BMSystems-business-description-and-case-studies-website

Bio-Modeling Systems SASDr. François Iris (PhD), Chairman & CSOManuel Gea, Chief Executive OfficerPaul-Henri Lampe CIO Integration Systems DirectorDr. Gérard Dine (MD, PhD), Chief Medical Officer

To contact usBio-Modeling Systems SAS3 rue de l’Arrivée- 75015 PARIS, [email protected]

Bio-Modeling SystemsThe R&D booster for life Sciences discoveries

© BMSystems - www.bmsystems.net

Bio-Modeling SystemsThe Mechanisms-Based Medicine Company

CADI™ Discovery is the first heuristic operational digital/biology disruptive innovationinvented and operated by biologists to create novel medical meanings from heterogeneousdata sources to discover cost-effective novel therapeutic/diagnostics solutions that already

delivered clinical stage novel therapies in 2015

Manuel GEA : CEO & Co-founder

http://www.persistentsys.com/Industries/LifeSciences.aspx

Bio-Modeling Systems - The R&D booster for life Sciences discoveries

The acceleration of the Industry Issues• The R&D Attrition Rate of our Industry is desperately growing, despite massive investments in state of the art

technologies mainly for efficacy and safety issues.

• The Pharma industry is facing an unprecedented pressure from multiple sources, of which payers no longerwilling to pay premium prices for novel therapeutics.

• .No doubt, we are clearly facing a “destructive” phase of the 6th Kondratieff–Schumpeter* cycle fed by thedigital “tsunami”: big IT players aim to deeply transform the healthcare and Pharma Industries to capturetheir attractive businesses and profits.

• Big Pharma leaders** already announced that the future will be technology and digital.

• Mechanisms of life are complex, non-linear and integrative, Bioinformatics and Mathematical tools that haveproven to be efficient to collect, structure, analyze, simulate specific functions. They cannot yet generatedisruptive innovative hypotheses, because discovery means finding unknown things and Mathematicalmodeling need to have already described the system to simulate it properly.

• Imported form the Internet world, the Big Data concept does not necessarily means high value Smart Data,due to life sciences reality, if not contextualized, lacking patients’ base-lines, and not related to biologicalmechanisms.

• The “garbage in, garbage out” reality, tells us that the information produced and published (even in leadingscientific journals) is necessarily ALWAYS incomplete, biased and erroneous to unknown extents.

Confidential BMSystems www.bmsystems.net * https://fr.wikipedia.org/wiki/Cycle_de_Kondratiev ** ex CEO Novartis, 2

The future will be biology and digital, but the final objective is to propose cost–effective novel therapies,The huge challenge is to create novel medical meanings from heterogeneous flows of data producedWhy despite huge investments with brilliant people the IT and “Omics” promises failed to deliver ?

http://www.bmsystems.net/


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The Life-modeling issue illustrated

If you dream of creating the firstoperational bird model…

Be sure to use the appropriate modelingconcepts & tools. If you don’t …

… a “basic” living Complex system thatnot only flies…

…you get a Complicated “Cartesian” system.It does fly, but…it will never lay eggs!

Bombs, perhaps…But the major issue is that, for modelers,

this is a bird!*

The challenge is clearly not a question of technologies only* Based on this model,1) when birds lay eggs, they explode; 2) the rear end of a bird is extremely hot when it flies; 3) a bird has three legs, etc….You may think this stupid, but it is what is being done with systems biology.


Combining the “human” & “silicon” brains strengthsCADI™* Discovery was invented in 2002 by Dr. François IRIS, geneticist, physiologist & molecularbiologist. Our IT people, form the digital world, developed the IT platform to “help” our biologists work: Itthe first operational “Mechanisms-Based Medicine” concept invented and operated by biologists:

The first time non-mathematical heuristic multi-systems multi-scale systems medicine platform to address complex,non-linear and integrative issues.

A revised discovery and 4 steps validation process to address complex diseases issues using necessary mechanismsunderstanding to better solve efficacy and safety issues.

A novel continuum between e-R&D and e-Health to enlarge and strengthen the translational medicine paradigmand extract the maximum pertinent medical meanings and value from scientific, medical, health, patients smart data.

Synergic collaborations with complementary mathematical modeling tools and teams to collect, structure, analyze,simulate systems behaviors , of which the smart data analytics.

A systematic and intensive exploitation of our proprietary CADI™ Knowledge database gathering all the non-confidential knowledge accumulated during these last 10 years from numerous diseases/disorders drugsmechanisms of action programs to gain time to market and money.

A proactive search of cost-effective solutions with lower short term failure risks exploiting the growing number ofwell documented off-patent molecules, multiple devices and e-health tools, and services in addition to the searchfor new drugs by our clients or partners .

© BMSystems - www.bmsystems.net 4

The CADI™ Discovery platform is a proven operational answer, addressing both efficacy and safetyissues exploiting for the first time a new class of heuristic modeling tools to discover unknown fields.

*CADI: Computer Assisted Deductive Integration

CADI™ brand means: Computer Assisted Deductive Integration


BMSystems’ science at a glance• CADI™ Discovery is the first operational "Mechanisms-based Medicine" platform, dedicated to the discovery of

cost-effective new diagnostic, therapeutic and prevention solutions for medicine, cosmetics, etc, ...

