for a lifestyle !
Thank you for your attention!
DNA: an economist’s perspective
Giovanni Barone AdesiProf USI, Lugano
The DNA structure
• The DNA is a sequence of four elements(letters), arranged in two spirals.
• To each element on one spiral mustcorrespond its complementary letter on the other spiral.
• Why has nature chosen four letters? • Why can only the complement fit on the
other spiral?
Efficiency and redundancy
• The task of DNA is to store information. Evolution selects the most efficient way to store the necessary amount of information.
• A serious drawback is that codinginformation in the most efficient way doesnot allow for any margin of safety.
• Well-used redundancy allows for error detection.
• Nature’s solution is truly remarkable.
How many letters in an efficientalphabet?
• Consider all the DNA’s in nature. To store a givenamount of information (withoutloss of generality, any numberup to C), we need N digits if weuse k symbols (usually K=10 in everyday life, 2 in computers). We need KN=C
• Such a coding requires N*Kelements
• To minimize N*K it is necessary to choose K=3.
K=2 2/ln(2)=2.9
K=3 3/ln(3)=2.7
K=4 4/ln(4)=2.9
Why 4 letters?
• The most efficient solution is 3. Humancomputers use 2, DNA uses 4. Why?
• Computers sacrifice a little efficiency to simplicityof design.
• Apparently DNA achieves the same efficiency as human computers, with a more complicateddesign.
• Moreover the second spiral carries no new information (it can be inferred from the first one)
Error control in computers• The error control mechanism most common in
computer is the ‘parity bit’• After 7 binary numbers the eigth is 0 if there is
an even number of ones, 1 if there is an oddnumber of ones.
• If there is one mistake it goes undetected only ifthere is one more mistake in one of the remaining 7 positions. If the probability of error isq, small, it means approximately 7q2 probabilityof undetected error. If q=0.001, 7q2=0.000007.
Error control in DNA• The second spiral is the error control system.
Computers use 1/8 of capacity, DNA ½ for error control. It is very important that genetic heritagebe stored correctly.
• The error rate of DNA is q2/3, because only if the complement on the other spiral is also wrongand it is the complement of the first error the mistake is undetected.
• Therefore DNA has an error rate=1/21 the computer rate.
Efficiency and error control in DNA
• To summarize, the DNA uses twice asmany components as strictly necessary, in order to achieve a very low error rate.
• A similar ternary arrangement would gain about 8% in efficiency, with a 50% deterioration in error detection.
Protein Structure
• A more difficult problem concerns proteins• They use only 20 aminoacids, out of all the
available ones, to fulfill many differentfunctions. Moreover functionality isdetermined by the spatial arrangement, common to many similar proteins.
Protein function
• To simplify the problem, assume that the maintask of proteins is to carry information.
• Then their alphabet size is likely to be the result of a compromise between the minimization of the necessary material, that would suggest aninfinite number of very specialized elements, and the necessity to control error, probablyentrusted to spatial structure.
The protein problem
• Hypothesis:The protein alphabet satisfiesthe minimization of synthesized material, or energy required in the synthesisprocess, subject to the need to havereasonably simple transmitters and receivers for the message. Spatialstructures control error rates, but othercontrol methods may apply.
Conclusion
• The DNA problem is an elegant exampleof life engineering. It is easily analyzed in terms of information theory. The solution isenlightening for similar problems in computing and communication.
• The protein problem is much more complex, because it seems to optimize a whole information system, rather than a static memory.
HCV Vaccine
Andreas CernyEOC, Prof. Dr. Med.
Outline
IntroductionNew developments that render therapeutic vaccination feasible.Obstacles to vaccine development.Therapeutic vaccine for chronic viral hepatitis C: current status.
Global death rates 2003
HIV and tobacco moved to the topHIV was 3 log‘s lower 20 years agoHBV and HCV are thesecond leading viral causesof death globally
Weiss RA, McMichael AJ Nature Medicine 2004; 10:S70
New developments that rendertherapeutic vaccination feasible.
Eine „tolle“ Entdeckung
1980 Christiane Nüsslein Volhard describes the „toll“ mutation of drosophila (Nobel price 1995)1998 Bruce Beutler identifies the receptor of lipo-poly-saccharide (LPS; TLR4)
The discovery of TLR‘s will impact not only vaccinedevelopment
O‘Neill LAJ Sci Am Jan 2005 38
Why should we be optimistic?
The discovery of the importance of toll like receptors as key elements in the initiation of an immune response and adjuvantsand drugs that target specific pathwaysElucidation of the role of costimulation and proinflammatorycytokines (IL-2, G-CSF, IL-12 ..) offer new opportunities to enhance immunogenicity.Data accumulated on the immunology of patients naturally clearing HCV infection demonstrate the feasibility of obtaining immune control and yield important information on what types of responses most likely confer immune control (“immune correlates of protection”)
Why should we be optimistic?
The discovery of the power of naked DNA delivered directly into tissues to stimulate vigorous humoral and cellular immune responses in some models and preclinical trials.
The use of recombinant live vectors derived from vaccinia (and other pox-) viruses, adenovirus, alphavirusus, human retroviruses to cite the most important to deliver immunogenic proteins of choice.
The discovery of the key role of dendritic cells and the pathways involved in the initiation of cellular and humoral immune responses leading to dendritic cell targeted vaccination.
Correlates of immunity to HCV
Well established correlation of cellular immune responses with protectionNumerous MHC class I and II restricted epitopes havebeen describedA recently established neutralization assay allows for thequantification of humoral immune responses Bartosch et al. J Exp Med 2003, 197:633-42
Outline
1. Introduction2. New developments that render
therapeutic vaccination feasible.3. Obstacles to vaccine development.4. Therapeutic vaccine for chronic viral
hepatitis C: current status.
Why should we be pessimistic?
The new approaches need to be in part individualized, this creates costs and renders them less practical.All types of foreign genetic material (naked DNA, live vectors) have the risk to alter the hosts genetic code.Powerful immune stimulants may have additional risks such as promoting lymphoma-genesis or autoimmune disease.
Vaccines are no good business
The global vaccine market isapprox. 2% of the whole Pharma -market ($6.5billion = one PPI)In the US the companies involveddropped from 37 (1967) to 10 (2002)Other disincentives include: limitedpatent protection, public pressureon pricing, liability...-> Need for incentives
Rappuoli, Miller, Falkow Science 2002, 297:937.
Initiatives to support vaccine development
Rappuoli, Miller, Falkow Science 2002, 297:937.
1981 WHO and UNICEF launched Expanded Program of Immunizations (EPI)
1983 Worldbank: defined vaccination as key tool for economic development
2000 Global Alliance for Vaccines and Immunizations raised $1billion (in part from the Gates Foundation)
Since 9/11 the US is spending enormously in vaccines for biodefense
The HCV patent geography is a jungle!
The Patent awarded to CHIRON for the discovery of HCV RNA sequences by the US Patent Office was very large including diagnostic and therapeutic claims.
Public founding (NIH and CDC) was heavily involved in the discovery.
Result:
Demotivation both for Industry and Academia
Legal battles: Abbott, Innogenetics..
Waste of time and money for attempts to circumvent patents
New Patents around the globe with overlapping claims generate additional insecurity
Outline
1. Introduction2. New developments that render
therapeutic vaccination feasible.3. Obstacles to vaccine development.4. Therapeutic vaccine for chronic viral
hepatitis C: current status.
Vaccination for HCV
Therapeutic vaccination for HCV:human studies: E1
26 patients received 20µg of rec. HCV E1 protein and 9 received placebo i.m. at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks50, 53, 56, 59, 62, and 65. They underwent a biopsy beforeand after 2 courses of E1, 17 months later. Plasma HCV-RNA levels remained unchanged, whereasALT levels showed a trend toward a decrease duringtreatment. E1 therapeutic vaccination was well tolerated.
Nevens F et al. Hepatology. 2003 Nov;38(5):1289-96.
Therapeutic vaccination for HCV:human studies: E1 (year 2)
Therapeutic vaccination for HCV:human studies: E1 (year 3)
Nevens F et al. Abstract 194 AASLD Nov 29 - Oct 2, 2004 Boston
Therapeutic vaccination for HCV:human studies: IC41 Intercell
Double blind, controlled, randomized, parallel group, multicenter phase2 study IC41 in CHC patients (synthetic vaccine containing 5 peptides harbouring several cytotoxic HLA-A*0201 and promiscuous T-helper epitopes of HCV).66 patients (non-responders to or relapsers from previous standardtherapy) were enrolled into five treatment groups, including two controlgroups (peptides only, Poly-L-Arginine only). Results: Tolerability and safety was oK. Immunogenicity: 50% hadmeasurable CD4 responses, 35% had CTL in Tetramer Assay and 15% developed CD8 responses Elispot. No significant effect on viraltiters was observed.
Manns M et al AASLD Oct 29 - Nov 2, 2004 Boston.
Chiron-CSL
Therapeutic vaccination for HCV:human studies: virosomal vaccines
Antigen presenting cellN H
N H
N H
N H
N H
N HH = HämagglutininN = Neuraminidase
= Antigen-X
Therapeutic vaccination for HCV:human studies: virosomal vaccines
Fig. 2a JY, T1, and T2 target-sensitization in comparison using the effector cell line D98b
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JY core 131(10)JY IRIV-c131(0.66)T1 core 131(10)T1 IRIV-c131(0.66)T2 core 131(10)T2 IRIV-c131(0.66)
Hunziker I et al. (International Immunol. 2002)
Therapeutic vaccination for HCV:mouse studies: liposomal vaccines
Humanized HLA A2.1 tg miceare a useful preclinical modelto optimize T cell vaccines.Liposomally formulated HLA A2.1 binding peptides wereused with and without CpG.CpG increased immuno-genicity in the lessimmunogenic preparations.
Engler O et al. Vaccine 23:58-68, 2004
Therapeutic vaccination for HCV:human studies: virosomal vaccines
Phase I study in healthy subjects to determine tolerability, safety and immunogenicity of virosomally formulated HCV derived „T cell peptides“.Objective „proof of principle“.Single center study planned with PEVION in Bern for 2nd quarter 2006. Results expected by end of 2006.The final vaccine will contain a mix of several peptides and also recombinant proteins covalently attached to the surfaceof the virosomes to elicit CD4 and Ab responses as well.
Summary
1. Introduction2. New developments that render
therapeutic vaccination feasible.3. Obstacles to vaccine development.4. Therapeutic vaccine for chronic viral
hepatitis C: current status.
?
Fondazione per la Ricerca sulle Malattie Virali
The FoRMVi ("Fondazione per la Ricerca sulleMalattie Virali" or "Foundation for the Research on Viral Diseases") is an independent foundation that supports research on viral diseases. Although acting at a regional level - the Italian-speaking region of Switzerland - it aims to be competitive at the international level, which is the only way to guarantee high quality scientific activity.
Fondazione per la Ricerca sulle Malattie Virali
Vision Viral diseases are in constant evolution. This requires parallel progresses in the field of both basic and clinical research. Rapid tests for early diagnostics, specific infection treatments, and polyvalent vaccines have to be developed. The individual characteristics of the diseased persons must be at the centre of medical and scientific activities.
Mission Having the ultimate goal to develop clinical applications, the foundation promotes and supports scientific activities in the field of medical virology. Focusingon the patient, it integrates research on infected persons with basic research, collaborating with national and international partners.
