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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%


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


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)


‚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


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


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


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


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


Come forbusiness, stay for a lifestyle !

Thank you for your attention!

DNA: an economist’s perspective

Giovanni Barone AdesiProf USI, Lugano

http://de.wikipedia.org/wiki/Bild:DNA.jpg

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




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


Fig. 2a JY, T1, and T2 target-sensitization in comparison using the effector cell line D98b

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E/T ratio

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


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




?

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

Contact

[email protected]

Thank you!

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


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.


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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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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1

2

3

4

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)

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

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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%

10%15%20%25%30%

0-10

0

100-

200

200-

300

300-

400

400-

500

500-

600

600-

700

700-

800

800-

900

900-

1000

1000

+

MW of novel Evolva compounds

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

http://www.evolvabio.com/

mailto:[email protected]

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


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


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


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


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


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


Antibody fragment pipeline of ESBATech

Indications Research Preclinic Phase I Phase II Phase IIIESBA105 Inflammation

ESBA105 Inflammation

ESBA105 Inflammation

ESBA212 Alzheimer

ESBA521 Glioblastoma


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


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


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


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)


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


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


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

mac

eutic

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

mac

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

mac

eutic

als

45

3936

3330 30

2622 21 20

16 1513 12 12 11

7 6 5 305

101520253035404550

Roc

he

Mer

ck

GSK

Sano

fi-A

vent

is

Pfiz

er

J&J

Nov

artis

Abb

ott

Ast

raZe

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

ring

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


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


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


How We FormedPharmaceutical Technologies & Services


Our Range of OfferingsPharmaceutical Technologies & Services


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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 %


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)


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


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.


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


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


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)


SXI Bio+Medtech®

Basket:Advanced medicaldevicesMedical suppliesBiotechnologyHealth-care providers

Medtech50.0%

Biotech50.0%

SXI Bio+Medtech®; basket composition(as per 31.12.2004)


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


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


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


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


Analyst coverage in the life-science sector

Source: Thomson Financial


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


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


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


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.

The SWX Swiss Exchange is a joint stock company established under the laws of Switzerland, operating a stock exchange authorised and regulated by the Swiss Federal Banking Commission. The SWX Swiss Exchange is a recognised stock exchange in France, Italy, Netherlands and the UK and is authorised to operate in Austria, Finland, Germany, Sweden and Belgium.

SWX®, SWX Swiss Exchange®, SMI®, Swiss Market Index (SMI)®, SPI®, Swiss Performance Index (SPI)®, SPI EXTRATM, SMIMTM, SXITM, SXI LIFE SCIENCESTM

and SXI Bio+MedtechTM are filed marks of the SWX Swiss Exchange. Their use is subject to licensing.

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

[email protected]

Biopolo Ticino Luca Bolliger [email protected]

http://www.biopolo.ch/

http://www.atc-ti.ch/

http://www.tinet.ch/ASIRB/

http://www.afti.ch/

The EndThank you to sponsors, presenters, participants

and exhibitors!

Let’s network and…We will be back in 2006!!!!

elissi 2005 expo life science svizzera italiana presentations/elissi 2005.pdf · 2012. 12. 14. ·...

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