• Understanding the mechanisms of a disease/disorder is the first objective. Finding the most adapted biomarkersand solutions are the necessary consequences of the first objective.

• BMSystems' team builds heuristic non-mathematical in-silico models to generate novel disruptive medicalmeanings from scientific, medical & health data.

• CADI™ Discovery is not domain (diseases, disorders, species) but information dependent.

• CADI™ Discovery addresses both efficacy and safety issues, the main culprits for the unacceptable R&Dattrition rate.

• BMSystems already generated a significant pipeline of internal research programs .

• The pharma’s proof of concept: CADI™ patented novel therapies, already contributed to the creation of twofunded Pharma SMEs at clinical stage in 2015:

• Pherecydes-Pharma (2006, novel M.R. bacteria nano-agents biotherapies),

• Theranexus (2013, innovative combined therapies for Psychiatric disorders).

Confidential BMSystems www.bmsystems.net 5

What we invented and did for ourselves, we can do for your companyin the biomedical, diagnostic, Pharma, cosmetics, nutrition, food, chemistry and IT domains

http://www.pherecydes-pharma.com/

http://www.bmsystems.net/download/Theranexus-raised-3.6-M-Euros-Theranexus-leve-avec-succes-3.6-M-Euros-en-amorcage-copatent-bmsystems-with-CEA.pdf


Prestigious R&D Collaborations network(2004-2015): Only medicine programs extract that we are allowed to mention

Pherecydes Pharma (2006)Spin-off BMSystems

The first two companies/start-ups issued from our work:Other programs (aging, neurodegenerative spin-offs are in the pipeline

Spin-off of CEA Winner: Concours NationalMinistry of research-Innovation 2010

Max Planck Institute (Munich): Project “Chronic Anxiety”.

CEA : Project “Creutzfeld-Jacob Disease CJD”.

INSERM: 3 Projects “Tumoral Progression”; “Therapeutic Resistance”; “RGD & Metastasis”.

CNRS: Project “Müllerian Regression”.

, Successfully completed 3 publications; 1 pending.

All 3 successfully completed, 3 publications.

Successfully completed, 1 publication.

US, EU & French Awards; 1 therapeutics class patent; 1 publication.Successfully completed.

© Bio-Modeling Systems www.bmsystems.net

Foundation FondaMental: Project “Bipolar Disorders & Schizophrenia”.On going, 1 publication pending.

Theranexus (2013)

Persistent Systems: Project “Allergic contact dermatitis” & Strategic IT technologiesalliance. On going.


BMSystems “Broad life sciences & IT” Expertise teamA strong multidisciplinary & experienced core founders’ team

• Dr. François Iris (PhD), Chairman, CSO-CTO - Geneticist, physiologist & molecular biologistCreator of Millennium Pharmaceuticals' (USA) high-throughput DNA sequencing unit. Former collaborator of Nobel Laureate Prof. Jean Dausset. Inventor ofnew technologies in molecular biology. MRC Overseas fellow, Member of H.U.G.O., Wellcome Trust Systems Biology experts board. Member of theCambridge Healthtech Institute Scientific Committee, Member of the Evaluation committee for the funding priorities in the “Medical Systems Biology-MedSys” program; German Federal ministry of Research. 14 original articles in international journals including Nature, Cell, Nature Genetics, Genomics, J MolEndocrinol, J Comp Biochem Physiol. 7 international patents, 3 patent applications currently undergoing examination, 5 book chapters, numerous invitedcommunications at international conferences.

• Manuel Gea, C.E.O & VP R&D Information Systems – Heuristic modeling specialistScientific Engineering Degree from Ecole Centrale. Dregree in sociology Paris IX Dauphine University. Former Chairman of the Supervisory board ofPHERECYDES PHARMA (anti-bacterial bio-agents pharmaceutical company); Former CEO Hemispherx Biopharma Europe. Founder and President of Centrale-Santé. Founding-Administrator of the computing firm Formitel. Former McKinsey executive, creator of Practice Pharma services in France. Former DivisionManaging Director with Boehringer-Ingelheim France. Former International business manager Colgate-Palmolive Company (US), Co-founder and VicePresident of the Biotech Committee of the Association of the Pharma companies operating France (LEEM). Member of the executive board of MedicenSanté, the world-class bio-cluster of Paris region. Vice-President Adebiotech Committee. Co-founder and Evaluation Committee member of Paris Biotech(leading biotech incubator).

• Gérard Dine (MD, PhD), Chief Medical Officer - Physician, biologistHead of the Haematology Dept. at Troye’s hospital. Founding member and Head of the Biotechnology Dept. at Ecole Centrale Paris. Founding-President ofTroye’s Institute of Biotechnologies. Former President of the Institute for Sports Medicine.

• Paul-Henri Lampe, CIO & Systems Integration Director - Systems Integration specialistScientific Engineering Degree from Ecole Centrale Lille. Master Degree in Applied Mathematics from Ecole Centrale Paris. Former IBM Systems IntegrationManager. Former Information Systems projects manager in an Acute Care Hospital in Paris.