Fondazione per la Ricerca sulle Malattie Virali – Foundation Board
Fabrizio Barazzoni, Dr. med., responsabile dellユArea sanitaria dell'Ente Ospedaliero Cantonale Enos Bernasconi, Dr. med., capo-servizio responsabile del Servizio malattie infettive dell'Ospedale Regionale di Lugano, presidente della Commissione federale per i problemi dell'AIDS Andreas Cerny, Dr. med., primario, capo del Dipartimento di medicina dell'Ospedale Regionale di Lugano, professore titolare alla Facoltà di Medicina dell'Università di Berna Francesco Lurati, Dr. rer. pol., Docente di Comunicazione Aziendale, Università della Svizzera italiana, Lugano Jean-Claude Piffaretti (Presidente), Dr. biol., direttore aggiunto dell'Istituto Cantonale di Microbiologia, professore associato alla Facoltà di Medicina dell'Uni- versità di Ginevra Marco Soldati, Condirettore presso Istituto Bancario
Fondazione per la Ricerca sulle Malattie Virali – Scientific Board
Prof. Hans Acha-Orbea, University of Lausanne
Prof. Otto Haller, University of Freiburg, Germany
Prof. Mario Mondelli, University of Pavia, Italy
Prof. Jürg Reichen, University of Bern
Prof. Amalio Telenti, University of Lausanne
Living is breathing
Paolo BassaniniBusiness Development
Mondobiotech SA
Disclaimers
This document includes forward-looking statements. These statements are based on current expectations and projections about future events. Actual results could differ materially from those discussed in, or implied by, these forward-looking statements.
The information contained herein is not for publication or distribution to persons in the United States of America. Any securities referred to herein have not been and will not be registered under the US Securities Act of 1933, as amended (the “Securities Act”), and may not be offered or sold without registration thereunder or pursuant to an available exemption therefrom.
This document does not constitute or form part of any offer for sale or subscription of or solicitation or invitation of any offer to buy or subscribe for any securities nor shall it or any part of it form the basis of or be relied on in connection with any contract or commitment whatsoever.
The redistribution of this material is specifically prohibited and neither mondoBIOTECH nor anyone acting on its behalf accepts no responsibility whatsoever for the actions of third parties in this respect.
mondoBIOTECH, a swiss biotech company focused onrare and fatal respiratory diseases
“we specialize in re-directing approved drugs and clinical compounds into new medical indications and transform academic innovations to patients”
with the goal to:provide safe and effective drugs
to patients with severe and rare lung diseasesWORLDWIDE
mondoBIOTECH at a glance
Focused on: Orphan indications in Respiratory Diseases
Proven track of orphan drug designations (4 granted; more in progress)
Pointed and precise method to select and manage new projects
Lead drug development product inhaled Aviptadil is in phase II/III clinical trials preparation for the treatment of Pulmonary Arterial Hypertension (PAH) and in phase I/II as infusion for Acute Respiratory Distress Syndrome (ARDS)
No venture capital financing / no debt
Strong intellectual property position
Key peptide drug production alliance with Bachem (SWX: BANB)
Headquarters in Basel and Lugano, founded in 2001
Selection strategy for drug candidates
Focussed Indications
Orphan Drug Markets
Scientific Rational
Defendable IP position
Development of drugs for rare and fatal lung diseases
Unmet medical needs - incentives by regulatory agencies, guaranteed temporarily market exclusivities (USA, EU)
Significant understanding of biological and medicinal mode ofaction in combination with specific disease knowledge through know-how and existing literature
Preferably, drug candidates are of human origin and agonistsClinically proven safety in humans from different indications
Freedom of operation in addressable marketsOrphan Drug status, production process know-how
Gain opinions of top-notch clinical specialistsSignificant understanding of specific disease characteristics
GlobalProduction
Worldwide drug manufacturing guarantee
Proven Drug Safety
Disease Knowledge
Definitions & advantages of orphan drugs
FDA definition of Orphan Drug Designation:Designation indicating a therapy developed to treat a rare disease (one that affects <200,000 people in the U.S.). Because manufacturers have little incentive to develop drugs for rare diseases, the government offers additional incentives (i.e. tax advantages and extended marketing exclusivity) for them to develop such drugs.
EMEA definition of Orphan Drug Designation:Orphan medicinal products are for diagnosing, preventing or treating life-threatening or very serious conditions that are rare and affect not more than 5 in 10’000 persons in the European Union. Pharmaceutical companies are unwilling to develop such medicinal products under normal market conditions, as the cost of bringing them to the market would not be covered by the expected sales of the medicinal products without incentives.
Orphan Drugs Regulations Advantages:Less patients in Clinical Trials, Free Protocol Assistance, Access to the Centralized Marketing Procedure (EMEA), Fee reduction for all type of centralized activities (EMEA), EU Funded Research (EMEA), Fast track registration (FDA), Orphan Product Grants (FDA), Market Exclusivity for 10 years in EU and 7 years in USA
Sources: FDA, EMEA
Pipeline overview
Aviptadil in pediatric PAH
Thymopentin alone or combinedin bacterial infections
IFN-γ / Genechip in IPF
IFN-γ in IPF
PartnersRegistrationPhase IIIPhase IIPhase IExploratoryProducts
Aviptadil in autoimmune diseases
Aviptadil in ARDS
Aviptadil in Sarcoidosis
Aviptadil in PAH
Amphocil™ (In-licensed from InterMune) prelaunch on the Swiss market
Bacteriophages as natural bactericidials in Cystic Fibrosis infections
Aviptadil in ILD
Development programsAviptadil
human peptide, 28 amino acidsimmunomodulator and neuromodulatorvasodilator of gastrointestinal vascular and respiratory smooth muscle cellsrelaxes precontracted blood vesselselevates cyclic AMP levelsanti-inflammatory propertiesinhibits basal and histamine-stimulated airway smooth muscle proliferationinhibits platelet activationanti-apoptoticimmunosuppressive properties by
inhibition of chemokine-dependent leukocyte recruitment modulation of dendritic cell maturation
Source: PubMed (10300 publications), own data
Development programsAviptadil
Human safety
Aviptadil after intravenous injectioncutaneous flushingincrease in heart beat rateincrease of cardiac outputdecrease of diastolic blood pressureincrease of plasma adrenalineat 10 fold serum levels, watery diarrhea develops (mimicking „VIPoma“ syndrome)
Aviptadil after 6 months inhalationno clinical side effects
Aviptadil market approved in combination with phentolamineindication: erectile dysfunctioncountries: New Zealand, Denmark, United Kingdom
Source:Said FDA IND 2001; Petkov 2003; Ardana Plc., Senetek Plc.
Development programsAviptadil
Indications
Pulmonary Arterial HypertensionClinical Phase II/III, inhaled administrationPrevalence: 100’000 patients. Competition: Tracleer®, Ventavis®, Flolan®, Revatio®Comment: Aviptadil to be used as monotherapy or in combination to any oral marketed product
Acute Respiratory Distress SyndromeClinical Phase I/II, infusionPrevalence: 90’000 patients. Competition: intensive care unit treatment (mechanical ventilation, oxygen therapy), Xigris®Comment: Aviptadil may become first line therapy
Pulmonary SarcoidosisClinical Phase II proof of concept, inhaled administrationCompetition: No drug approved yet, Corticosteroids administered, but treatment not satisfacoryPrevalence/incidence: 32’000 patients. Comment: Aviptadil may become first line therapy
Pulmonary associated autoimmune disorders (scleroderma)Clinical Phase II proof of concept in preparation, inhaled administrationPrevalence/incidence: 22’000 patients. Current Treatments: Tracleer ®.
Development programsInterferon- γ
Indications
Idiopathic Pulmonary Fibrosis (IPF)Second Clinical Phase III trial, subcutaneous administration, performed by InterMunePrevalence: 112’000 patients. Competition: No approved drugs, lung transplantationComment: Interferon-γ may become first line therapy
Interferon-γ in certain combinations + Genechip as second generation treatment options in IPFClinical Phase II proof of concept in preparationComment: Chance to offer the first ever end-to-end clinical package in IPF:
Molecular Diagnosing Therapeutic Agents Monitoring the progress of the disease and adjustments when needed
Certain Intellectual Property Rights licensed out to InterMune, Inc.Upon drug approval by InterMune, royalties expected
Research platformsThymopentin
Indications
Alone or combined in all types of Mycobacteria induced TuberculosisCombination with other peptides as second generation treatment options in IPF
BacteriophagesIndications
Cystic Fibrosis associated bacterial infections
Milestones achievedLicensing agreement for IFN-γ in IPF and Asthma with InterMune (NASDAQ: ITMN)
Distribution agreement for Amphocil® in Switzerland with InterMuneBSI Bank invest in mondoBIOTECH through its New Biomedical Frontier FundEuropean Orphan Drug Status for Aviptadil in PAH and CTEPH (EU/3/03/173) received 23/12/2003
BSI fund New Biomedical Frontier re-invest in mondoBIOTECHExclusive licensing agreement for manufacturing Aviptadil for studies in different orphan indications with Bachem (SWX: BANB)Foundation of mondoBIOTECH US, Inc., in New York
FDA Orphan Drug Status for Aviptadil in PAH received 22/02/2005Collaboration agreement for production & supply of Thymopentin for studies in different orphan indications with Bachem (SWX: BANB)European Orphan Drug Status (EU/3/05/281) for Interferon gamma in IPF received 30/05/2005FDA Orphan Drug Status for Aviptadil in ARDS received 01/06/2005Interferon gamma patent (EP 0 795 332 B1) for: “Medical use of Gamma Interferon in Interstitial Lung Diseases” received 01/06/2005
2002
2003
2004
2005
Next milestones
Marketing Approval for Aviptadil in PAH
Advancement in Pivotal Clinical Trial for Aviptadil in ARDS
Proof of Principle Clinical Trial for Aviptadil in Sarcoidosis
IPO 2006
Increase in- and out- licensing
Increase the pipeline
Management teamFabio Cavalli CEO & Chief Business Architect, Co-founderEntrepreneurial vocation has driven Fabio Cavalli to found numerous successful start-up in the tertiary, IT and sport goods fields. Fabio has developed a great business concepts, marketing and sales experience.
Dorian Bevec CSO, Co-founder Molecular biologist with a Ph.D. degree from Ludwig-Maximilians University Munich and Venia Docendi from University Vienna. Worked for ten years at Sandoz/Novartis Research Institute Vienna, latest as Program Team Head, and for two years in a biotech start-up company.
Patrick Pozzorini CFO, Co-founderBusiness economist from the University of Zurich, Patrick managed for many years national and international audit assignments for PriceWaterHouseCoopers, worked as auditor for Fidinam Group, and as CFO for an e-commerce technology based start-up company.
Vera Cavalli Chief of Sales & Marketing, Co-founderPharmacist from the University of Basel. Vera gained six years experience in the pharmacy business in the sales department for the Swiss market of the Pharmaceutical company Searle SA, Aubonne (Monsanto group).
Simona Küng Stimolo COOPharmacist from the Polytechnic School of Zurich. Simona is also Chief of Clinical Trials & Regulatory Affairs Department. Worked from 1996 to 2001 in the Clinical Research Department & Regulatory affairs of Johnson&Johnson and as consultant partner for R&D activities. From 1993 to 1995 Simona was CRA for Covance in several European multicentric studies.
Maria Teresa D’Antonangelo, Legal Counsel & Intellectual Property ManagerAttorney at Law specialized in Intellectual Property, Pharmaceutical and Chemical Patents Law. Maria Teresa worked until July 2005 for Avv. Prof. Franzosi in the Law Firm Franzosi, Dal Negro, Pensato, Setti in Milan, one of the leading world IP and Patent Law firm. From 2004 to 2005, she collaborated to the Commentary of the New Italian Intellectual and Industrial Property Code.
