Lower Normandy offers genuine potential in the pharmaceutical field: industries, research, innovation and training opportunities are all present throughout the region. Following a CESR study, published in 2007, new relationships have emerged among the sector’s various players. All that remains is to reinforce inter-regional cooperation, an essential ingredient for large-scale development.

Research laboratories in the pharmaceutical sector : Cancer | Bacteria | Oestrogen and reproduction | Extracellular matrix | Cellular biology | Medicinal drugs | Memory | Mycology | Neurosciences | Molecular chemistry |

Industry-research: partners fighting against disease | Laboratoires Gilbert, the sterile unidose specialists | Holding on to budding young talent |

Cancer
Within the Regional Cancer Research Group (GRECAN, UCBN), the Bioticla « Biology and innovative therapies for locally aggressive cancers » team develops and assesses, via pre-clinical models, new therapeutic approaches for the treatment of ovarian cancer and mesothelioma, thanks to a combination of small ribonucleic acids (interfering RNA and microRNA) and/or small molecules (BH3 mimetics). This research, part of which

is in partnership with the CERMN (UCBN), involves the development of vectorisation protocols aimed at transporting these therapeutic agents to the heart of the tumour. The team’s short-term ambition is to launch an early phase clinical trial via a partnership between the CLCC F. Baclesse and the industrial groups involved.
>Director Pascal Gauduchon Tel: 02 31 45 50 70 E-mail: p.gauduchon@baclesse.fr

Bacteria
Caen University’s EA 2128 research team, entitled « epithelial host and micro-organism interactions » and coordinated by Pr. Roland Leclercq, is based at the Caen University Hospital. It reunites bacteriologists and virologists working on the virulence of the bacteria responsible for nosocomial infections (enterococcus) and of the viruses responsible for respiratory infections. Part of the team’s work focuses on elucidating the mechanisms involved in the antibioresistance of certain bacteria, hence enabling the pharmaceutical industry to modify certain existing antibiotics or to develop antibiotics with new structures to combat such resistance. The mechanisms leading to resistance to new antibiotics are envisaged in order to define how these new resistance-predicting drugs should be used.
> Director Roland Leclercq Tel: : 02 31 06 45 72 E-mail: leclercq-r@chu-caen.fr

Oestrogen and reproduction
Within the Institute of Fundamental and Applied Biology, the research work conducted by Caen University’s « Oestrogen and Reproduction » team (EA 2608 in association with the INRA) focuses on the study of the molecular and cellular mechanisms that regulate aromatase gene expression (enzyme converting androgens into oestrogens) within gonadic cells, and the analysis of the intragonadic role of oestrogen. These new research approaches in endocrinology have potential applications in the field of reproduction (both human and animal). The laboratory works in partnership not only with the University Hospital in Caen, but also with those in Lille, Amiens and Rouen, together with a number of pharmaceutical laboratories.
>Director Serge Carreau Tel: 02 31 56 54 88 E-mail: serge.carreau@unicaen.fr

Extracellular matrix
The research team from the UCBN Extracellular Matrix and Pathology Laboratory (EA 3214, IFR 146 ICORE) has been, since its creation within the Department of Medicine twenty years ago, studying the molecular and cellular mechanisms responsible for pathologies induced by misregulation of the cellular matrix: osteoarthritis, fibrosis, etc. The team strives to understand how these pathologies develop and to offer therapeutic solutions. As such, the extracellular matrix and pathology laboratory contributes towards fundamental and applied research projects focusing on the development of therapeutic molecules, in association with industrial partners (Johnson&Johnson, Negma-Lerads, Nicox, laboratoires Pierre Fabre and Expansciences).
> Director Karim Boumediene Tel: 02 31 06 82 18 E-mail: karim.boumediene@unicaen.fr