• Pablo Santamaria, IT & Internet Systems Director - Internet technologies specialistScientific Degree from Ecole Centrale Paris, Founder and President of the computing firm Formitel (1988). Founding President of the Centrale-Ethics Think-Tank. Vice-President of Centrale Human Resources Professional group. Former Senior Consultant Information Systems Evaluation (INSEP). Former IndustrialMaintenance Manager at Glaxo Pharma ( Evreux, France)



BMSystems’ Group at a glance• Independent Private Company incorporated in 2004, profitable since 2006, thanks to its clients

• 100% owned by its founders, experienced professionals of the life sciences, Pharma, Biotech and ITindustries sharing common interests in biology and disruptive innovation.

• A pure biology driven company operating IT equipments only and CADI™ softwares we do not sell.

• 24 FTE* of which 9 FTE senior scientists/professionals focused on CADI**™ Discovery programs.

• All non-strategic resources (15 FTE*) are adaptable and subcontracted to long-term partners.

• Long term strategic R&D and business collaborations with more than 100 partners’ professionals worldwideworking on BMSystems’ related R&D programs.

• Original dual business model that generates revenues through contractual R&D programs & patentednovel therapeutic & prevention solutions through collaborative R&D programs with its partners.

• The validation phases, the production of necessary data and the patented discoveries developments areimplemented outside the company with its partners’ worldwide network.

• BMSystems is the “powerful an highly productive discovery engine” and start-ups “generator” of itscompanies’ and academics’ network, generating the necessary decision making, and novel disruptiveconcepts and innovations for novel therapies, diagnostics and businesses.

• CADI**™ Discovery industrial secrets are not transferable nor disclosed even with NDA.


An unique business model to optimize R&D productivity and ROI :in the biomedical, diagnostic, Pharma, cosmetics, nutrition, food, chemistry and IT domains

*FTE: variable Full Time Equivalent, 15 non-strategic resources subcontracted & 90% Variable. **CADI: Computer Assisted deductive Integration.


Program NameValidation /BusinessPartner(s)

CADI™compliance

CADI™vers. 0

Ind. Valid.Patents / Publi.

First Proof ofConcept

(POC)

Mid scale orpreclinic.

P.O.C.

Businesslaunched

Nano-Bioagents Pherecydes

TAPE (protein improvement) Pherecydes

Chronic Fatigue Syndrome Open

Ebola virus ecology Open

Hepatitis C Open

Auto-immune global concept Open

Psychiatric combination treatment CEA Life Sciences

Creutzfeldt-Jakob disease mechanisms CEA Life Sciences

Alzheimer Disease Mechanisms Open

Parkinson's Disease Treatment Confidential

Psychiatric inflammatory mechanisms FondaMental Foundation

Fibromyalgia, facial pain Aepodia

Pain (Central/Peripheral) Open

Migraine Mechanisms Open

Multiple Sclerosis Mechanisms Open

Psychiatric disorders biomarkers Max Planck Munich

Program Synthons ARD-IBT-L'Oréal

Program Synthons ARD-IBT-Rhodia

Program Synthons ARD-IBT-Arkema

Human Glycosylation with Yeast Open

Breast cancer-Hras INSERM

Tamoxifen resistance INSERM

Specific Metastasis control INSERM

Global Metastasis control Open

Müllerian regression Mechanisms CNRS

Adipocytes growth control Open

Skin Contact Allergy Mechanisms Open

Skin pigmentation Mechanisms Open

Skin aging Mechanisms Open

Hypercholestemia Mechanisms Open

New global concept for Diabetes type 1 Open

Metabolic Syndrome Open

BMSystems’ CADI™ programs: Internal & collaborative programs only

© BMSystems - www.bmsystems.net9

Infection-Immunology Oncology/InflammationCNS-PNS/Inflammation Tissue Differentiation

Industrial biotech/ bioprocesses Metabolism/Inflammation

Dermatology/Inflammation


The success of a therapeutic approach largely arises from the coherent manipulation of aphysiological system as a whole

and not from that of a target in a molecular context.

© Bio-Modeling Systems www.bmsystems.net

What is Therapeutic success?

Therefore, any given medical problem should be approached from a “systems medicine” standpointIn this context, novel therapies can be combinations of drugs, nutriments, devices, e-health, etc…

(while targeted therapies belong to the “target in a molecular context” concept)

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The Global Discovery stepwise approach places diagnostic / therapies / preventionsolutions & validation processes in the right order:

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Understanding and validating the mechanisms of a disease/disorder becomes the first objective.Finding the most adapted solutions is a necessary consequence of the first objective

•Redefine the definitions and descriptions of the physiopathology of thedisease/disorder/syndrome with physiologists, clinicians and patientsfeedbacks.* Do not forget & integrate that for a disease/disorder/syndrome, similar symptoms can havevery different functional origins, while similar dysfunctions can produce different symptoms.Download** the dedicated presentation with the psychiatry case study

1-DISEASE*

•Discover the causal versus symptomatic mechanisms of the disease/disorder.2-MECHANISMS•Indirectly based on causal mechanisms, identify relevant biomarkers or specificcombination, signatures of biomarkers (biological, imagery, physical signals, etc…)that could measure defined mechanistic deregulations at different stages of thedisease/disorder.

3-BIOMARKERS

•based on the causal mechanisms, identify what could be the best targets (notonly one) to specifically address the causative deregulations.4-TARGETS

•We harness the mechanisms. Propose the most practical solutions to address therelevant mechanistic deregulations.