Second Level Managerssignificant experience in R&D, CRO and Sales & Marketing with: Amgen, Asta Medica, Axxima and Servier
Experienced board of directors
Prinz Michael von Liechtenstein, Board President & Chairman BIOPHARMAinvest AG
Robert Huber, Nobel laureate, Max Planck Institute of Biochemistry
Walter Isler, Vice President Bachem AG
Luca Bolliger, Director Biopolo Ticino
Matteo Pagani, CEO Studio Fiduciario Pagani SA
Vera Cavalli, Chief Sales & Marketing mondoBIOTECH group
Giovanni Cusmano, CEO ABM S.p.A.
Massimo Radaelli, CEO Dompé International SA
Leading scientific advisory boardNazzareno Galié, University of Bologna, Italy: Clinical trials in cardiovascular diseases
Sami Said, University of Stony Brook, USA: Clinical evaluation of neuropeptides
Mario Delgado, University of Granada, Spain: Preclinical evaluation of neuropeptides
Maurice Beghetti, University of Geneva, Switzerland: Pediatric clinical trials
Adam Torbicki, University of Warsaw, Poland: Clinical trials
Michael Roth, Woolcock Institute, Sydney, Australia: Clinical Trials in pulmonary diseases
Joachim Hauber, Heinrich-Pette-Institute Hamburg, Germany: Molecular biology
Franz Kerek, Martinsried, Germany: Biochemistry, organic chemistry, natural products
Hans-Dieter Klenk, University of Marburg, Germany: Clinical and experimental virology
Uwe Heemann, University of Munich, Germany: Internal Medicine, Animal models
Alexander Steinkasserer, University Erlangen, Germany: Preclinical, dendritic cells
ContactsmondoBIOTECH AGBasel Stadt
Executive office:
mondoBIOTECH groupVia Pasquée 23CH - 6925 GentilinoSwitzerlandPhone +41 (0) 840 200 010Fax +41 (0) 840 200 [email protected]
We welcome you @ www.mondobiotech.com
Thank you
Genetic Chemistry: Evolving and Improving Small Molecule Drugs
Melya Hughes CrameriVP Alliances & Intellectual Property,
Evolva Bio Ltd
Evolva SA
Company Company BackgroundBackground
Management team with track record in biotech and pharma companiesBIAcore, Biotage, Geron, Maxygen, Merck, Novo, Novartis, Pharmacia, Phytera, PNAD, Quadrant, Roche, Topotarget
In March 2005 completed CHF 21.5 ($ 18) million A-round
Located in Basel (HQ) Evolution, Screening, Pre-Clinical, CommercialCopenhagen Genetic Analoging, ProductionisationHyderabad Libraries, Clones, Bioinformatics, Synthetic Chemistry
Evolva SA
WeWe AddressAddress TwoTwo CoreCore PharmaPharma ProblemsProblems
Very inefficient R&D paradigm250 man-years/compound that entersclinic
Shortage of truly novel drugs makingit to market, despite investment
Suggests solution not close to current industry approach
Economist (2002), J.Nat Prod (03)
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d ($
bn in
USA
)
New Chemical Entities Approved R&D Spend
Evolva SA
Overall Overall LogicLogic
Natural products provide different, valuable structuresRigid structures, complex motifs, useful structural blueprintsContributed to 61% of the 877 NCEs launched in last 20 years
But nowadays outside mainstream discovery paradigm>90% of species too small or too rareSource material almost always highly variableComplex mixture effects hinder identificationVery challenging scale-up and production
Evolve host to produce a compound having a desired functionDo not rely on them being created as side-effect of natural evolution
Evolve compounds in an ”industrialisable” system fast growing, tractable host – in our case yeast
A. terreusOrigin of the statins
WatchmakerWatchmaker®®
TheThe evolution evolution ofof optimisedoptimised small small moleculemolecule drugsdrugs
Evolva SA
CreateCreate CompoundCompound EnabledEnabled YeastsYeasts (CEYS)(CEYS)
GeneticDiversity
InterestingReactions
Source Genesfrom Relevant Sources
InterestingStructures
InterestingFunctions
Combinatorially Clone Genes into YACS
Combinatorially build CEY Populations
2 x 102 genes x 109 cells
Haploid cells mating
type a
Haploid cells mating
type α
MateX
109 Diploid cells
Evolva SA
Assay Guided Evolution of CompoundsAssay Guided Evolution of Compounds
Assay Each CEY
FACS or Colony PickingArchitectures
Cellular or Biochemical Assays
NHRNHR
Ligand
NHREs GFP4 EYACS
Yeast cell
Evolve through breeding
Explore new combinations of best genes
One generation = 2-3 weeks
Non-induced
Induced
Fluorescence level
Num
bero
fcel
ls
Analyse Optimised CEYS
What compounds are theymaking
What genes do they use to make these compounds
OH
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↑↑FitnessFitness
Generation1 2 3 4 5 6
Numberof CEYS
Founder
=
Evolva SA
AnalogingAnaloging & & ProductionProduction ofof CompoundsCompounds
Analog using specific genes or gene familiesGlycosyl-TransferasesOxidoreductaseLyaseAldolaseLigaseIsomeraseHydrolaseetc.
Mate XOH
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Me O
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0
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0 5 10 15 20Time (hours)
Cul
ture
gro
wth
(opt
ical
den
sity
)
Control
25 g/l Vanillinβ-Glucoside
1 g/l vanillin
5 g/l vanillin
0,5 g/l vanillin
Toxicity of vanillin vs. its β-glucoside in S. cerevisiae
Produce synthetically, or via fermentation
Evolva SA
CarotenoidsCarotenoids--11Collect Genes
From plants, fungi, marine algae & bacteria
Assay
whole cell phenotype(colour detection by eye)
↑↑FitnessFitness
Generation1 2 3
3 Generations of Evolution
Longer (> 10 step) syntheticpathways
More diverse compounds
Novel structures
Unexpected structural classes
Increased yields
Founder Population
Obtain 4-5 step synthesispathways
Founder
Numberof CEYS
XMate
NuclearNuclear Receptor Receptor AgonistsAgonists
With An Initial With An Initial FocusFocus onon PPARsPPARs
Evolva SA
PPAR PPAR AgonistsAgonists
0
0.2
0.4
0.6
0.8
1
1.2
PPAR
γLBD
Avandia10µM
10µM 1µM 0.1µM DMSO
Two on market drugs (both full agonists) Actos (Takeda/Lilly) & Avandia (GSK)Generally considered effective insulin sensitizersAnnual sales c. $3-4 billion
BUT serious side effects that restrict useWeight gain - c. 4 Kg per 0.1 % increase in insulin sensitivityHeart failure - c. 5% patients, (15% if also on insulin)
Gene sources: from extract data, structure knowledge, phylogenetics
Assay: PPAR activation driving reporter gene
Evolved selective PPARγ agonistsNanomolar active compoundsNew structural class (MW 300 – 400)Do not recruit adipocyte differentiation co-factorsOnly weakly induce adipocyte differentiation
EV-04011
00.5
11.5
22.5
33.5
4
PPAR
δLBD
L165041 EV-04011 DMSO
Evolva SA
EV04EV04--4444 StimulatesStimulates SignificantSignificant GlucoseGlucose UptakeUptake
At 1 µM EV04-44 has a similar glucose up takeefficiency as Avandia
ImprovingImproving ADMET ADMET PropertiesProperties
Evolva SA
CurrentCurrent FocusFocus: : UseUse ofof GlycosylGlycosyl TransferasesTransferases
Cloned > 100 genes/enzymes encoding for glycosyl transferasesPlant, mammal and insect genesHave a medium throughput system for testing and scaling compounds
Offers site specific, scaleable, glycosylation, with various substratesBoth in cell-free and cell-based systems
Can generate small molecules with better ADME propertiesAround 50 glycosides on market today (Etoposide, Vancomycin, Glucobay f.x.)Success on > 50% of compounds tried to dateIncrease bioavailability, improve drug administration profile, improve targeting, productrescue & lifetime extension
Will extend process to other gene/enzyme classes over time
Evolva SA
CanCan PerformPerform SiteSite SpecificSpecific GlycosylationGlycosylation
OHO
OH
O-GlcO
OH
OHO
O-Glc
p-OH Benzoic Acid
GT-X Product
GT-Y Product
Evolva SA
Can Stabilize MoleculesCan Stabilize Molecules
OH
OH
CN
p-hydroxymandelonitrile t1/2 = 1 min at pH 7 in H2O
O
OH
CN
Glc
p-glycosyloxy-mandelonitrile t1/2 =60 min at pH 7 in H2O
OH
O
CNGlc
p-hydroxymandelonitrile-glucoside
t1/2 = Stable compound at pH 7 in H2O
Evolva SA
GlyGly--compoundscompounds
L-dopa glycosideL-DOPA gold standard treatment for Parkinsons but only 1% of dose reaches CNSHave made 3 different L-DOPA glycoside isomers to gram scaleInitial animal tests show active transport across the BBBHas expected benefits in a standard mouse modelLonger half-life & better BBB penetration = more stable dose and less on/off effects
Sulfasalazine glycosideSulfasalazine used to treat Crohn’s disease and Rheumatoid ArthritisSulfasalazine is an NMDA receptor blocker - promising mechanism of action for stroke, epilepsy and Huntington'sBioavailability ~20% when administered orallyInitial animal work commenced with a sulfasalazine glycosideExpect Improved bioavailability and BBB penetration
Benefitsallows treatment of diseases with derivatives of a known compound
OH
OHNH2
COOH
OH
NN
SNHO
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COOH
Evolva SA
BenefitsBenefits ofof WatchmakerWatchmaker®®
Can create diverse, novel compounds19 structure classes confirmed to dateFrom 20% - 80% novel, depending on programMajority of structures < 500 MW
Can access and scale compounds thatsynthetic chemistry will not take you to
Parallel optimisation against complex criteriaFunctionality in a cellular environmentActivity, specificity-profile, toxicity, ADME etcImprovement/rescue of existing compounds
Basis for a shorter, cheaper discovery processUnderlying throughputs several orders of magnitude greater than current paradigm
0%5%
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Evolva SA
Business Model : A Business Model : A BalancedBalanced ProductProduct PortfolioPortfolio
We are a product producing platform companyWatchmaker is a technology platformBut a platform that directly creates products
Building a pipeline of compounds and indicationsPartnering in principle at any/all stages of the processEvolva or partner originated targets & structures
Three internal ”thematic areas” over next 2-3 yearsNuclear receptors – PPARS, othersProtein:protein interactions – WnT/Beta-catenin, othersGenetic/enzymatic improvement of existing compounds (ADMET etc.)
