Three Megatrends

Generating Challenges and Opportunitiesin Drug Research

Christian R. NoeUniversity of Vienna

Barcelona, February 23rd, 2010

„sociological“Service to society„From knowledge to advice“

The „peer review system“ will not be enough to secureprogress of science!

Activities of a Scientist

Get out of the ivory tower!

„ideological“Progress of the research field„From hypothesis to knowledge“

„technological“Transfer of knowledge into society„From knowledge to innovation“

„sociological“Service to society„From knowledge to advice“

Long term scientific planning has to consider long term trends!

3 Megatrends

„ideological“Progress of the research field„From hypothesis to knowledge“

„technological“Transfer of knowledge into society„From knowledge to innovation“

The Fading Power of Innovation

The Loss of Fundaments of Co-operation

Robots and Humansin Scientific Work

I.The Fading Power

of Innovation

Innovation is the majordriver of economicprogress!

Joseph Alois Schumpeter(1883 – 1950)

The Theory of Innovation

Kondratjew – Schumpeter cycles

Biotech

The Discreditation of Entrepreneurhip

• Communism: Dual system of workerand capitalist;

• No discrimination betweenentrepreneur and feudalist/ capitalist;.

• Entrepreneur is class enemy.

• Financial feudalism developed and took over power in the shadow of entrepreneurship..

• Entrepreneurship is still discredited as capitalism.

Spirited entrepreneurship is the source of innovation. It has to be promoted!

Alois Schumpeter:The entrepreneurdrives innovation!

Capitalist and entrepreneur

is not the same!

Prototypes of Human Behaviour

Has goals, takes risks,creates innovation

Operates

Entrepreneur Worker Feudalist

Individual characteristis are at the same time socioeconomic prototypes.

Exerts power via assets, usesand imitates innovation

Animal Farm

Funding of Innovation

Low expectation for public researchfunding due to budget constraints.

Mergers „destroy“ technology andinnovation: 2 x 100% = 1 x 150%

Governments have littleroom to move financially.

„Big pharma companies“ are playersin a finance feudalism driven world.

Neither the public sector nor industry may be expectedto secure long term funding of research and innovation.

Innovation and Imitation

High level innovation NDAs:Still funded by „Big Pharma“

Zero innovation generics:Strong support for imitationby Public Sector

Medium level innovation:No chance forimplementation

The antiinnovative character of generics will hamper pharmaceutical innovation more and more.

Funding of drug discovery and early development

Translation of projects into enterprises

Reducing cost of clinical development

New business models for new therapies

Sustainable SMEs

PPP-Systems

Finding alternatives for “generics” regulations

Supporting Innovation

II.The Loss of Fundaments

of Co-operation

Lack of co-operation is lethal forcomplex tasks

The concept of „evolution“ dominated the thinkingof society in the 19th and 20th century by

suggesting „development“ and „progress“.

It included also the „progress of science“.

Charles Darwin1809 - 1882

Jean Baptiste de Lamarck: 1744 - 1829

Gregor Mendel1822 - 1884

The work for a better world - For a long time theethic fundament of scientific cooperation

An amazing amalgam of Kantian idealism and Darwinian rationalismreplaced religion basedethical concepts of co-operation.

Fundaments of cooperation

Immanuel Kant1724 - 1804

Catastrophies oftechnology

Contributions to the end of the trust in progress

Decoding of thehuman genomeG. Venter, 2000

Milestone of greatexpectations and at thesame time end odexaggeratedexpectation.

A Great Goal

Also „positive“ singular events may contribute to thedistruction of the trust in progress.

The End of „Darwinian Idealism“

„Individualistic“ conceptsprevail.

The fundamental trust of scientists in the usefulness of their work as a contribution to the progress of mankind

is exstinugished.

Pseudodarwinism:„Selection“ suggests an active process.„Survival of the fittest“ isactively pursued.

An ethical crisis of science?

The Prisoners´ DilemmaInvented by Merill Flood and

Melvin Dresher, 1950

It is advantageous to be a defector(in a defect system)!

Oscar Morgenstern

John von Neumann

Theory of Gamesand Economic

Behaviour1944

The Evolution of Co-operation

1981

Robert AxelrodtWilliam Hamilton

The world is not only „struggle“ and „war for survival“.

Kinship

Reciprocity

Indirect Reciprocity

Network Reciprocity

Group Selection

Natural selection favours co-operation!