•It is important to notice that the proposed solutions, integrating diagnostics,therapies & patients follow-up, can be new drugs, combinations of existing drugs,nutriments, devices, e-health, disease prevention tools and services, etc …

5-SOLUTIONS

•Global validation loop at each steps of the process: Integrate the results from e-R&D or e-Health experimentations into the validation process to improve globalpatient and disease/disorder follow-up.

6-VALIDATION

The mechanisms-Based Medicine Concept

** Download the dedicated presentation with the psychiatry case study

http://www.bmsystems.net/download/BMSystems-Mechanisms-Based-Medicine-to-redefine-diseases-definitions-and-descriptions-case-study-psychiatry.pdf


The differences and complementarities between“heuristic” and “mathematical” approaches.

HEURISTICS is a problems solving approach evaluating each step in a process, searching forsatisfactory solutions rather than for optimal solutions, using all available qualitative informationinstead of only quantitative information.

Thus,

Heuristic modeling starts from accumulated information to produce a model capable of describing themechanisms that generated the observed outcome / data and predict their modifications associatedwith a different outcome;

It plays the role of an architect.

While

Mathematical (Bayesian) modeling starts from quantitative data to produce models capable ofreiterating this data and predict the outcome of a different experimental paradigm.

It plays the role of an engineer.

Hence

© BMSystems 2011 - www.bmsystems.net 12

Far from being incompatible, these two approaches are complementary.


CADI*™ the first multiple-scale non-mathematical heuristicmodeling approach, successfully applying 5 principles

(more information is available on our website)• An “Architectural Principles” Approach

• Our “Negative Selection” Process

• Our “4 steps validation” Process

• Our “Broad life sciences & IT” Expertise

• Our “synergic collaboration” with classical/mathematical systems biology and IT partners

*Computer Assisted Deductive Integration 13© BMSystems - www.bmsystems.net

A complex system being studied A CADI™ model representingmultiple-scale systems in a specific context

Different organs level

Different cells level

Molecules levelScal

e/

leve

l

Clearly the challenge is to think out of the box and to ask the right questions!

http://www.bmsystems.net/download/BMSystems-scientific-EPA-conference-heuristic-mathematic-concepts-synergies-and-achievements-cns-2011.pdf


CADI™ Discovery negative selection processThe first operational application of the negative selection concept

Download our scientific presentation from our website to understand CADI principles and the Differences &Complementarities between “Heuristic” and “Mathematical” approaches - Concepts & Examples


Componentsidentificatio

n

Identifiedcomponen

ts

DataAcquisi

tion

MEDLine

DATA Base n

DATA Base 1

IndexedDB

inde

xing

filters

Species

A Data of interest

Injection

Sequences 1, 2, 3 …n

NucleicacidsProteins, etc..

C1,C2,C3 … Cn

B

visualisationmanipulation

C

D

E

Integration

visualisation

F

SpecificExperimental data

Potential BiomarkersOmics

Hypothesesto be destroyed

Un-destroyedhypotheses

In-silico BiologicalModel

Hypothesesgeneration

http://www.bmsystems.net/download/BMSystems-scientific-EPA-conference-heuristic-mathematic-concepts-synergies-and-achievements-cns-2011.pdf


CADI™ Global discovery & validation processexploiting Smart Data (contextualized, with patients based lines, related to mechanisms data)

CADI™ Discovery from bench to bed to real patient health processes

Information technologiesData acquisition, Simulation, collaborative, data Storage, Big Data, Smart Data, Mobility

CADI™ Smart Data (contextualized, with patients based lines, related to mechanisms)


Clinical data

Patients data

New version ofCADI™ map

Experimentationsimplementation

CADI™ experimentationsdesign

Analysis of experimentalresults

1

4

3

2

Publications

Scientific data

E-R&D Continuum/Synergies E Health

Clinicians / MD inputs

Patients feedbacks

Persistent Systems Ltd worldwide IT non-exclusive world wide partnerLeading Indian IT company 7000 people, 250 M$, 85% of business in the USA

http://www.persistentsys.com/Industries/LifeSciences.aspx


BMSystems’ CADI™ cross-fertilization business strategy:


BMSystems’ R&D capacity and productivity KFOSCADI™ knowledge DataBase & CADI ™ Cross-fertilization Process applied successfully to neurology, psychiatry,

dermatology, immunology, cancer, application domains generating novel opportunities and huge time and moneysavings for our programs

Real Illustration: The bacterial mechanisms and their possible business applications

KFOS: Key factors of success

Up to 4 independent possible programs with very different key issues butexploiting the same CADI™ knowledge Database with the best partners


BMSystems’ answers to clients/partners issuesReduce time to result, improve success rate and reduce development costs to address specific markets:


• New therapeutic / diagnostic / cosmetics strategies,• New associations of molecules & devices• New associations of existing molecules• Molecules / Devices Mechanisms of action

BMSystems’outputs

• Physiological / Diseases Mechanisms understanding• Multi-Systems mechanisms• Multi-Scale mechanisms description• CADI™ knowledge DataBase• CADI ™ Cross-fertilization Process

• Proposition of new bio-production processesthrough micro-organisms modifications (bacteria,yeast).