Internal pre-clinical work focused on oncology & metabolicOutside collaborations to exploit other areas
Evolva Evolva
www.evolvabio.comwww.evolvabio.com
MelyaMelya Hughes Hughes CrameriCrameri PhDPhD, EPA, EPAVP Alliances& VP Alliances& IntellectualIntellectual [email protected]@evolvabio.comTelTel: +41 61 485 20 15: +41 61 485 20 15
NiKem Research: a potent drug discovery partner
Carlo FarinaCEO
Nikem Research
History
Spin-off from GSK Milan (Italy), August 2001Privately owned: Founders, Employees, GSK (7.5%)Drug Discovery: Service Model
Multiparametric Lead Discovery and OptimizationKey Competencies: Med Chem and eADMET
Drug Discovery: R&D ModelFour preclinical projects, two Preclinical CandidatesFocus on CNS (neuropathic pain) and oncology
74 FTEs (80% Ph. D. and MS, 30% temporary)Management team with almost 20 year experience in drug discovery (SmithKline Beecham Italy)
8 M€ projected revenues in 2005 (Services)>25% yearly increase since 2003
Technology Platform
Lead OptimizationLead Optimization
eADME & In vivo DMPKeADME & In vivo DMPK
Biochemical Pharmacology
Biochemical Pharmacology
Analytical & Structural Chemistry
Analytical & Structural Chemistry
Parallel & Combinatorial Chemistry
Parallel & Combinatorial Chemistry
Computational Chemistry & Library design
Computational Chemistry & Library design
Hit validation (H2L)Hit validation (H2L)
Lead Generation by Computer-Assisted
Rational Drug Design
Lead Generation by Computer-Assisted
Rational Drug Design
Pharmaceutical QualityPharmaceutical QualityPrePre--Clinical DrugClinical Drug
CandidatesCandidates
LeadsLeadsHitsHits
TargetsTargets
Widely Recognized Service Provider
Major clientsGSK (UK, I)Wyeth (US)Chiesi (I)Addex (CH)Congenia (I)Hybrigenics (F)Athelas (CH)
Drivers for a Change: the Dual Model
Value increase: internal R&D projectsFour IP protected projects in the pipeline
Focus on CNS and oncologyGenerated by internal competence or by in-licensing patents previously invented by our team
Team capable of sustained R&D developmentServices: substantial cash flow, help financing R&D, access biology-based biotech partners
Project Pipeline
Depression
2Q/05 End of 2006
Cancer
Parkinson
NeuropathicpainNeuropathic pain
Learning & MemoryObesity
Learning & Memory
Neuropathic pain
Hit H2L Lead Optimization
Preclinical
PhaseI
NiK-001
NiK-002
NiK-003Learning & memory
NiK-004 Depression, Schizophrenia
Unique Strengths of NiKem
Cutting edge competence in preclinical R&D Almost 20 years experience in big pharma, with impressive track record of successCapable of generating novel products with only limited resources
Powerful medicinal chemistry platformPharmaceutical quality drug candidates at biotech speedIndustrial validation by big pharmaAttractive for biology-based biotech partners
Advancing Antibody Fragment Therapeutics
Dominik EscherCEO
ESBATECH AG
Advancing antibody fragment therapeutics
ESBATech at a glanceSpin-off: Institute of Molecular Biology, University Zurich
1.200 sqm state-of-the art labs and offices in Schlieren, Zurich’s Biotech cluster (Jan. 2002)
28 employees: 11 PhD, 1 MD PhD, 7 M. Sc.
Winner of Swiss Life Sciences Prize 2004 (October 2004)
Red Herring Top 100 European private companies(April 2005)
Proprietary technology focusing on antibody fragments
Product candidates with phase IIa data in two indications by end of 2007
Advancing antibody fragment therapeutics
Next generation of antibody products will gain momentum
Classical monoclonalantibody
Antibody fragment comprising natural antigen-binding pocket:
• Neutralization of endogenous proteins • No ADCC required• Short-in vivo half-life wanted• High tissue penetration
Companies: e.g. Celltech / UCB, Genentech,Alexion, ESBATech
Fragment or conjugated
Modified glycosylation of Fc part:• Increased ADCC• Oncology indications
Companies: e.g. Glycart, Genentech, XencorBioWa and others
Novel glycosylation
Emergingnew technologies
Advancing antibody fragment therapeutics
Enormous growth forecast for antibody fragments
Type of antibody Sales ($m) Forecast ($m) 2004 2005 2007 2010 Murine 17 15 33 68 Chimeric 6,172 7,326 9,565 11,139 Humanized 3,164 4,485 7,246 10,334 Fully human 852 1,547 2,799 5,719 Fragment 0 0 585 2,784 Source: Datamonitor 2005
Advancing antibody fragment therapeutics
ESBATech is an antibody fragment company
VH
VL
CH1CL
CH3
CH2
VHCL
CH2
CH1
CH3
VL
IgG
CH1
VH VL
CL VHVL
SS
Fab scFv
Advancing antibody fragment therapeutics
ESBATech’s unique approach
VH
VL
CH1CL
CH3
CH2
VHCL
CH2
CH1
CH3
VL
IgG
IgG gene segments Human
VH 1200
VL κ 850
λ 400
> 1.5 Mio fully human frameworks
Advancing antibody fragment therapeutics
USP Antibody program
Only Company that ever screened whole human pool of antibody fragments (VH and VL domains)
Proprietary, fully human antibody fragments
High stability and no aggregation of antibody fragments
High production yield of antibody fragments in microorganisms
Proprietary screening technologies, no phage display (Royalty stacking)
Proof-of-Concept of platform: from discovery to animal PoC with clinical candidate in 11 months
Advancing antibody fragment therapeutics
Antibody fragment pipeline of ESBATech
Indications Research Preclinic Phase I Phase II Phase IIIESBA105 Inflammation
ESBA105 Inflammation
ESBA105 Inflammation
ESBA212 Alzheimer
ESBA521 Glioblastoma
Advancing antibody fragment therapeutics
Dose response in acute monoarthritis
PBS
TNF
TNF
+ 18
0ug
scFv
TNF+
156
ug E
SBA1
05
TNF+
45u
g ES
BA10
5
TNF+
11u
g ES
BA10
5
TNF+
156
ug IF
X
TNF+
45u
g IF
X
TNF+
11u
g IF
X
0.00
0.05
0.10
0.15
0.20
0.25
mea
n ch
ange
kne
e di
amet
er (c
m) ESBA105 Remicade
Collaboration with Prof. Georg Schett, Department of Rheumatology, University Hospital of Vienna, Austria
Advancing antibody fragment therapeutics
Opportunity for ESBA105
Comparable in vivo efficacy as Remicade
Short systemic exposure: safety profile
Small protein size for optimal penetration
Reduced CoG compared to monoclonal antibodies
ESBATech aims to be first in clinic and on market applying anti TNFα antibody fragment for local applications
Advancing antibody fragment therapeutics
Board of Directors
Thomas Hecht, M.D. Chairman, former Director Medical Affairs, VP Marketing, Amgen
Dominik Escher, Ph.D. Vice-Chairman, CEO ESBATech AGProf. Helmut Fenner, Ph.D. SAB HBM Partners, former TA Head
Inflammation Roche, Amgen (Kineret), BASF Pharma (Humira)
William Harrison, M.D. Head Global Search & Evaluation Europe BD&L, Novartis Pharma AG
William Jenkins, M.D. Former Head of Clinical Development and Regulatory Affairs World-wide, Novartis Pharma AG
Arnd Kaltofen, M.D., MBA General Partner VI Partners AG
Advisors to the BoD:Fritz Kunz, Ph.D. Chairman Speedel Holding AG and SenTech
AG, former CEO of Straumann AG, various former R&D positions at Sandoz Pharma AG
Georges Haas, Ph.D. Former Head of R&D Ciba-Geigy
Advancing antibody fragment therapeutics
Intellectual property Antibody program
ESBATech has built up highly valuable intellectual property in the antibody field. These comprise:
IP on screening technology:Screening system (priority 22 June 98): Granted AU757385,
US 6,821,728CDR Screening (priority 28 December 99): Granted AU768827,
EP1242457SCINEX (priority 22 May 02)
IP on library generation:CDR Screening (priority 28 December 99): Granted AU768827Toxin recombination (priority 11 April 03)
IP on fully human scFv antibody frameworks:Human scFv frameworks (priority 22 May 02)
Advancing antibody fragment therapeutics
Freedom-to-operate on scFv
May 2003: As first Company, ESBATech obtains Patent License on Single-Chain Antibodies from Micromet/Enzon
71 national, granted patents; 23 patent applications
Sublicense for collaboration partners
Advancing antibody fragment therapeutics
Collaborations
Lombardi Cancer Center, University of Georgetown, Washington DC
Medical University of Vienna, Austria
University Hospital of Nijmegen, Netherlands
University of Zurich, Switzerland
Viventia Biotech Inc.
Upfront and FTE funding
Milestones and Royalties
Advancing antibody fragment therapeutics
Collaborations cont.
Press release 31 March 2005:
“ESBATech starts drug discovery collaborationwith Novartis”
Novartis Institutes for BioMedical ResearchCambridge, MA, USA
ESBATech AGWagistr. 21CH-8952 Zurich-SchlierenSwitzerland
phone +41-1-733 4900fax +41-1-733 4990e-mail [email protected] www.esbatech.com
Advancing antibody fragment therapeuticsELISSI15 September 2005
Cells as source for the biodrugs of the future
Maria Luisa NolliCEO
Areta International Srl
124MLN September 05
ARETA INTERNATIONAL
A CMOA CMO
FOR TAILORFOR TAILOR--MADE SUPPLY OF BIODRUGS MADE SUPPLY OF BIODRUGS
Cells for Cell TherapyCells for Cell TherapyAntibodiesAntibodies
RecRec Proteins Proteins
FOR CLINICAL TRIALSFOR CLINICAL TRIALS
125MLN September 05
ARETA INTERNATIONAL
A SPIN OFF OF CELL BIOLOGY LABS OF LEPETIT A SPIN OFF OF CELL BIOLOGY LABS OF LEPETIT
RESEARCH CENTER, PART OF MULTINATIONAL RESEARCH CENTER, PART OF MULTINATIONAL
COMPANIES OF DOW CHEMICAL COMPANIES OF DOW CHEMICAL
ARETA WAS CONSTITUTED AT THE END OF 1999 WITH ARETA WAS CONSTITUTED AT THE END OF 1999 WITH
PRIVATE CAPITAL PRIVATE CAPITAL AND IS LOCATED IN THE VICURON AND IS LOCATED IN THE VICURON
INDUSTRIAL PARK 30 KM NORTHWEST OF MILANINDUSTRIAL PARK 30 KM NORTHWEST OF MILAN
126MLN September 05
ARETA INTERNATIONAL
KNOW HOWKNOW HOW
15 YEARS EXPERIENCE OF 15 YEARS EXPERIENCE OF HER FOUNDER AT HER FOUNDER AT
LEPETIT CELL BIOLOGY LABS ON:LEPETIT CELL BIOLOGY LABS ON:
Generation and production of monoclonal antibodies, ELISA and Generation and production of monoclonal antibodies, ELISA and immunoaffinity resins for the following projects: immunoaffinity resins for the following projects: propro--UPA, tUPA, t--PA EPO, GCSF, GPPA EPO, GCSF, GP--120,REV,GAG, beta120,REV,GAG, beta--AMYLOIDAMYLOID
Recombinant proteins (uRecombinant proteins (u--PA, proPA, pro--UPA, GAUPA, GA--EPO, GCSF)EPO, GCSF)for therapeutic use for therapeutic use
FOR ALL GLOBAL RESEARCH CENTERS OF DOW CHEMICAL’S FOR ALL GLOBAL RESEARCH CENTERS OF DOW CHEMICAL’S MMULTINATIONAL PHARMA COMPANIESULTINATIONAL PHARMA COMPANIES
127MLN September 05
ARETA INTERNATIONAL
THE ORGANIZATIONTHE ORGANIZATION
ARETA IS ORGANIZED IN TWO DIVISIONS:
ARETA GMP (Therapeutics)
ARETA RESEARCH (R & D and diagnostic)
128MLN September 05
ARETA INTERNATIONALCOMPANY ACHIEVEMENTSCOMPANY ACHIEVEMENTS
1996 Start scouting of Dr M.L. Nolli of biotech contract services market (EU and US)
1999 Areta constitution (end of 1999) as a spin off of cell biology labs of Lepetit Research Center
2000 Areta becomes operative with the high containment plant for mammalian cell culture ISO 9001 certification at the end of the year
2001 Start production of validation lots of monoclonal antibodies, human cells for cell therapy and rec-proteins
2002 Break-even2003 ISO 9001:20002004 GMP authorization by the AIFA for Phase I and II lots of
cells for cell therapy2005 GMP extension for monoclonal and rec proteins
129MLN September 05
ARETA INTERNATIONALMANUFACTURING HIGHLIGHTS
2001 Production of a MAB (150 L) for Phase I/II Purification and filling of 150 vials
2002 Production (150 bags of human T lymphocytes for Ph I/II Production of alpha-glycogenase for US (200 vials)
2003 Formulation and filling of transgenic MAB gel (Ph I 1200 vials) Production of a second lot of the MAB produced in 2001 (600 L) Purification and filling of 400 vials
2004 Production of mutated toxin (300 L) for Phase I in US Production of a humanized MAB for preclinical studies (200L)
2005 Release of 150 bags of T lymphocytes for Phase I/II
130MLN September 05
ARETA INTERNATIONALAreta can tailor the production schedule to the real need of the customeravoiding massive production at the beginning of the project that may result in huge losses of product and money by the proper application of process development at the beginning of the development of the long trail of a drug to become a product
Through:production process optimization, strain yield
improvement, adaptation to serum free media, most suitable bioreactor choice, set up of purification
methods, set up of analytical teststhat are carried out to build a robust process for the more advanced phases.