Cellular biology
Via a multitude of technological and pluridisciplinary approaches, the aims of the UCBN Cellular and Molecular Biology Signalisation Laboratory (LBCMS/EA 3919), also a constituent of the Department of Medicine, include the caracterisation of new prognostic factors in haematological malignancies and colon cancer, improved inderstanding of the mechanisms involved in colon and haematopoietic carcinogenesis, and the development of innovative therapies. Various projects developed by the LBCMS consequently have a direct link with the pharmaceutical industry. For example, the laboratory works towards measuring the sensitivity of multiple myeloma cells to chemotherapy using shRNA, or towards re-expressing the CDX2 tumour suppressor protein in colon cancer.
> Director Brigitte SOLA Tel: 02 31 06 82 25 E-mail: brigitte.sola@unicaen.fr

Medicinal drugs
Incorporated within the Department of Pharmaceutical Sciences, Caen University’s Normandy Study and research Centre in Medicinal Drugs (CERMN / EA4258, FR CNRS 3038 INC3M) is a constituent of the Normandy Doctoral School of Integrative Biology, Health and Environment (EdN BISE 497), and a member of inter-regional networks such as CRUNCh Orga, LARC Neurosciences, and of the CNRS 3038 INC3M Research Federation (Normandy Institute of Molecular, Medicinal and Macromolecular Chemistry). Its activity focuses on the development, synthesis, physicochemical study and biological evaluation of new molecules of therapeutic relevance (in oncology and the neurosciences). Research work is more often than not conducted in partnership with the pharmaceutical or fine chemicals industry. The chemical and analytical methods used should enable the compilation of targeted combinatorial libraries.
> Director Pr. Sylvain Rault Tel: 02-31-56-68-01 / 02-31-56-59-10 E-mail: sylvain.rault@unicaen.fr

Memory
At the crossroads between the Department of Pharmaceutical Sciences and the IBFA, Caen University’s Memory and Behavioural Plasticity Group (GMPc / UPRES EA 4259) develops new quantitative methods to study behaviour - in particular in the fields of learning and memory. The team also studies the influence of molecules on learning and memory parameters, via memory-deficient animal models. The GMPc’s expertise is therefore regularly sought after by industrial partners in the medicinal drug sector (for the validation of new therapeutic strategies), for whom the lab also conducts experiments, from in vitro specification of the affinity and selectivity parameters of new molecules (in the research for new drug candidates) in association with the CERMN, to the specification of their in vivo potential based on behavioural parameters.
> Director François Dauphin Tel: 02 31 94 72 55 E-mail: francois.dauphin@unicaen.fr

Mycology
One of the missions of Caen University’s Mycology Research and Study Team (E.R.E.M.), created in 2004 and a constituent of the Department of Pharmaceutical Sciences, is the development and maintenance of a regional inventory and the biological study of fungi (macrofungi and microfungi) responsible for the destruction of building wood in residential constructions. Its other fields of activity include cultivating fungi in order to test new potentially fungicide substances, and the identification of any impact of such fungi on human health (toxic or allergenic bioaerosols…). Both of the aforementioned topics have led to a number of collaborative projects within Caen University’s Department of Pharmaceutical Sciences.
> Director Jean-Philippe Rioult Tel: 02.31.56.60.16/ 02.31.56.64.94 E-mail: jean-philippe.rioult@unicaen.fr

Neurosciences
The GIP (Public Interest Group) Cyceron is a medical imaging platform comprising a unique group of laboratories and equipment available for use by teams from the Centre for Imaging – Neuroscience and Applications in Pathology (CI-NAPS/CNRS, CEA, INSERM, UCBN, University of Paris Descartes laboratory). They conduct research focusing on the development of the normal human brain and its cognitive functions, together with its disorders (Alzheimer’s disease, stroke, schizophrenia and tumours). Their aims are, over and above the emergence of knew knowledge, to define novel diagnostic tools and to perfect new therapeutic strategies. CI-NAPS also works towards the development of new tracers and their evaluation in preclinical research.
> Director Bernard Mazoyer Tel: 02 31 47 02 00 E-mail: mazoyer@cyceron.fr