• Targets discovery & validation.• Signatures of biomarkers discovery & validation.• Marketing strategies rational support• Adaptive clinical trials rational support• Market Access rational support

• R&D / Molecules / clinical programs evaluation:• Next Phase GO / NO GO decision• Novel Clinical phases end points / processes• Drug (re) positioning / (re) profiling / rescue• Rare diseases drugs repositioning• Drug side effects analysis for rescue• Chemical entities safety issues (Allergy, PE, etc…)

biomedical, diagnostic, Pharma, cosmetics, nutrition, food, chemistry, environment, energy.


BMSystems’ original dual business modelthat generates cash through contractual deals & patented novel

diagnostic/therapies/prevention solutions through collaborative R&D programs.


• Contract Research : cash generation• Pharma, diagnostic, Cosmetics, functional food.• Chemical, Environment, Energy Industries

• Consortiums / J.V. : cash & value creation• Synthons program: Industrial biotech• Persistent Systems: IT healthcare and life Sciences

• Academic Research (6 publications)• Access to clinical expertise• Access to experimentation capabilities

• Spin-Off, Out-Licenses: value creation• Spin-off: Pherecydes-Pharma (Nanotech bio-agents)• Out-license: Co-patent (psychiatry) with CEA life

Sciences granted to Theranexus a start-up of CEA• IDUNN: Novel combined therapy for degenerative

disorders such as the Parkinson's’ disease

• Technology Developments• CADI™ Processes and Tools, CADI™ Knowledge

Database• 4 Patents from CADI™ outputs (collaborative programs)

BMSystems’value production


BMSystems’ CADI™ publications to dateCADI™ Models published in prestigious peer-reviewed journals: (click on the blue links to get the pdf)

• 2014: CNS Psychiatry publication: American Journal of Psychiatry and Neuroscience. Second publications with the Max Planck Institute ofPsychiatry in Munich: Differential proteomics analyses reveal anxiety-associated molecular and cellular mechanisms in cingulate cortexsynapses. The first output of the DECIUS CNS research program.

• 2012, CNS NEURODEGENERATIVE & PSYCHIATRY: PharmacoPsychiatry publishes the first review describing a productive vision of SystemsMedicine that will change R&D organization and interactions between clinicians & researchers & reveals how the world's first explanationof the mechanisms of the Creutzfeldt-Jakob disease led to the discovery of a truly innovative psychiatric treatment.

• 2011, CNS PSYCHIATRY: Pharmaco Psychiatry publication: Proteome-Based Pathway Modelling of Psychiatric Disorders. Publication withThe max Planck Institute of Psychiatry in Munich

• 2010, INFECTIOUS DISEASES: Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science :Genetically Engineered VirulentPhage Banks in the Detection and Control of Emergent Pathogenic Bacteria. Publication with Pherecydes-Pharma.

• 2009, TISSUE DIFFERENTIATION: Médecine & Sciences: Müllerian duct regression explanation. Integrative systems biology & experimentalBiology. Publication with CNRS experimental data.

• 2005, CANCER: Journal of molecular Endocrinology: Integrative analysis of gene expression patterns predicts specific modulations ofdefined cell functions by estrogen and Tamoxifen in MCF7 breast cancer cells. Publication in collaboration with INSERM unit 553.

• 2003, CANCER: Nucleic Acids Research: Integrated transcriptome analysis of the cellular mechanisms associated with Ha-ras-dependentmalignant transformation of the human breast epithelial MCF7 cell line. Publication in collaboration with INSERM unit 553. World first. Firstin-silico model of a complex human disease validated in-vitro and published.

Collaboration to scientific reference books:

• 2014, Dermatology Cosmetics. The first reference book on “Computational Biophysics of the Skin” edited by Prof. Bernard Querleux ,scientific chairperson of the International Society for Biophysics and Imaging of the Skin

• 2008, CNS: Biomarkers for Psychiatric Disorders. (Ref. ISBN: 978-0-387-79250-7, November 2008). Dr. François Iris, is the author of theIntegrative Biology chapter of the book. The editor, Prof. Christoph W. Turck, is head of the Proteomics and Biomarkers branch at the MaxPlanck Institute for Psychiatry


http://www.bmsystems.net/download/Psychiatric-Systems-Medicine-PharmacoPsychiatry-creutzfeldt-jakob-CNS-neurodegenerative-bmsystems-2012.pdf

http://www.bmsystems.net/download/Pharmacopsychiatry-bmsystems-max-planck-publication-biomarkers-cns.pdf

http://www.bmsystems.net/download/Pherecydes-Pharma-bmsystems-biodefense-Publication.pdf

http://www.bmsystems.net/download/papier-CADI-canal-muller-Med-Sci-june2009.pdf

http://www.bmsystems.net/download/Tamoxifen-resistance-publication.pdf

http://www.bmsystems.net/download/article-NARcancer-ras.pdf

http://www.crcpress.com/product/isbn/9789814463843

http://www.springer.com/biomed/neuroscience/book/978-0-387-79250-7


BMSystems’ 9 scientific & businesses proof of concepts

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Selected POCs and their outputs of CADI™ Programs (next slides):1. Case study A: Domain: CNS neurology and Psychiatry. Collaborative CADI™ program with CEA life sciences (1

patent, 1 publication, 1 spin-off).