131MLN September 05
ARETA INTERNATIONAL
TECHNOLOGYTECHNOLOGY
ARETA’ARETA’s s biotechnologicalbiotechnological platformplatform includesincludes the the developmentdevelopment of “of “proprietaryproprietary” ” methodsmethods forfor::
production production processprocess optimizationoptimizationstrainstrain yieldyield improvementimprovement and and adaptationadaptation to SFM to SFM most suitable bioreactor choicemost suitable bioreactor choiceset up of purification methodsset up of purification methodsset up of analytical testsset up of analytical testsproduction of lots for preclinical and production of lots for preclinical and clinicalclinical studiesstudiesset up of production/manufacturing plan set up of production/manufacturing plan withwith CustomerCustomer
((Areta’Areta’s s clonesclones) and/or ) and/or technologytechnology transfer to transfer to ownown facilityfacility
132MLN September 05
ARETA INTERNATIONAL
TThe cell culture processes in Areta are carried outusing modular and disposable bioreactors
•BIOREACTORS AND MODE OF CULTURE
High surface volume ratio bioreactors are used
They are sterile, mono use bioreactors, easy to use, saving space, money and personnel dedicated
Their use avoids cross contamination
Batch or fed-batch mode of culture is used
Short processes are preferred
133MLN September 05
ARETA INTERNATIONAL
SET UP OF CELL CULTURE PROCESSSET UP OF CELL CULTURE PROCESS
BIOREACTORSBIOREACTORS AND MODE OF CULTUREAND MODE OF CULTURE
CellCell Factory Factory isis a a veryvery easy , easy , modular modular bioreactorbioreactor designeddesignedforfor anchorageanchorage dependentdependent cellscellsbutbut working working alsoalso withwithsuspensionsuspension cellscells. Big . Big modulesmodulescan can guaranteeguarantee largelarge scale upscale up
134MLN September 05
ARETA INTERNATIONALSCALE UP WITH MODULAR AND DISPOSABLE SCALE UP WITH MODULAR AND DISPOSABLE
BIOREACTORSBIOREACTORS
•• CELL FACTORY PRODUCTION SYSTEMCELL FACTORY PRODUCTION SYSTEM
135MLN September 05
ARETA INTERNATIONAL
In our short history we have demonstrated to be able to:
Produce and release lots of biodrugs as needed
In respect to ISO 9001 and international GMP certification
We are used to be inspected both by regulatory authorities and by clients
We are authorized to produce both bulk and finished products
136MLN September 05
ARETA INTERNATIONAL
The company is expanding its activities both on national and international market taking advantage of the GMP authorization obtained from the ItalianMinistry of Health for the production of lots for celltherapy for the phase I and II clinical trials, and isplaying a greater role as partner in reasearch projects.We think that TICINO is a very interesting area to collaborate withWe hope to have/ build the chance to establishpartnerships with biotech/res instituteHere are some of the research projects where ARETA isinvolved as partner
137MLN September 05
ARETA INTERNATIONAL
Research Projects
Induction of bone regeneration by implant in patientsof autologous Mesenchimal Stem Cells (MSC).
The project, in collaboration with Istituti Ortopedici Rizzoli di Bologna (IOR), has the obiective of validating a protocol based on the cell therapy withMSC. The validation, scheduled on a sample of 5 patients, starts from the sampling of the cells from the patient (IOR) and consists on their expansionand preparation for the implant in GMP conditions (Areta); it will supply the data for the protocol that will have to be run to introduce this kind of treatment in medical pratice.
138MLN September 05
ARETA INTERNATIONAL
Use of recombinant acid maltase in substitutivetherapy of Type 2 Glycogenose (rare Disease)
The project, in collaboration with Transactiva and Ospedale Pediatrico Burlo (Trieste), has the aim of treating patients with a new form of alpha-glicogenase enzyme (rhGAA), demonstrated to be more activethat already available. Areta International, is involved in preparingtherapeutic doses of the enzyme. Areta has already set up the protein production and purification processin large scale moving from the reasearch protocol to the industrialmethod. The first therapeutic doses will be released within 2006.
Research Projects
139MLN September 05
ARETA INTERNATIONAL
Immunotherapy of lymphoproliferative HCV-correlatedpathologies through vaccination with recombinantclonotipic immunoglobulins:
The project, in collaboration with the Aviano Oncology Center (CRO), has the objective to develop new recombinant immunoglobulin molecules forthe immunotherapy of lymphoproliferative HCV-correlated pathologiesthrough vaccination. We started the process development of the original recombinant strain to obtain, through the productivity increase, the set up of production, purification and analytical methods, a robust and reliable industrial processable to produce these molecules for patients.
Research Projects
140MLN September 05
ARETA INTERNATIONAL
Research Projects
Human mesenchimal cells for the myocardial tissuereparation:The project is in collaboration with Istituto Cardiologico Monzino in Milano and has been funded by EU (LSHB-CT-2004-502988)
One of the objectives of this project is to plan a clinical Phase I study using human autologous mesenchimal cells (MSCs). Areta is involved in expanding the mesenchimal cells coming from the patients in respect to the GMP law, to manipulate the cells whennecessary and to set up/perform the QC tests for the preparation and release of the lots for patient treatment.
Biopharmaceutical analysis at SolviasSpecializing in Capillary Electrophoresis Technology
Erik HahnDirector Bioanalytical Services,
Solvias AG
© Solvias AG
• Custom Synthesis• Catalysis• Polymorphism and Salts • Analytical Services
Practical Solutions to Complex Problemsin Synthesis and Analysis
History
Solvias AG has emerged from a scientific “Competence-Centre“ out of Novartis. Our origins can be traced to the former Ciba-Geigy research centre, which later merged with Sandoz to form Novartis.
Since October 1st 1999: Solvias AG is a fully autonomous and independent technology company
Comprehensive analytical servicesfor Protein, Peptide, Oligonucleotidebased drugs
Complete Characterization programs
Method development and validation
Release testing
Stability studies
Guidance - Solvias will provide ongoing expert consultation
to assure that your program can proceed with confidence.
Characterization programs
Structural characterisation and conformation
Physicochemical properties
Content assay
Process and product related impurities
Customized - Programs and methods are individually
tailored to meet your needs and the properties of your drug.
Efficient - Formal project management systems ensure that
programs are completed on-time and on budget.
Techniques
Chromatography
Capillary electrophoresis & Flat-bed electrophoresis
Mass spectrometry
Spectroscopy and other physico-chemical techniques
Special techniques (Amino acid analysis, Q – PCR, Elisa, Threshold
Optimum - With a broad range of capabilities and
instrumentation, Solvias can always implement the best
solutions to your problem.
Practical solution to complex problems....
Disulfide bridging by LC-MS
Isoelectric focusing by CE
Carbohydrate profiling by e.g. HPLC and CE
Determination of oxidative forms by e.g. LC-MS
Topoisoform profiling of plasmids by CE·
Impurity profiling of oligonucleotides by CE
Experienced - With years of pharmaceutical industry
experience, Solvias can solve the most complex analytical
challenges quickly and cost-effectively.
cGMP : inspected by FDA (FDA-CNF-No. 9617363)
cGMP : approved contract lab by Swissmedic
ISO 9001 : certified QM-system SQS
Quality StandardsQuality Standards
Assurance - Solvias’ quality assurance programguarantees that all work will meet the strictest guidelines for regulatory compliance.
We would be pleased to get in touch with you
Are you interested? We welcome your inquiries and would be pleased to provide you with further information about our service
Your contact: Dr. Erik [email protected]. Guido [email protected]
We welcome you at our booth!
............thank you!
Premio ASIRB - Roche
Gianni SoldatiPresident ASIRB
Premio ASIRB – Roche 2005 assegnato aPaola LUCCA per il lavoro:
Fighting dietary deficiencies: rice enriched with vitamin A and iron
Discussions at poster outside
Pausa - Break
The Challenge of Productivity:The Roche Innovation Model
Uwe MeyaHead of Research Portfolio Management,
Hoffmann-La Roche Ltd
Phar
mac
eutic
alsRoche 1998 Pipeline
All the appearances of a strong pipeline
Phase III / Registration
Phase 0 Phase I Phase ll
Phar
mac
eutic
alsPipelines Don’t Come with Guarantees…
Phase III / Registration
Phase 0 Phase I Phase ll
Phar
mac
eutic
alsWhat’s the Problem…
And what is Pharma doing about it?
• The same messages are well known:– Decreased productivity– The “innovation deficit”– Increased costs; higher regulatory hurdles; flat sales
“Despite massive increases in investment, R&D productivity continues to decline...”
“...more money is poured into the black hole that is R&D”
Economist Pharmaceutical Roundtable, Geneva 2003
Phar
mac
eutic
als
Phar
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als
Dia
gnos
tics
How are we dealing with it?Roche Group R&D: A unique global innovation network
Phar
mac
eutic
alsThe Roche Innovation Model
Same philosophy throughout the group
GenentechChugai
Penzberg
Palo Alto
Basel
NutleyInnovation
Engine
Alliances, collaborations and In-Licensing
Roche Research Sites
Spin-offsRoche Group Member
Phar
mac
eutic
alsWhat makes the Roche Group
Distinct?