Molecular chemistry
Molecular chemistry is at the very heart of the research conducted by the Laboratory for Molecular and Thio-organic Chemistry (LCMT – CNRS, ENSICAEN, UCBN laboratory). Specialised in fine organic synthesis, in the chemistry and physicochemistry of macromolecules, the laboratory, with a team of 70 (including a permanent staff of 40), concentrates its research efforts on synthesis methodology, biomolecules and molecular materials, focusing on three key research themes: sulphur and phosphorus; fluorine and nitrogen; polymeric materials and catalysis. The laboratory’s fundamental research aims at preparing new molecules and synthesis intermediates. As soon as an interesting molecule is selected, the LCMT’s research, upstream of the medicinal drug chain, is exploited by pharmacologists, biologists and physicians.
> Director Annie-Claude Gaumont Tel: 02 31 45 28 74 E-mail: annie-claude.gaumont@ensicaen.fr

Industry-research: partners fighting against disease
For the clinical research team at the François Baclesse Regional Cancer Centre (CLCC), partnerships with industry are far from out of the ordinary. On the contrary. Around half of the unit’s activity involves investigation: trials put forward directly by pharmaceutical groups. “Our aim remains to offer our patients access to therapeutic innovation,” insists Bénédicte Griffon, the unit’s clinical research officer. “These partnerships enable us to offer treatment solutions years before they are placed on the market”. In 2007, the François Baclesse centre was top of the list of CLCCs, with over 14% of its patients included in clinical trials. The same type of partnership can apply to fundamental research, but the Cyceron project goes even further. Early 2010, the biomedical imaging platform will be welcoming a production unit for the company Cyclopharma, a radiopharmaceutical manufacturer. “The company’s arrival will enable us to establish a “public-private” partnership through which a genuine and mutual transfer of skills and knowledge is sure to accelerate the accessibility of radiopharmaceuticals for clinical research,” highlights Louisa Barré, in charge of the “Positron Emission Tomography Methodology Development Group” within the CI-NAPS mixed research unit, hosted by Cyceron. Industry-Research: These partnerships contribute, first and foremost, towards winning time in the fight against disease. > Louisa Barré In charge of the Positron Emission Tomography Methodology Development Group, CI-NAPS (CNRS, CEA, INSERM, UCBN, University of Paris Descartes) / Cyceron Tel: 02 31 47 02 24 E-mail: barre@cyceron.fr www.cyceron.fr > Bénédicte Griffon Administration officer at the François Baclesse CLCC’s clinical research unit Tel: 02 31 45 50 98 E-mail: b.griffon@baclesse.fr

Laboratoires Gilbert, the sterile unidose specialists
Created in 1904, Laboratoires Gilbert (LG) were originally devoted to the production of a willow leaf-based plaster for the treatment of corns and callosities. Bought over in 1958 by Jacques Batteur, the company moved to Hérouville Saint-Clair in 1962. It then launched its range of ready—to-use plasters and individually wrapped dressing gauze. An ingenious move, for the market was ready to explode. In 1989, after Laurent Batteur took over management of the group, LG developed its very first physiological saline solution unidose production line, capable of producing 20 million unidoses per year. “We needed to find an original niche that would distinguish us from major groups: and the unidose was just perfect!” smiles Jean-Jacques Dronne, delegate managing director. Today, with an annual production of some 500 million units (antiseptic, mouthwash, nasal solutions, etc.) - and an annual turnover of 85 million Euros – LG has become France’s second-ranking manufacturer of sterile unidoses. And the market remains a healthy one. “It has even been reinforced with the development of home-based health care,” notes the pharmacist. In 2007, the group consequently decided to invest in a new, 12,000m2 plant, equipped with three new production lines. Due to open early 2010, it should enable LG to ultimately attain a total production capacity of one billion units per year, hence becoming one of Europe’s leading laboratories in the field of sterile saline solution unidoses. > Jean-Jacques Dronne Delegate managing director and head pharmacist of Laboratoires Gilbert Tel: 02 31 47 15 15 E-mail: jjdronne@labo-gilbert.fr www.labo-gilbert.fr