2. Case study B: Domain: Infectious diseases. Collaborative CADI™ program with Pherecydes-Pharma (our firstspin-off) (3 patents, 1 publication, 1 spin-off).

3. Case study C: Domain: CNS neurology/Parkinson’s disease. Collaborative CADI™ program with Belgiumpartners (novel combined therapy proposed for POC in humans).

4. Case study D Domain: Oncology. Collaborative CADI™ program with Inserm unit 553 (2 publications, Novelstrategy proposed for R&D collaboration)

5. Case study E: Domain: Dermatology. Contractual program CADI™ for a client (8 new targets, cosmetic companyconfidential).

6. Case study F. Domain: Cosmetics. Collaborative CADI™ program) (low allergy mechanisms identified for safetyissues).

7. Case study G: Domain: Type 2 diabetes. Contractual CADI™ program for a client (NO GO decision for safetyissue, pharma company, confidential).

8. Case study H: Domain: Industrial biotech. Collaborative CADI™ program with ARD, IBT, CVG, L’Oréal, Rhodia,Arkema (1 patent filed by an industrial partner).

9. Case study I:Domain: Tissue differentiation / embryogenesis. Collaborative CADI™ program with CNRS (1publication).


Mechanisms-Based Medicine: 9 proofs of concept:A new paradigm qualified for industrial use


A: Program objectives and achievements

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Domain: Central Nervous Systems. Collaborative CADI™ program• Context: 2004; Creutzfeldt-Jakob Disease (CJD) is a complex & poorly understood neurodegenerative disease with

equivalent animal and human forms.• Request: Conduct the world’s first systems biology program to be validated in-vivo. Understanding and validating the in

vivo mechanisms of CJD pathogenesis & progression.

Work done & International rewards, start-up creation:• Disease understanding: CJD is not a neurological disease stricto sensu. It is a disease that primarily affects

astrocytes structures and functions which, over time, lethally affects healthy glial & neuronal cells through« bystander effects », leading to widespread CNS disorganization (spongiosis) and functional failure.

• New mechanism Discovery: The program identified the connexins (gap junctions), responsible for neuro-glialcommunication, as major players in the disease process. It also provided an understanding of key mechanismsassociated with psychiatric disorders.

• Truly novel & innovative psychiatric therapies combining an anti-connexin and various psychotrops thatallows very significant dosage reductions (from 5 to 20 times). Patent (WO/2010/029131) in 2008. Exclusivelicense granted in 2013 to Theranexus, a start-up from CEA.

• This word’s first was the only European program to received in 2009 the prestigious Bio-IT World Best practiceAward from the Cambridge Healthtech Institute.

• It also was selected in 2010 as 1 of the 3 pan-European « state of the art examples of systems biologyapproaches of benefit to medicine » by the European Commission’s DG Research, Directorate of Health.

• 1 publication, 1 patent, 1 spin-off.

• Theranexus raised 3,6 M€ in 2014 to enter into clinic stage in narcolepsy

Complete BMSystems’ “Mechanism-based Medicine” science and business proof of concept1 publication, 1 patent, 1 spin-off entering clinical stage



B: Program objectives and achievements

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Domain: Multi-resistant infectious diseases. Collaborative CADI™ program

Request: How to rapidly (less than 30 min) and efficiently detect and destroy anyunknown bacterial pathogen or emerging strain without using:

1. Antibiotics: too many resistant strains, and very rapid resistance acquisition2. Vaccines: much too slow to act, and small strain variations often lead to inefficacy

Work done, start-up creation• 2005: Two CADI™ models constructed to describe bacterial resistance mechanisms and

bacteriophages-bacteria co-evolution mechanisms.• 3 patented new disruptive technologies invented (TAPE, ABACCUS, RIPH), 3 publications.• 2006: Successful launch and financing of our first spin-off Pherecydes-Pharma, the first

bio-defence and bio-security company in France• 2009: Creation of the first operational large-scale engineered bacteriophage bank to fight

“uncharacterized multi-resistant” bacterial infections.• 2011: Pherecydes Pharma secures 900 k€ in DGA funding for evaluating the use of

bacteriophages on soldiers suffering infected burn-wounds• 2013: Pherecydes Pharma Phagoburn consortium granted 3,8 M€ by FP7 program to

enter into clinic.• 2014: Pherecydes Pharma Phosa consortium granted 760 k€ French Ministry of Industry

to develop second indication

World’s 1st company entirely created from a systems biology program© BMSystems - www.bmsystems.net

http://www.phagoburn.eu/


C: Program objectives and achievements

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Domain: Aging / Parkinson’s disease. Collaborative CADI™ program• Context: Numerous attempts to utilize low-toxicity metabolic co-factors have been made

over the years but all have proven ineffective.• Objective: Build a CADI™ model that describes the mechanisms which:

1. could give rise to mitochondrial dysfunctions that would2. most severely affect dopaminergic neurons.

Work done or to be done:• The IDUNN program led to a combinatorial therapeutic approach utilizing

1. two molecules that had long been on the market,2. neither of which has any known toxicity or undesirable effects.

• This potential treatment was exposed, under strict confidentiality, to the criticism ofinternationally respected clinical specialists.

• It received their full approval.• Implementation of the clinical proof of concept upon Parkinson’s disease patients is currently

under negotiation.