• “Hub and Spoke” model for the Group
• Invest in Rx and Dx, spanning from predisposition to monitoring
• Biotechnology
• Targeted therapies aimed at clear clinical differentiation
• We will not go into “mega mergers”
• We invest in R&D in markets with high intellectual resources
Phar
mac
eutic
alsThe Roche Innovation Model is Distinctive
Provide the freedom to innovate…TargetAssess
LeadId
LeadOpt
EIH Enable
PhaseI Reg
PhaseIII
PhaseII On Market
New MedProposal
Leverage Global Systems to support innovation centers
• Informatics: Rodin, NMP• Screening; Library• Knowledge management• Portfolio management
GNE
CHU
PA
NU
BA
PZ
Philosophy:
• Foster innovation; “central control inhibits innovation”
• “Performance Units” are the Innovation Centers
• Global systems’ goals are to make the performance units more successful
• Assess success against common standards
Challenges:• Complex
management model
• Aligning organization to the model
• Measuring performance around appropriate measures and timeframes
• Discipline to stay with the strategies
Phar
mac
eutic
alsChange the Shape of the Funnel
Accelerate attrition earlier in development
TargetAssess
LeadId
LeadOpt
EIH Enable
PhaseI Reg
PhaseIII
PhaseII On Market
New MedProposal
Research R&D Development
Enhanced Safety Testing:• Tools for earlier
predictions: e.g. Toxicogenomics
• Earlier clinical safety evaluations: e.g. non-critical path
• “Knowledge” not “data”Mix of small molecule and
protein approaches
Eliminate the compounds that would be terminated due to safety earlier during less expensive phases
Reduce attrition in Phase 2b/3 due to safety failures
Phar
mac
eutic
alsChange the Shape of the Funnel
Earlier identification of efficacy
TargetAssess
LeadId
LeadOpt
EIH Enable
PhaseI Reg
PhaseIII
PhaseII On Market
New MedProposal
Research R&D Development
Efficacy predictions:• Biomarkers
•Responsers/non-responders•Side effects
• Translational medicine
• Patient studies in Phase 1
• Meaningful preclinical efficacy studies
Provide better prediction of outcome in phase 2, 3 and on market
Increase the success rate in phase 2, 3, and value of medicine to patients
Phar
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eutic
als
01020304050607080
2000 2001 2002 2003 2004 2005
Ph 0 Ph 1 Ph 2 Ph 3 Major NI*
The Portfolio is Showing Positive Indications…But a portfolio is only a surrogate for value
* Major new indications (NI) in development phase III only; not counting those filed
No of NMEs and Major NIs
No standarddefinition on NI
Phar
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als
45
3936
3330 30
2622 21 20
16 1513 12 12 11
7 6 5 305
101520253035404550
Roc
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Mer
ck
GSK
Sano
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vent
is
Pfiz
er
J&J
Nov
artis
Abb
ott
Ast
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neca
Wye
th
Bay
er
BM
S
Sche
ring
Boe
hrin
ger-
Inge
lhei
m
Lilly
Nov
oNor
disk
Take
da
Am
gen
Eisa
i
Sche
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Plou
gh
We Are Also Accessing External InnovationRoche Group # 1 in 2004 Deals
Source: Recombinant Capital
Phar
mac
eutic
alsA word from our partners…
“Roche involved us from the outset in the development of our compound and enabled us to build our company around it.” Dan Santi, CEO Kosan Biosciences
“Roche involved us from the outset in the development of our compound and enabled us to build our company around it.” Dan Santi, CEO Kosan Biosciences
“The alliance directors at Roche make a partnership work –not a big pharma way, not a biotech way – but a better way.”
Dan Korpolinksi, CEO, Stressgen Biotechnologies
“The alliance directors at Roche make a partnership work –not a big pharma way, not a biotech way – but a better way.”
Dan Korpolinksi, CEO, Stressgen Biotechnologies
“Roche’s team is very fast, very clear with its decision-making process and very efficient in the way it moves to final contracts.” Glyn Edwards, CEO Antisoma
“Roche’s team is very fast, very clear with its decision-making process and very efficient in the way it moves to final contracts.” Glyn Edwards, CEO Antisoma
“It’s a true partnership. Roche involves us in decision making and execution.” Tony Scullion, CEO Memory Pharmaceuticals
“It’s a true partnership. Roche involves us in decision making and execution.” Tony Scullion, CEO Memory Pharmaceuticals
Phar
mac
eutic
alsKey Messages
• We have successfully managed the „productivity crisis“ of the late 90‘s
– Distinct Roche Group R&D model– Unique way to access external innovation
• We have also implemented internal processes to enhance the quality of our programs and molecules
Big Pharma and Biotech: United we stand, divided we fall
Margaret BeerDirector,
Licensing and External Research, Europe,Merck &Co
Mission control we have a problem
0
5
10
15
20
25
30
35
1980 1984 1988 1992 1996 2000 2004
Industry R&DExpense
($ Billions)Annual NME
Approvals
-200-180-160-140-120-100- 80- 60- 40- 20- 0
Source: PhRMA, FDA, Lehman Brothers; The 2004 Industry R&D expense is an estimate
R&D InvestmentNME Approvals
Merck’s Research and Development Strategy
Internal R&D
Early research programs
Product candidates
Formulations/Drug delivery
Enabling/Platform technologies
•Accelerate research•Broaden pipeline•Enlarge current franchises
• Ensure a strong internal research capability and leverage it with the best external science
• Continually evaluate potential transactions – from early to late stage product opportunities – in a coordinated approach across the Company
Democratization of Drug Discovery
• “Big Pharma” discovery tools are now widely available- Molecular biology- HTS assays- Sample collections- Medicinal chemistry- Assays for “off target” activity- P450 assays- QT prolongation assays
• The barrier to entry to Phase I is going down- Experimental Use IND
• This is increasing the number of PCCs & PI compounds across the industry
Collaborations between Biotechs and Big Pharma Create Value for Both Parties
Big Pharma• Access to Technology• Access to Products
Biotech• Discovery/Development Resources• Commercialization Resources
Combined Innovation / Value
• Validation of scientific approach• Increased speed and ability to tackle projects in parallel• Ability to bring projects forward that could not exist withoutpartnership
• Creation of new IP/technology/products by working together
Commitment to R&D and External Alliances
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1998 1999 2000 2001 2002 2003 2004
Bill
ions
$
14% CAGR - No floor or ceiling for number of deals- Equal incentives for licensed / internal programs
- Transactions in all R&D stages- Flexibility in deal structures- Speed in deal making-Creation of value for each partner-Leverage strengths of each partner- Long-term thinking• 2004 R&D spending
-$4.0 billion
• 2005 R&D spending projected at same level as 2004
Ideal profile of an In - licensed NCE
• Unmet medical need; Novel MOA; First / best in class• Selectivity against a large range of receptors, enzymes, ion
channels• Potency• Oral bioavailability (if a small molecule)• Evidence that molecule “hits the target” in animals
- Minimally a PD assay- Ideally a response in a validated animal model that
recapitulates the disease• Preliminary safety data• A strong IP position • If not novel, then clinical data is needed to discriminate from its
rivals
Areas of Focus for Merck
In Current Merck Therapeutic Areas
In New / Must Win Therapeutic Areas
Type II DiabetesObesityNeuroscienceOncologyAtheroma
Anti-InfectivesAnti-ViralsAtherosclerosis CardiovascularGastrointestinalImmunology/RheumatologyOphthalmologyRespiratoryWomen’s/Men’s EndocrinologyUrologyVaccines
Technology Platforms
Drug Delivery Research TechnologiesMolecular ProfilingBiologics & AntibodiesNew Vaccine Technology
Biotech/Big Pharma Will Continue to Enjoy a Symbiotic Relationship
• Given the recent explosion in drug discovery approaches, biotechwill play an increasing role in providing compounds and technology to large pharma
• These products will continue to require big pharma expertise andresources (financial and personnel)
• This will enable biotechs to learn so these companies can becomemore independent and market own products
What has Merck done in this respect?
Merck’s Licensing Process- Creation of:
• Worldwide Licensing & External Research position at Sr. VP Level• Merck External Research Team• Alliance Management Group
- Objective setting and continuous prioritization in place and running• Cross divisional• Linked with worldwide business strategy for each franchise
- Efficient screening of all opportunities• Over 7000 per year• Proactive and reactive• Strategic and opportunistic• Involvement of 235 Merck therapeutic experts in basic biology and chemistry,
preclinical, patent, clinical and worldwide marketing- Rapid access and involvement of senior management on daily basis- Large outreach program ongoing
50 Completed Transactions in 2004 –Including 6 Compounds in Clinical Development
Compounds in Development
Other Compounds and Programs
Increasing R&D Productivity / Technologies
Aton – Cancer BMS – Diabetes Dov – CNS Lundbeck – CNS
Nastech – Obesity Ono – Stroke
Acumen – CNS Alnylam – Ophthalmic Intercell – Bacterial vaccines Kyorin – Infection Metabasis – HCV Pierre Fabre – Cancer Rigel – Cancer Sunesis – Infection TransTech – Diabetes Vertex – Cancer
Benitec – RNAi technology BioImage – imaging technology Celera Diagnostics – Alzheimer’s Chembridge – Chemistry deCODE – Pharmacogenomics Genetronics – Vaccines Gene Bridges – Genomics High Throughput Genomics – AssaysIngenium – Genomics Ingenuity – Screening Mouse Clinical Institute –
Phenotyping technology Norak – Screening Oxford Biomedica – Gene technologyRobarts – Imaging technology SurroMed – Screening
Excludes transactions not publicly disclosed
10
22 23
38
4750
0
10
20
30
40
50
60
1999 2000 2001 2002 2003 2004
Conclusions
• External alliances with biotech companies are essential for Big Pharma’s growth
• Because there is a high risk of failure in drug discovery, multiple partnerships are critical to help increase the probability of success
• Various types of partnerships, integrated throughout the drug development process will increase productivity
• Merck views the creation of alliances as critical for continued success - Alliances at all stages of the discovery and development
process complement our robust and therapeutically diverse pipeline
Merck Partnering Benefits
• Premier scientific research organization- Excellence in translating cutting-edge science into break-
through medicines• Product development and regulatory expertise• Extensive manufacturing infrastructure• Demonstrated worldwide marketing capabilities• Excellence in deal making and alliance management
Back Ups
Merck’s Research and Development Strategy
• Ensure a strong internal research capability to capitalize on scientific innovations which can address medical needs
• Leverage this capability through collaborations with the best external scientific organizations to drive growth
• Continually evaluate potential transactions - from early to late stage product opportunities - in a coordinated approach across the Company
Build on Merck’s true competitive advantage the quality of Merck Research
Cardinal Health: from early development to commercial manufacturing
Lorenzo PradellaBusiness Development Director,
Cardinal health Ltd
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Cardinal Health Corporate Overview• Leading provider of innovative products
and services to the health care industry• A $65 billion, Fortune 16 company• 55,000+ employees on
5 continents• Market leadership positions in
– Pharmaceutical development, manufacturing and packaging
– Pharmaceutical distribution– Medical-surgical manufacturing
and distribution– Automation and information services
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Cardinal Health Core Business SectorsMedical Products and Services
• Manufacturing• Distribution• Provider consulting• Medicine safety consulting
• Drug distribution and logistics• Blood products• Formulary consulting• Pharmacy management• Franchised retail pharmacies
Pharmaceutical Distribution and Provider Services
Clinical Technologies and Services• Development and marketing of products
for safe delivery of IV medications– IV med and infusion therapy
delivery systems, software applications, needle-free disposables and related monitoring equipment
– Track record of breakthroughs in improved safety and streamlining
• Automated dispensing• Clinical and market information
Pharmaceutical Technologies and Services
• Discovery and development• Drug delivery• Manufacturing• Packaging• Healthcare marketing services
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Overview—Who We ArePharmaceutical Technologies & Services
• Nearly $3 billion in revenue• 16,000 employees worldwide• Significant intellectual property and
expertise covering oral, sterile and pulmonary dosage forms
• 4 million sq ft of manufacturing and laboratory space on 5 continents
• Nearly 2 billion doses produced per week
• 85% of the top 200 drugs utilize our services
• Comprehensive provider of proprietary, best-in-class solutions
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
How We FormedPharmaceutical Technologies & Services
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Our Range of OfferingsPharmaceutical Technologies & Services
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Discovery and DevelopmentPharmaceutical Technologies & Services
• Over 1,000 scientists and technicians worldwide
• Proven track record of product approvals• Superior analytical capabilities with difficult
and complex drugs• Extensive development expertise in virtually
all dose forms• Leader in global clinical trial supplies
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Discovery and Development• Bioanalytical services• Small and large molecule synthesis• Cell culture development• Biologics development capabilities• Dose form/formulation development• Analytical methods development
and validation• Structural chemistry
1 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Discovery and Development• Inhalation development and analytics• Microbiological testing• Import/release testing• Stability studies (protocols, ICH
storage, analysis)• Clinical manufacturing and packaging
2 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Enhancement and Delivery TechnologiesPharmaceutical Technologies & Services
• World leader in both traditional and advanced drug delivery
• Unique, patented technologies with demonstrated market results
• Proven dose forms with real benefits• Expertise with drugs and biologics • Experience in formulations that can improve
performance—in clinical trials, in patients and in the market
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Enhancement and Delivery Technologies
Oral Technologies:• Soft gelatin capsules
(enhance bioavailability)• Vegicaps® Soft capsules (plant derived)• Zydis® (fast-dissolve dosage form)• EnSolv® (improve dissolution)• EnCirc® (higher drug loading)• EnVel® (taste masking)• Particle coatings (controlled release)• PhoqusTM Technology (controlled release,
branding)
1 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Drug Enhancement and Delivery Technologies
Sterile Technologies:• Lyophilization• Sterile liposomesInhaled Technologies:• MDIs• DPIs• Nasal spraysTopical Technologies:• Microsponge® (time-released)• DelPouch® (unit dosing)
2 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Gene Product Expression (GPEx)• Mammalian Cell Line Engineering Technology• Patent protected/proprietary, first GPEx Patent
(No. 6,852,510) Issued 02/08/05
• High producing GPEx clonal cell lines are produced in 10 – 12 weeks
• Protein is available for analysis starting 3 weeks after initial cell transductions
• The GPEx process is very consistent for a wide variety of proteins, antibodies and fusions with good specific productivities obtained
• Solid regulatory path with FDA has been established
Pharmaceutical Technologies & Services
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Gene Product Expression (GPEx)• No need for antibiotic selection or use of
toxic compounds for gene amplification• Rapid creation of stable, high yielding
mammalian cell lines from client cDNA –0.5-1.25 g/l in less than 5 months
• Applicable to a wide variety of mammalian cell types, including CHO and 293 HEK
• Scaleable from µg to kg• Solid regulatory path with FDA has been
established• Cardinal Health offers manufacturing and
support services from gene to the clinic…and beyond
1 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Gene Product Expression (GPEx)• 43,000 sq. ft. multi-purpose facility in Middleton, WI• Administration• GPEx™ cell line engineering
• Molecular biology• Biocontainment suites (18)
• Vector design/optimization• Cell line development
• Process development, tox. lots (100L), etc.• Protein biochemistry• Regulatory Oversight (QA, QC, etc.)• Cell Banking area - Class 100 bio. cabinet, controlled rate freezer, etc.• Cell based mfg. - Class 100,000 air (2 suites in operation, with 3rd under construction)• Protein purification - Class 10,000 air (2 suites in operation, with 3rd under construction)• Support functions - raw material approval, storage, shipping, etc.