Holding on to budding young talent
In Lower Normandy, young talent is often the product of public research. Within the UCBN, the CERMN is one of its most fertile laboratories. It has already prompted the creation of several companies in the field of research development, such as Syntheval and Borochem. The latest project: Predireach, initiated by Elodie Lescot-Fontaine, a Doctor in pharmacochemistry and molecular modelling, and Ronan Bureau, a Caen University lecturer in molecular modelling and biophysics. Thanks to the use of computing tools using QSARs methods and cross referencing, the project enables businesses concerned by REACH legislation in particular to establish the link between the chemical structure of a molecule and its toxicity. The advantage for businesses: cost-cutting and an enhanced image, for this innovation enables them to bypass animal experimentation. The project has benefited from support from Oséo (winner of the 2008 business creation competition, in the “emergence” category), from the Lower Normandy Regional Council, via the support allowance for young business creators, and from Normandie Incubation. However, Elodie Lescot-Fontaine believes that, “shared experience with local industry is still lacking”. Other start-ups, such as Borochem, have met with difficulties in finding suitable premises for their activity, “It would be a wise move to create shared premises to welcome these start-ups, within the north platform, alongside the Department of Pharmaceutical Sciences (UCBN), the CHU and industrial partners,” believes Philippe Hugo. “We need to secure these businesses within Lower Normandy, otherwise, they could well be tempted to leave the region.” > Elodie Lescot-Fontaine Predireach • Tel: 02 31 56 68 23 • E-mail: elodie.lescot@unicaen.fr

Everyone has heard of Doliprane®, the most widely distributed drug in France over the past years, Synthol®, reputed to “faire du bien là où ça fait mal” (ease where it aches) as the ad goes, or even the famous green Dermophil Indien stick. However, how many know that these three leading pharmaceutical products are “Made in Normandy”. Far from restricting its activity to these three leading drugs, the region’s pharmaceutical industry is, first and foremost, diverse.

A number of large-scale companies from the field are well-established throughout the region, some of them in rural settings. And although Hérouville Saint-Clair reunites the giants Schering-Plough, Farmaclair (formerly GlaxoSmithKline) and the regional Groupe Batteur (Laboratoires Gilbert), the town of Coutances is also home to Unither Pharmaceuticals’ manufacturing site, and Creully home to Nestlé Clinical Nutrition… “There is a genuine pharmaceutical tradition in Lower Normandy: family businesses have emerged here, others arrived in the 1960s, with the relocation of industrial activities from the Paris basin,” explains Philippe Hugo, Project Coordinator at the Lower Normandy CESR (Regional Economic and Social Council). In 2007, in partnership with the DRIRE (Regional Directorate for Industry, Research and Environment), the Council conducted a study on “The pharmaceutical industry and its related activities in Lower Normandy”(1). It revealed that Lower Normandy’s nine pharmaceutical companies operating under an AMM - Autorisation de Mise sur le Marché (marketing authorisation) represent, alone, 1,700 jobs(2).
Their common denominator: 100% production-based activity, due to the absence of integrated R&D centres. Nevertheless, Lower Normandy also offers excellent research potential in a number of closely related disciplines. Certain laboratories consequently work upstream of the drug design process. For example the Laboratory for Molecular and Thio-organic Chemistry (LCMT, CNRS, ENSICAEN, UCBN), focusing on the preparation of new molecules, or the Normandy Study and Research Centre on Medicinal Drugs (CERMN, UCBN) working on the development of new therapeutic molecules (see boxed articles).

“Working towards technology transfer”

Cyceron is another fine example, in the field of neuroscience: several research teams from the CI-NAPS (CNRS, CEA, INSERM, UCBN, University of Paris Descartes), based within the biomedical imaging platform, focus part of their work on pharmaceutical issues. This is particularly the case at the « Positron Emission Tomography Methodology Development Group », coordinated by Louisa Barré. The group develops new generation radiotracers, integrating short-lived radioisotopes.

“They may enable the earliest possible visualisation of the amyloid plaques responsible for Alzheimer’s disease,” highlights Louisa Barré. And where this fundamental research comes to an end, preclinical and clinical research teams take over. They work on validating the efficiency and the innocuousness of new molecules, in the same manner as the clinical research team at the CFB (François Baclesse Cancer Centre). Within the framework of its promotional activities, in other words the development of clinical trials conducted under the impetus of physicians, the unit works in close partnership with the region’s chemistry and biology laboratories, including the GRECAN (UCBN).