Because the mechanisms are not correctly represented in animal models and the two non-toxic drugs are not given atthe same time, the Proof Of Concept will be conducted directly in humans. Savings in time and money



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D: The oncology Individualized therapy IssueThe Individualized therapy mirage vs. novel concept & multi-therapies

Request: The DNA targeted treatments does nothing more than selecting resistant cancer cells:.What alternative solutions could be proposed (full presentation available)

CADI™ past programs and novel therapeutic strategies2003, CANCER THERAPEUTIC STRATEGY: Integrated transcriptome analysis of the cellular mechanisms associated with Ha-

ras-dependent malignant transformation of the human breast epithelial MCF7 cell line. Nucleic Acids Research.Collaboration with INSERM unit 553.Outputs: Identification of 4 differently deregulated pathways in malignant cells. Test of a combination of 3 drugs, neverused in oncology, that showed synergistic apoptotic activity in-vitro in malignant cells only. Additional outputs: anti-farnesylase can’t work!

2004, CANCER METASTASIS MECHANISM : Mechanisms targeted by the ADAM-15 RDG peptide to induce cytostasis invery aggressive breast cancer cells in vitro (MDA-MB 231)and in vivo. Collaboration with INSERM unit 553.Outputs: Identification of the ADAM-15RGD mechanism of action and the limits of its therapeutic application. Themechanism is used for normal tissue repair and can’t be blocked without dramatic consequences.

2005, UNDERSTANDING OF TAMOXIFEN RESITANCE (CANCER) : Integrative analysis of gene expression patterns predictsspecific modulations of defined cell functions by estrogen and Tamoxifen in MCF7 breast cancer cells. Journal ofmolecular Endocrinology. Collaboration with INSERM unit 553.Outputs: explanation for the relapse mechanism: “antibiotic resistance-like” form of selection mechanism identified.

These three programs show that the interpretation cancer as a chronic disease raises numerous long term efficacy issues due to the"antibiotic resistance-like” behavior of tumor cells.Poor efficacy and too high prices of treatments only reinforce payers reluctance to reimburse them. Based on HIV experience, anew paradigm, simultaneously addressing different targets combined with a novel metastasis control strategy, must beinvestigated.

A tumor is rarely composed of one type of malignant cells. BMSystems, through his 3 programs, identified the narrowlimits of mono-targeted therapies and proposes a new approach to oncology, based on a therapeutic strategy thatdoes not only target the tumor itself but uses the possibilities of surrounding tissue to control metastatic processes

while starving cancer cells.




D: Brest cancer: multiple types of cancer cells within the same tumour

Source:Giesen C. et al. 2014

Nature Methodsdoi:10.1038/nmeth.2869



D: Targeted treatment does nothing more than selecting resistant cancer cells:The cancer first diminishes & then starts again and cannot be stopped.

Lung cancer

Source: Lee JC et al. 2013Cancer Res Treat. 45(2):79-85.


© BMSystems 20124- www.bmsystems.net 27

Ductal breast cancer Non-ductal cancer off-shoot

Complementary therapy:Peri-tumoural tissue could be induced to“encyst” the tumour, preventing metastaseswhile starving the cancer cells. Pancreatic cancer

Multiple types of cancer cells withinthe same tumour

(each colour indicates a different type of cancercell)

Source: http://flagshipbio.com/pancreatic-cancer-drug-development/

D: A novel approach to cancer therapy to validated.


BMSystems’ applications focus in dermatology and cosmetics

28

1. Skincare: Strong integrated understanding of the global systems:

1. The mechanisms associated with constitutive and facultative epidermal pigmentation

2. The mechanisms associated with senile/solar lentigines (aging issues)

3. Components specific to pigmentation from production to destruction

2. Skincare: Collaborative CADI™ program, (low allergy mechanisms identified for safety issues)open for partners or consortium participation.

3. Domain: Tissue differentiation / embryogenesis. Collaborative CADI™ program with CNRS (1publication).

4. 2014, Dermatology Cosmetics. The first reference book on “Computational Biophysics of theSkin” edited by Prof. Bernard Querleux , scientific chairperson of the International Society forBiophysics and Imaging of the Skin.

5. Skincare Project: Personalized, “mechanisms-Based” supported for prevention, diagnostic,treatment and follow-up to support premium marketing strategies proposing innovativesolutions (services, products) to address targeted populations issues (aging, skin/timing/treatment adaptation, etc…).


Mechanisms-Based Medicine applied to cosmetics and dermatologyA new paradigm qualified for novel solutions for premium personalized marketing strategies

http://www.crcpress.com/product/isbn/9789814463843


E: Program objectives and achievements

29

Domain: Dermatology. Contractual CADI™ programRequest: Review of a complete domain, R&D strategy and programs• Build a strong integrated understanding of the global systems to redefine the R&D strategy and portfolio programs;

• The mechanisms associated with constitutive and facultative epidermal pigmentation• The mechanisms associated with senile/solar lentigines (aging)• Components specific to pigmentation from production to destruction

• Review coherence of existing Expert’s requests, and pertinence of Expert’s answers;• GO/ NO GO decision for two existing programs;• Identify new pertinent targets with mechanisms of action;• Suggest potential molecules for new targets;• Propose a validation strategy and assist client’s team in experimentation outputs analyses.