cGMP
2 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
ManufacturingPharmaceutical Technologies & Services
• World leader in dose form manufacturing• Nearly every type of dose form available on
the market today – oral, sterile, topical, respiratory and ophthalmic
• Clinical and commercial scale• Multisite capabilities for launch demand• Specialized capabilities for lyophilized,
cytotoxic and potent drugs, as well as biologics
• Proven regulatory track record
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Manufacturing• Clinical and commercial manufacturing• Proprietary and traditional oral dose forms• Inhaled dose forms• Blow/fill/seal• Liquid and lyophilized sterile products• Prefilled syringes• Creams and ointments • Proprietary cell line creation• Mammalian cell culture process development
and cGMP manufacturing
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Packaging and PrintingPharmaceutical Technologies & Services
• Global contract packaging facilities with standardized packaging equipment
• Over 240 individual packaging suites • Leader in pharmaceutical product launches • Produces over 120,000,000
pharmaceutical cartons per month• Clinical packaging available in the U.S. and
Europe• Commercial printing for promotional needs• One partner for blisters, pouches, bottles
and specialty packaging
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Healthcare Marketing ServicesPharmaceutical Technologies & Services
• Comprehensive service portfolio encompassing medical education, medical communication, field meeting logistics, sales services and third-party logistics
• Sales force, continuing education and promotional tactics and services that drive strategy and content into the marketplace
• Integrated commercialization platforms—from development to delivery, from orphan drugs to blockbusters
• Launch support, “ramp-up” strategies and brand repositioning plans
• Dedicated regulatory/compliance resources
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Scientific and Regulatory ServicesPharmaceutical Technologies & Services
• Strategic global approach – U.S., Europe, Canada, and Japan
• Highly-experienced staff and extensive network of leading experts
• Long-term relationships with many U.S. and international clients
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Scientific and Regulatory Services• Scientific regulatory affairs and strategic
planning• Preparation and submission of regulatory
documentation in traditional, CTD and/or electronic formats
• CMC operations• CMC scientific consultation
– Analytical methods: development, validation and transfer
– Formulation development: study design, optimization, process validation design and reports
• Contract manufacturing, packaging and testing
1 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Scientific and Regulatory Services• Nonclinical and clinical operations• Project coordination, facilitation, design, placement
and monitoring of studies• Preparation and quality assurance review of
documentation– Perform GLP and GCP audits– Integration of nonclinical and clinical programs,
sections and full reports– Ph.D. toxicologist on staff, extensive network of leading
experts– Specialized research studies
• Training programs– Qualified team, up-to-date training courses, including GxP
regulations, FDA guidance documents, regulatory submissions and other regulations
– Courses may be offered on-site at client locations
2 of 2
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Logistics and DistributionPharmaceutical Technologies & Services
• Comprehensive logistics, receivables, returns and chargeback management for drug and biologics
• Specialty distribution for drugs and biologics requiring specialized or controlled handling
• RAPIDistributionSM – 48 hours from launch to pharmacy shelf
• Clinical, commercial and sample distribution capabilities
206
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Cardinal Health
• Drug development– Expertise in every phase of the product life cycle– The added benefits of working with a single
source for multiple processes
• Product supply– A leader in manufacturing and distribution– Outstanding products and services for all
aspects of the health care industry
• Health care marketing– Assistance in the promotion and
commercialization of products and technologies– Unique insight into the people and practices of
the health care industry
The success of your business is our business.
Partner with Cardinal Health
© 2004, Cardinal Health, Inc., or one of its subsidiaries.
Life Sciences on SWX Swiss Exchange
Philippe-Jean Allamel VP Issuer and Investor Relations
SWX AG
July 2005SWX Swiss Exchange
The SWX Group : an international exchange services provider
50 % 100 % 33.3 % 100 %100 %
July 2005SWX Swiss Exchange
Source: FESE
0
50'000
100'000
150'000
200'000
250'000
SWX Gro
upLondon
Euronex
t
Copenhag
en
OMX
BMEBorsa
Italia
naEUR m.
Deutsc
he Börse
Status: July2005
SWX Swiss Exchange : a leading Life Sciences exchange in Europe
Largest stock Exchanges in Healthcare(Market Cap. approx. by Dow Jones Stoxx TMI companies)
July 2005SWX Swiss Exchange
Switzerland : a strong Life Sciences presence with clusters effects :
Novartis Roche SeronoBerna Biotech
Federal Institute of Technology
Universities
Technoparcs
Incubators
Source: UBS and Ernst & Young
July 2005SWX Swiss Exchange
Peer Group (companies with primary listing on SWX)
Source: SWX
As per 31.05.05Included in SMI
Short name Mkt value F. float Country2004
TOTAL HEALTHCARE 290'227 96.9%NOVARTIS N 153143.2 0.941 81.3% CHROCHE GS 110583.4 1 114.7% CHSYNTHES N 7161.1 0.3515 25.4% USNOBEL BIOCARE I 6406.5 1 84.0% CHSERONO -B- I 4199.9 0.5958 222.8% CHACTELION N 2634.7 0.9368 163.5% CHSTRAUMANN N 1913.7 0.4903 131.5% CHPHONAK N 1940.5 0.6459 98.2% CHBASILEA N 371.9 0.6145 76.6% CHBERNA N 343.6 1 63.7% CHTECAN GROUP AG N 384.3 0.8761 198.5% CHYPSOMED HLDG 413.2 0.25 81.2% CHUNILABS I 219.6 0.783 54.0% CHCYTOS N 166.9 0.8757 61.9% CHISOTIS N 122.7 1 47.7% CHARPIDA 74.8 0.3298 n.a. CHORIDION SYSTEMS 50.2 1 n.a. ILCARD GUARD N 40.4 0.87 68.4% CHIVF HARTMANN N 28.8 0.4 11.8% CHSHL TELEMEDICINE 27.9 0.3964 n.a. IL
Liquidity ratio in % of market cap.
July 2005SWX Swiss Exchange
SPI industry breakdown 2005
Breakdown as of July 2005
Source: SWX Swiss Exchange
Healthcare34.1%
Banks21.3%
Food & Beverage16.4%
Other7.0%
Cyclicals Goods & Services
3.7%
Insurances7.9%
Chemicals3.3%
Industrial Goods & Services
6.3% > CHF 300 bn
July 2005SWX Swiss Exchange
Benchmarks for one of Switzerland’s leading Sectors:
SXI LIFESCIENCES®
including pharma, medtech and biotech companies
The more focused SXI Bio+Medtech®
subindex
Two major indices : SXI LIFESCIENCES® and SXI Bio+Medtech®
Investment CompaniesIndex
Securitieswith freefloat <20%*
Swiss shares(Swiss All Share Index)
Foreignshares
July 2005SWX Swiss Exchange
SXI LIFE SCIENCES®
Basket:Advanced medicaldevicesMedical suppliesBiotechnologyPharmaceuticalsHealth-care providersQualified investmentcompanies(>50% of portfolioholdingsin non-index companies)
Biotech36.2%
Medtech42.3%
Pharma21.5%
SXI LIFE SCIENCES®; basket composition(as per 31.12.2004)
July 2005SWX Swiss Exchange
SXI Bio+Medtech®
Basket:Advanced medicaldevicesMedical suppliesBiotechnologyHealth-care providers
Medtech50.0%
Biotech50.0%
SXI Bio+Medtech®; basket composition(as per 31.12.2004)
July 2005SWX Swiss Exchange
Performance of SXI LIFE SCIENCES®
0
50
100
150
200
250
Dez 99
Mrz 00
Jun 00
Sep 00
Dez 00
Mrz 01
Jun 01
Sep 01
Dez 01
Mrz 02
Jun 02
Sep 02
Dez 02
Mrz 03
Jun 03
Sep 03
Dez 03
Mrz 04
Jun 04
Sep 04
Dez 04
Mrz 05
Jun 05
Adj
uste
dIn
dex
Valu
e
SXI Life ScienceDJ STOXX 600 HealthcareAMEX Healthcare Index
Source:
SWX Swiss Exchange
July 2005SWX Swiss Exchange
Performance comparison – bio & medtech
0
50
100
150
200
250
Dez 99
Mrz 00
Jun 00
Sep 00
Dez 00
Mrz 01
Jun 01
Sep 01
Dez 01
Mrz 02
Jun 02
Sep 02
Dez 02
Mrz 03
Jun 03
Sep 03
Dez 03
Mrz 04
Jun 04
Sep 04
Dez 04
Mrz 05
Jun 05
Adj
uste
dIn
dex
Valu
e
SXI Bio & MedtechDJ EURO STOXX Pharma + BiotechAMEX BiotechnologyNasdaq Biotechnology
Source:
SWX Swiss Exchange
July 2005SWX Swiss Exchange
Comparison of market multiples
No valuation gap between US and leading European stock exchanges in the life science sector High medtech multiples in Switzerland
Market Multiples 2004Pharma / Biotech (MSCI Classification)2004 EV/EBITDA EV/Sales
Switzerland 14 4.1France 13.9 4.4UK 11.3 3.5Germany 8.9 1.9Europe 12.6 3.7USA 13.5 4.8Healthcare Equipment & Services (MSCI classification)2004 EV/EBITDA EV/Sales
Switzerland 17.7 3.8France 9.6 2.3UK 12.1 0.8Germany 8.6 0.3Europe 12.6 1.1USA 7.3 0.5
Source: UBS Investment Bank EquityResearch
July 2005SWX Swiss Exchange
Life science at SWX – High Visibility
Analyst coverage:Strong coverage by 60 brokers/banks International research providersCoverage provided for life science companies > CHF 100 m (~threshold value in terms of free float)
Media coverage:High attention to every IPO at SWXHigh attention of listed companies due to manageable size of total market
Investor attention: Strong peer groupLong tradition in life science investmentsFocus on small and mid caps
July 2005SWX Swiss Exchange
Analyst coverage in the life-science sector
Source: Thomson Financial
July 2005SWX Swiss Exchange
Basic listing requirements at the SWX
*Segment SWX Main
MarketSWX
Local CapsInvestment
CompReal Estate
Comp.Funds (ETF)
Accounting Standards IFRS, -US-GAAP**
Swiss GAAP FER** Swiss GAAP FER** Swiss GAAP FER** AFG/AFV
Interim Reports half year half year half year half year half year
Track Record 3 years 2 years - - -
Free Float 25% 20% 25% 25% 25% or Market-Makingobligation
Min. market cap. of Free Float (CHF)