Training and interaction

“We have progressed over the last two to three years towards “technology transfer” research, hence ensuring continuity between knowledge and therapeutic and diagnostic application,” highlights Professor Florence Joly, in charge of the unit. “Consequently, innovative treatment protocols are put into practice.” From the discovery of new molecules to their evaluation on man, the region boasts “a genuine research continuum”, confirms Philippe Hugo. Another of Lower Normandy’s assets in the field: its higher education and training offer. Caen University’s Department of Pharmaceutical Sciences offers a number of options: medicinal, internship (for which the university department obtained the highest admission rate in 2006), industrial and research. Concurrently, the department of continuing and professional education and training also offers a range of courses.
And for over a year now, the University Technical Institute has been in close contact with the region’s industrial fabric, in order to integrate increased consideration for their specific needs in its training offer. A major challenge: according to the LEEM, the French Pharmaceutical Companies Association, retirements among employees from the “baby boom”, scheduled from 2005 to 2012, represent 42% of total staff in the pharmaceutical sector… “We are short of qualified operators and technicians,” indicates Jean-Jacques Dronne, delegate managing director of Laboratoires Gilbert. “Many positions remain vacant and we need to train internally. A situation which can put the company at a serious disadvantage.” The IUT’s initiative should come to fruition as early as the 2009 term with the launch of a new Professional Degree in Chemical and Pharmaceutical Industries: Pharmaceutical Processes and Technologies.
“This new course should create the breeding ground we will be in need of in the coming years,” Jean-Jacques Dronne is delighted to remark. “And it’s an excellent way of initiating long-lasting relationships!” Bringing the pharmaceutical industry’s players closer together is, indeed, one of the recommendations of the CESR report. For although Lower Normandy “has demonstrated excellent potential in terms of industrial production, public research, innovation and training,” the sector’s players have developed but few collaborative relationships.

Reinforcing intra and inter-regional collaboration

From a research point of view, the missing link, in my opinion, is a connection between start-ups with potentially available molecules ready to be tested and clinical research units like ours,” considers Florence Joly. “Such a connection could offer great prospects in oncology.” Whereas Philippe Hugo appeals in favour of the “creation of a network effect”. And it’s precisely with that approach in mind that MIRIADE (Regional Mission for Innovation and Economic Development Action) is preparing to launch a new R&D gateway in the biomedical field. Aim: “to put businesses and research units in touch with each other,” explains Farhana Oueslatie, MIRIADE’s Project coordinator for research development.

Indeed, the CESR study highlighted the needs of businesses and laboratories in the field.” The gateway, organised in partnership with the UCBN, is due to take place on the 26th of October. Inter-regional reinforcement is also increasingly probable, thanks to the proximity of the pharmaceutical cluster which currently comprises the regions of Upper Normandy and Centre (3). “All the more so since strong research partnerships already exist,” highlights Philippe Hugo. Within the framework of the 2008 call for proposals launched by Cengeps (National Centre for Management of Trials on Health Products), the CFB’s clinical research unit’s early phase department has become the network leader for France’s north-western inter-region (Nord-Pas-de-Calais, Somme, Upper and Lower Normandy) for the development of early phase trials. Similarly, the CRUNCH ORGA network (Normandy University Chemistry Research Centre) is already federating a number of the region’s research teams (Universities of Caen, Rouen and Le Havre, ENSICAEN, INSA, CRNRS )… Collaborative opportunities that continuously offer Lower Normandy’s players an opportunity to develop and expose their know-how beyond regional frontiers.

(1) Source: Robert Le Moan ; the study was unanimously approved during the plenary session on the 22nd of October 2007.
(2) The pharmaceutical sector represents a total of over 10 000 jobs. For further details, please consult the CESR’s complete report.
(3) The Upper Normandy and Centre regions announced their support for the “Pharma Valley” pharmaceutical cluster last June.

Philippe Hugo, CESR Project Coordinator
Tel: 02 31 06 96 10

Pr Florence Joly, In charge of the clinical research unit at the François Baclesse Regional Cancer Centre
Tel: 02 31 45 53 93
Website: www.baclesse.fr/

Farhana Oueslati, MIRIADE Project coordinator - technology watch
Tel: 02 31 53 34 52
Website: www.miriade-innovation.fr

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