Work done:• Global integrated set of 6 CADI™ sub-models describing the mechanisms and cross-talks between sub-systems at

different maturation & differentiation status for an organ composed of 3 main cell types;• NO GO decision for two existing programs;• Identification of 8 new targets of interest 5 of which went to the Phase 2 (validation);• Identification by BMSystems of 5 tool-molecules to test the 5 targets (3 of which arose from our internal “CNS CADI™

Knowledge Database”);• 3 targets/tool-molecules couples validated in-vitro;• 4 not-anticipated additional questions answered at marginal cost;• Identification of a screening test issue and explanation of the problem;• Contribution to client’s team behavior and dynamic evolution (some difficulties due to resistance to research paradigm

changes).

Clearly, investing in a CADI™ Standard Full Multi-Scale/Systems program is a better investment vs. “spreading”investments through independent experts’ requests and their inconsistent answers


F: Program objectives and achievements

30

Domain: Dermatology/cosmetics. Collaborative CADI™ program

Request: Eliminate as much as possible the Use of Animals in ContactAllergy Testing for cosmetic products• May 2013, the European Unions bans the import and sale of cosmetics containing ingredients tested on

animals.• Objective of the program: Offer to the industry a highly effective, competitive and reliable alternative to

detect & characterize the potential for irritant contact dermatitis and/or allergic contact dermatitis complexformulations could have in normal skin in vivo, using reconstructed skin, in-vitro and in-silico tools.

• Develop a range of products/services to fit clients’ needs.• R&D Partners: Open for complementary partners (research, industry, tec…)

Work completed under progress or to be done:• CADI™ model under construction.• Identification of the parameters characterizing pathway-specific & cross-talk inductions.• Construction of the complementary mathematical in-silico model.• Identification of appropriate program validation tests.• Development of the future tools and software to run and exploit the tests.• Contact Allergy Testing solution evaluation by Cosmetics partners.

The operational solution combining heuristic modeling and mathematical modeling


G: Program objectives and achievements

31

Domain: Type 2 diabetes. Contractual CADI™ program

Request: GO / NO GO decision for “lead A”• Mechanisms whereby “Lead A” produces anti-glycemic effects;• Understand the drug’s potential mechanisms of action that could explain pre-clinical results;• Identify the side-effects mechanisms;• Assist client’s team in experimentation outputs analyzes.

The information we were provided with were:• the 2D chemical structure of this molecule (confidential),• the fact that it had “strong anti-glycemic effects in the rat”, and• Some receptor-binding data.

Work done:• We proposed & fully documented the mechanisms of action of the molecule;• We identified potential deleterious side-effects;• We explained why “lead A” couldn’t be improved;• At least 2 of the predicted undesirable effects (induction of hypothermia and decreased nociception) turned out

to be correct in vivo;• Development of this particular “Lead” was abandoned (NO GO decision);• Financial consequence for Client: significant Clinical Trial costs savings + new mechanisms to exploit.

Robust consensus that generated significant savings of time and money for the Pharma company



H: Program objectives and achievementsDomain: Industrial biotech : Collaborative CADI™ program

Request: Feasibility study Industrial biotech program for 16 chemical molecules:Synthons major collaborative industrial biotech research platform funded by the ministry of Industry in the IAR world-class cluster in France. Search for innovative processes non-existing patent dependent

A complementary collaborative team:

• A.R.D.: Leading Industrial Biotech research company with experimental capacities, pilot to scale-up, pilot plant (2000Tons) a key factor of success, etc.

• I.B.T.: One of France’s leading Technology Transfer Institutes.

• BMSystems: integrative Biology & metabolic engineering expertise.

• C.V.G.:“green chemical” sourcing research institute.

3 companies (public information) proposing their molecules to the platform:

• L’Oréal: (world leader in cosmetics)

• Rhodia: (ex. Sanofi Aventis fine chemical entity)

• Arkema: (ex. Total chemical entity)


OUTPUTS: A unique significant bacteria metabolic pathways database of strong interest.2 engineered bacterial strains generated are under evaluation anda finalized process under mid-scale validation (patent pending).

The program was funded by the ministry of Industry and supported by IAR world-class cluster


I: Program objectives and achievements

33

Domain: Tissue differentiation/embryogenesis. Collaborative CADI™programRequest: Build a CADI™ model that could explain an organogenesismechanism that had remained obscure for over 60 years.

• Context: In early embryos, the male & female genital tracts are initially identical. Then inmales (AMH) the organ degenerates while in females (no AMH) it continues development.

• Only mesenchymal cells (majority) express the AMH receptor.• Only epithelial cells (minority) visibly respond to AMH (most undergo an EMT and some enter apoptosis).• The regression (transformation of the duct into a fibrous mensenchymal cord) begins at the posterior end

while the anterior end continues to grow normally.• Regression progresses as a wave that propagates along the duct much faster than the rate of growth of

the structure

Work done• Detailed functional understanding of the mechanisms.• Discovery of a 3 phases response to AMH signaling.• In-vivo validation of the key discoveries in collaboration with CNRS.• One of the key, largely obscure mechanisms (EMT) may be associated with malignant transformation (cancer).• 1 publication.

A CADI™ model explained a major organogenesis mechanism involved in embryogenesis and led tonew hypothesizes in malignant transformation mechanisms.



34

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