Martin Novak Carl Sigmund

Bio-mathematical Models

DrugDiscovery

PreclinicalPhase ´Clinical Development

DrugReg. Marketing

2009 2011 2013 2018 2019 2020

Pharmacodynamics, -kinetics

Toxicology

Galenic Development

Chemical Development

New TargetLead - First Claims

L. OptimisationDrug Candidate

Phase 1Phase 2

Phase 3

NDA FirstIncome

First marketing activities

TRANSLATIONAL STEPS – „CULTURES“

A Biologist - Designer T.B Pharmacologist - Designer T.C Academia - Industry T.D Lab – Plant T.E Industry – Regulatory T.F Bench – Bed T.G Industry – Health System T.H Doctor – Patient T.

CC

FF

GGEE HH

BB

BB

DD

BB

AA

Target Search

Evolution favours co-operating groups ! (from project team to scientific communitiy and society)

To define and restructure “pharma” sciences

To optimise science communication at all levels

To reorganise education fundamentally

To promote specific professional profiles

To connect training courses and curricula

To promote regulatory-industrial-academic co-operation

To support financially European Scientific Organisation

To build up thematic networks

To establish a European grant system

Measures to promote co-operation

III.Robots and Humans

in Scientific Work

Notitia

Scientia

Investigatio Ars

Ars ()

Scientia

Investigatio

Notitia

„Technique“ isTechnology

Collection of Knowledge

ExperimentalResearch

Awareness of a Problem

around 1750 around 1850

Pharmaceutical industry evolved out of emerging chemicalindustry (frequently based on pharmacies)

Experimental sciences led to innovation andthe „First Industrial Revolution“.

Reductionistic Research:To know more and more about less and less.

Technology Transfer

Collection of Knowledge

InstrumentalResearch

Awareness of a Problem

„Technique“ isTechnology

Collection of Knowledge

ExperimentalResearch

Awareness of a Problem

around 1850 from 1950

LHC-CERN

The „Revolution of the Thinking Machines“

Technology Transfer

Collection of Knowledge

ExperimentalResearch

Awareness of a Problem

TranslationalSciences

KnowledgeManagement

AutomationRobotics

Awareness of a Problem

2009: Robot Scientist Adam

Functional genomicsof orphan genes

Robot Scientist EveDrug screening

from 1950 2009

TranslationalSciences

ArtificialIntelligence

Automation Robotics

Awareness of a Problem

TranslationalSciences

KnowledgeManagement

AutomationRobotics

Awareness of a Problem

2009 around 2050

Artificial and humanintelligence

Tasks for future scientists: To identify problems – To translate knowledge

Bioinformatics allow theinterpretation of huge amounts of data from

genomics, transcriptomics, proteomics, metabolomics and…..

The central task of the scientist also in future: „Develop hypotheses! – Look for answers!“

Robot Scientists can do a lot, but not everything!

Systems Biology: The Fundament of Metabolic Network based Drug Research

Contains a total of 219 reactions and 322 species.

Established by help of CellDesigner ver. 2.0 http://www.systems-biology.org/002/

Oda et al., Molecular Systems Biology 1 doi:10.1038/msb4100014 publishedonline: 25 May 2005

The EGFR Pathway Map

From subtypespecificity to multi target design and to metabolic network based strategies

Would be only of value, if basedon reliable data

From Reductionisms to Systems Analysis

„Systems Biology“ expands to „Science of Systems of Life“

„General Pharmaceutical Systems Biology“Questions are inbedded into a „system“, whenever feasible.

„Holistic“ - „Systemic“ - „Translational“Research in „field“ und „lab“

Nomenclature and terminology

Harmonised Data Collection

Systems suited information on “old” drugs

“Systems” of particular interest for drug R&D

Disease simulations down to the molecular and metabolic level

Pilot studies with novel strategic avenues

Systems Biology and Drug Research

IMI for Innovative Medicines

IMI – An Innovative Initiative

Dilemma: vast increase of R&D costassociated with decreased outputSolutions: New research strategies, but also critical analysis of the R&P process: „Critical Path“ bzw. „New Safe Medicines Faster“, now IMI

The „Implementation Gap“

Betz, U (2005) Drug Discovery Today 10(15):1057-63.

R&D Investments (US)

Registration of new APIs (global)

DrugDiscovery

PreclinicalPhase ´Clinical Development

DrugReg. Marketing

2009 2012 2014 2019 2020 2021

Pharmacodynamics, -kinetics

Toxicology

Galenic Development

Chemical Development

New TargetLead - First Claims

L. OptimisationDrug Candidate

Phase 1Phase 2

Phase 3

NDA FirstIncome

First marketing activities

TRANSLATIONAL STEPS – „PROJECT“

1 Target – Lead T.2 Discovery – Development T.3 API – Medicine T.4 Preclinical D. – Clinical D. T.5 Clinic – Market T.

T r a n s l a t i o n a l S c i e n c e s11

22

44

55

33

Target Search

Significant bottlenecks are generated in thetransfer of projects from one phase to the next.