25 Mio. 5 Mio. 25 Mio. 25 Mio. 25 Mio.
Equity Capital (CHF) 25 Mio. 2,5 Mio. 25 Mio. 25 Mio. 100 Mio. assets
Requirements *
* Special rules apply to young companies**The national standards from Australia, Canada, Japan, New Zealand,
South Africa are accepted for foreign issuers with a primary or secondarylisting at SWX
July 2005SWX Swiss Exchange
Advantages of a listing at the SWX
Continental Europe's most international marketplaceLeading financial centre for equity-investing institutionalsHigh attention for IPOs (and beyond) – high placing powerApproval of several accounting standards (US-GAAP, IFRS, FER) for both equity and bondsRapid listing procedure (approx. 4 weeks), no qualitative audit of the issuer by SWXStrong private banking investor baseShort communication paths – high concentration of investors in few locations : Geneva and ZurichMultilingual and multicultural Swiss investorsNumerous banks with strong research activitiesLow currency risk (listing in CHF)Active derivative and bond market
July 2005SWX Swiss Exchange
Thank you for your attention !
SWX Swiss Exchangewww.swx.com
GENEVA OFFICE :Philippe-Jean Allamel – tel : +41 58 854 56 32Vice President - Issuer & Investor Relations
ZURICH HQ :Dr. Yvonne Wegmann, Vice President, Head of Issuer & Investor Relations
Christoph Schuler,Relationship Manager Issuer & Investor Relations
July 2005SWX Swiss Exchange
Disclaimer
None of the information contained herein constitutes an offer to purchase or sell a financial instrument traded on the SWX Swiss Exchange. The SWX Swiss Exchange assumes no liability for the accuracy or completeness of said information nor for any damage arising from actions taken on the basis of information contained in this or any other of its publications. The SWX Swiss Exchange expressly reserves the right at all times to alter the prices or product composition.
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BioValley, a unique trinational Bioregion
Romeo Paioni Head Scientific and External Affairs
Novartis Pharma
RP 2005ELISSI, 2005
Vision of the BioValleyBioValley Project
The Life Sciences Network
The BioValley initiative aims to encourage the foundingThe BioValley initiative aims to encourage the foundingof new companies and the creation of new and innovativeof new companies and the creation of new and innovative
jobs in life sciences/biotechnology in the crossjobs in life sciences/biotechnology in the cross--border regionborder regionsituated around the Upper Rhine betweensituated around the Upper Rhine between
Germany, France and Switzerland.Germany, France and Switzerland.
RP 2005ELISSI, 2005
Project : A Project : A TrinationalTrinational InitiativeInitiative
AssociationAlsace BioValley
BioValleyDeutschland e.V.
BioValley PlatformBasel
Colmar
Strasbourg
Freiburg i.B.
Basel
Mulhouse
•• > 4 Million > 4 Million InhabitantsInhabitants•• 4 major 4 major UniversitiesUniversities•• 30 Life Science Institutes30 Life Science Institutes•• ~ 100´000 ~ 100´000 StudentsStudents•• 4 Life Science Global 4 Life Science Global PlayersPlayers•• > 450 Life Science SME´s> 450 Life Science SME´s
(~ (~ 11//33 foundedfounded sincesince 1990)1990)•• HighlyHighly developeddeveloped infrastructureinfrastructure•• ExcellentExcellent educationaleducational facilitiesfacilities
Spotlights on BioValleyin Nature and Science2000 - 2001 - 2002
Spotlights on Spotlights on BioValleyBioValleyin Nature and Sciencein Nature and Science2000 2000 -- 2001 2001 -- 20022002
RP 2005ELISSI, 2005
Main Activities and ServicesMain Activities and Services
•• Trade Show representationTrade Show representation(e.g. BIO, USA ; (e.g. BIO, USA ; BiosquareBiosquareBasel, Lyon)Basel, Lyon)
•• National Round TableNational Round TableMeetings (“Stammtische”)Meetings (“Stammtische”)
•• BioValley UniversitiesBioValley UniversitiesPartnership Partnership ProgrammeProgramme
•• BioValley FinancialBioValley FinancialCounsellingCounselling (Business plans)(Business plans)
•• BioValley Life BioValley Life SciencesSciences WeekWeek
Promotion Tools
• BioValley Journal(4/a, 6000 Copies)
• BioValley Guide(Synopsis, CD-ROM)
• BioValley e-Newsletter
• Internet Domain• BioValley Report
www.biovalley.comwww.biovalley.com
RP 2005ELISSI, 2005
Novartis Pharma: Innovation StrategyNovartis Pharma: Innovation Strategy
Diseases AreasDiseases Areas Core TechnologiesCore Technologies
Strong internal Research & Development (CH, US, UK, F, A, Strong internal Research & Development (CH, US, UK, F, A, J)J)
AI&TXAI&TX CVCV MDMD MuSMuS RDRD ONCONCNSNS
Aligned external R&D (Biotech, Academia) through BD&LAligned external R&D (Biotech, Academia) through BD&L(~ 30% of R&D Budget)(~ 30% of R&D Budget)
IDID FGAFGA CTACTA
New MethodsNew Methodsphotons / 25 µsphotons / 25 µs
num
ber o
fnu
mbe
r of
part
icle
spa
rtic
les
Fluorescence Intensity Fluorescence Intensity DistributionDistribution
Miniaturization in HTSMiniaturization in HTS
old 96 wells MTPold 96 wells MTP(200 µl /well)(200 µl /well)
Proprietary Fluorescence AnalysesProprietary Fluorescence Analyses
FF
new 2400new 2400--well CD waferwell CD wafer
V = 1.5 µlV = 1.5 µlE.coliE.coli
laserlaser
1..3 mm1..3 mm
1 mm1 mm
testingscientificconcepts,
new targets
rapid entry - new fields
accesslead
therapies
accessnew enablingtechnologiesand IT tools
RP 2005ELISSI, 2005
Reminder: R&D Process, Chances and Costs Reminder: R&D Process, Chances and Costs (Average(Average
Probability
PoC*Selection
PRECLINICAL CLINICAL
Phase I II III IV
RESEARCHRESEARCH DEVELOPMENTDEVELOPMENT MARKETMARKET
Identification
10’00010’000-
>100’000Compounds
12%12% 75%75% 100%100%
11
ca. 1/3ca. 1/3 ca. 2/3ca. 2/3
500 500 --800 Mio $800 Mio $
Costs
Phase ofIntroduction
66--88 1.51.5
2 2 -- 4 years4 years 4 4 -- 7 years7 years
* * PoCPoC = Proof of Concept= Proof of Concept
RP 2005ELISSI, 2005
Novartis Pharma and Corporate Research:Novartis Pharma and Corporate Research:Worldwide Community 2004Worldwide Community 2004
JapanCardiovascul
arDiabetes
La JollaGNF
Functional Genomics
New JerseyOncology,
Arthritis + Bone Metabolism
FunctionalGenomics
Cambridge/Boston(built up)
Metabolism, Cardiovascular Disease
Infectious Disease
BaselFMI
SingaporeNITD
Tropical Diseases
ViennaDermatology/
Immunpathology
UKRespiratory
DiseaseChronic Pain
BaselNervous systemTransplantation
OncologyArthritis/Bone
MetabolismFunctional Genomics
Ophtalmics
>3300 scientists2004: >1 bio USD
RP 2005ELISSI, 2005
““Big Pharma” and “Biotech” CollaborationsBig Pharma” and “Biotech” Collaborations
RESEARCHRESEARCH DEVELOPMENTDEVELOPMENT MARKETMARKET
Discovery Technologies Transfer, CompoundsDiscovery Technologies Transfer, CompoundsInIn-- and outand out-- Licensing, CoLicensing, Co--CommercializationCommercialization
In a “winIn a “win--win” Partnership Dealwin” Partnership Deal
RP 2005ELISSI, 2005
NOVARTIS Pharma: Major R&D Collaborations 2004NOVARTIS Pharma: Major R&D Collaborations 2004
Chiron
Myriad
Tanox
Medarex
Celgene
KTFEvotec
GeneData
Univ. Wien
GenProt
Rigel
Biosite
Titan
BiotransplantDana-Farber
Pharmacopeia
John Hopkins
Scripps
Trega
Incyte
Cubist
Infigen
Yoshitomi
FMIKnollGenentech
Versicor
Celera
Vertex
ZNZ
Protana
Mochida
Morphosys
Emisphere Tech.Elan
Xenogen
MPRCBiozentru
mCytos
RP 2005ELISSI, 2005
National Strengths through competent clusters National Strengths through competent clusters
Source: Swiss Biotech
RP 2005ELISSI, 2005
Largest "Biotech Clusters" in Europe Largest "Biotech Clusters" in Europe (>100 Companies(>100 Companies
Köln/DüsseldorfKöln/Düsseldorf
London/CambridgeLondon/Cambridge
ParisParis
Lyon/Lyon/GrenobleGrenoble
Stockholm/UppsalaStockholm/Uppsala
MediconMedicon ValleyValley
BerlinBerlin
MünchenMünchen
adapted fromSpectrum, Juni 2002
RP 2005ELISSI, 2005
RP 2005ELISSI, 2005
Major Global Regions ofMajor Global Regions ofBiomedical Scientific ExcellenceBiomedical Scientific Excellence
California
New England
SE Asia
United Kingdom
NewJersey/NY
Japan
Maryland/North Carolina
Central & NorthernEurope
RP 2005ELISSI, 2005
Conclusion Conclusion
Big Pharma & Big Big Pharma & Big BiotechBiotech Big Big BiotechBiotech WorldWorld
Partners in InnovationPartners in Innovation
Domande?Questions?
AFTI
Valter [email protected]
Giovanni [email protected]
Michele Mü[email protected]
ASIRBTiziano Balmelli
Gianni [email protected]
ATCMassimo Bossi
[email protected] Macchi
Biopolo Ticino Luca Bolliger [email protected]
The EndThank you to sponsors, presenters, participants
and exhibitors!
Let’s network and…We will be back in 2006!!!!