TargetDiscovery

LeadDiscovery

LeadOptimisation

„Holistic DrugDiscovery“

IMI-JU(New Safe Medicines Faster,

Critical Path)

Early LADME Research, Biomarker..

Forward translational

DRUG DISCOVERY

DRUG DEVELOPMENTMarketed

Drug

Reverse translational

IMI GovernanceIMI is composed by the IMI Joint Undertaking and it

has two External Advisory Bodies

36

IMI will fund research recommendedin its Research Agenda.

2000

2002

2004

2007

2008

• The IMI Research Agenda describes the research bottlenecks in drug development and recommendations how to solve those.

• These recommendations represent the outcome of an extensive consultation between Europe’s key stakeholders under the lead of EFPIA, organised within the European Technology Platform on Innovative Medicines Initiative

• The review of the IMI Research Agenda will start in 2010 with the IMI Scientific Committee.

37

IMI Research Agenda - Pillars

EFFICACY

KNOWLEDGE MANAGEMENT EDUCATION & TRAINING

SAFETY

Source: EFPIA 3838

IMI Research Agenda

39

The Matrix of Diseases

40

IMI Call process

41

To reduce the medical need

To support breakthrough of novel therapeutic avenues

To harmonise reductionistic and systemic approaches in drug research

To optimise the Drug R&D Process

To implement new techniques and technologies

Great Tasks

“Extracorporal” Therapies

Immunotherapies – Vaccines

Nucleic Acid Therapies

Nuclear Medicine and Imaging Based Approaches

The Three D´s: Drugs – Diagnostics - Devices

Novel Therapeutic Avenues

Gene TherapyMany unmet promises, huge research investments, still little success!Nevertheless many opportunities!

Gene SurgeryPrediction: The greatest challenge and medium term most promisingopportunity of pharmaceutical sciences!

From molecular to cellular concepts!

http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/Lecture25.htm

Stem Cell ResearchFashion – Fund Raising Machinery - Challenge – Important Approach

Adult stem cells contain the patient´s genome.Techniques for their in vivo activation will come up.There are already now therapeutic applications.

Adult stem cells will probably outperform embryonic stemcells in therapeutic applications,

Tissue Engineering

Medium term challenges:Organ reconstructionNeuronal regeneration

Tissue engineering is an opportunity to expand the scopeof pharmaceutical sciences

NF

P

MRP

PP SM

DNA

mRNA

TS TL

AS ODNAS ODN

NR

CellCell AnswerAnswer

New Paradigm: „Block the receptor or prevent its formation!„

Nucleic Acids The next big thing to come! (Scrip Magazine)

Nucleic Acids - miRNA

PET Imaging

Optical Imaging

MR Imaging

ImagingAn obvious opportunity not only fordiagnostics and tissue research, but also forpharmacokinetic studies in drug discovery and development and aCornerstone in Theragnostics

I m a g i n g

Ravindra K. Padney,Roswell Park Cancer Institute (above);

Vladimir P. Torchilin, NortheasternUniversity, Boston (right above);

Siemens (right).

T h e N a n o s c a l a r C h a l l e n g e

A G a p i n U n d e r s t a n d i n g

m o r e t h a n j u s t

N a n o t e c h n o l o g y

From; The Richard E. Smalley Institute for Nanoscale Sciences at Rice University

Chemical Biology(Synthetic Biology, Biological Chemistry)

An obvious opportunity and avenue intolife sciences for scientists from „old“ disciplines

Many challenges bothfor „cutting edge“scientistsand engineers

Giambattista Vicoaround 1750

Recurrent events

Hiddenopportunities

Charles Darwinaround 1850

Linear evolution

Obviousopportunities

Bertrand Russellaround 1900

Singular events

Unpredictableopportunities

Strategic Planning and Elements of Time

The Black Swan

Nicholas Nassim TalebThe prophet of singular events

A Theory of Singular Events

Research Investments and the Crisis of the Financial Markets – A Singular Event!

?

Recurrent events:IMI is an implementation tool for theIndustrial revolution of „biotech“!

Linear evolution:The translational character of IMI will helpto close the „implementation gap“ in Drug R&D!

Singular events:The PPP concept of IMI will hopefully inducenovel models of research co-operation!

Ambitious hopes for IMI

Thank you!