Berlin, Germany
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EPISODEs goal is to maximize the regional benefits of Structural Biology Research Infrastructures in NMR and associated technologies for the economic development of the pharma/biotech industries in Tuscany, Berlin-Brandenburg and beyond. As traditional Structural Biology research moves towards new horizons, a major goal has become a systemic view of Life, implying a change of focus from single molecules and interactions to an integrated view of networks of interactions at varying levels of biological organization. NMR and associated technologies are an integral part of such research, and their importance has recently been reflected in the ESFRI Roadmaps INSTRUCT Integrated Structural Biology Infrastructure. While this emerging paradigm presents myriad new opportunities for the R&D programs of the pharma/biotech sectors, the technologies and their associated research infrastructures have not yet been fully exploited, a situation that must urgently be understood and rectified. Berlin-Brandenburg and Tuscany are uniquely poised to meet this challenge, in part through the presence of strong research infrastructures. EPISODE will encourage cooperation and collaboration among regional research institutions, business and areas agencies to couple research with revenue, through the following actions: (i) research-driven clusters will be expanded and stimulated interregionally and transnationally; (ii) current regional capabilities in terms of research potential and exploitation will be studied; (iii) a Joint Action Plan will be developed to define how to drive future economic development. Dissemination and outreach efforts, the encouragement of collaborations, support measures for SMEs and spin-offs, and the mentoring of less-developed regions will be given a special place throughout the project. EPISODE will positively impact research potential and economic potential, with corresponding effects on the health and welfare of regional, European and global populations.


David Meek a ajouté : « 2016 a été une année très riche pour Ipsen avec l’approbation et le lancement de Cabometyx® en Europe dans le traitement de deuxième ligne du carcinome avancé du rein, le lancement de nouvelles indications pour Dysport® aux Etats-Unis, la mise en place d’une nouvelle structure de gouvernance, et plus récemment, l’acquisition d’Onivyde®, qui renforce notre stratégie en médecine de spécialité dans l’oncologie. En 2017, l’accent sera mis sur le maintien de la forte dynamique des activités courantes, ainsi que sur la réussite du lancement de Cabometyx®, qui combinés à Onivyde® et aux nouveaux produits de médecine générale, contribueront significativement à la croissance et la profitabilité du groupe dans les prochaines années. » Les indicateurs financiers des activités sont des indicateurs de performance qui permettent de comprendre et d’analyser la performance du Groupe. Ipsen estime que ces nouveaux indicateurs financiers, excluant les éléments non directement liés à l’activité et qui peuvent varier de manière significative, reflètent plus clairement les tendances sous-jacentes de l’activité et permettent une comparaison plus pertinente d’une année sur l’autre. Les bonnes performances de Dysport® en esthétique aux Etats-Unis avec Galderma, ainsi qu’en Russie et au Moyen-Orient ont été compensées par des difficultés d’importation au Brésil survenues au cours du second semestre de l’année, suite à une annulation temporaire de certificat de bonnes pratiques de fabrication (BPF). Les ventes de Décapeptyl® reflètent une forte croissance des volumes en Europe et en Chine compensée par une pression sur les prix dans la région. Au cours du quatrième trimestre, le Groupe a enregistré les premières ventes de Cabometyx® en Europe, principalement en Allemagne, en Autriche et en France, suite à l’approbation du produit par les autorités européennes (EMA) en septembre. Le Groupe a dépassé les objectifs relevés et communiqués le 26 octobre 2016 pour les ventes de médecine de spécialité et la marge opérationnelle courante, et a atteint la borne haute des objectifs révisés pour les ventes de médecine générale. Ipsen est un groupe pharmaceutique de spécialité international qui a affiché en 2016 un chiffre d’affaires proche de 1,6 milliard d’euros. Ipsen commercialise plus de 20 médicaments dans plus de 115 pays, avec une présence commerciale directe dans plus de 30 pays. L’ambition d’Ipsen est de devenir un leader dans le traitement des maladies invalidantes. Ses domaines d’expertise comprennent l’oncologie, les neurosciences, l’endocrinologie (adulte et enfant). L’engagement d’Ipsen en oncologie est illustré par son portefeuille croissant de thérapies visant à améliorer la vie des patients souffrant de cancers de la prostate, de tumeurs neuroendocrines, de cancers du rein et du pancréas. Ipsen bénéficie également d’une présence significative en médecine générale. Par ailleurs, le Groupe a une politique active de partenariats. La R&D d'Ipsen est focalisée sur ses plateformes technologiques différenciées et innovantes en peptides et en toxines situées au cœur des clusters mondiaux de la recherche biotechnologique ou en sciences du vivant (Les Ulis/Paris-Saclay, France ; Slough / Oxford, UK ; Cambridge, US). En 2016, les dépenses de R&D ont dépassé 200 millions d’euros. Le Groupe rassemble plus de 4 900 collaborateurs dans le monde. Les actions Ipsen sont négociées sur le compartiment A d’Euronext Paris (mnémonique : IPN, code ISIN : FR0010259150) et sont éligibles au SRD (« Service de Règlement Différé »). Le Groupe fait partie du SBF 120. Ipsen a mis en place un programme d’American Depositary Receipt (ADR) sponsorisé de niveau I. Les ADR d’Ipsen se négocient de gré à gré aux Etats-Unis sous le symbole IPSEY. Le site Internet d'Ipsen est www.ipsen.com. Les déclarations prospectives et les objectifs contenus dans cette présentation sont basés sur la stratégie et les hypothèses actuelles de la Direction. Ces déclarations et objectifs dépendent de risques connus ou non, et d'éléments aléatoires qui peuvent entraîner une divergence significative entre les résultats, performances ou événements effectifs et ceux envisagés dans ce communiqué. Ces risques et éléments aléatoires pourraient affecter la capacité du Groupe à atteindre ses objectifs financiers qui sont basés sur des conditions macroéconomiques raisonnables, provenant de l’information disponible à ce jour. L'utilisation des termes " croit ", " envisage " et " prévoit " ou d'expressions similaires a pour but d'identifier des déclarations prévisionnelles, notamment les attentes du Groupe quant aux événements futurs, y compris les soumissions et décisions réglementaires. De plus, les prévisions mentionnées dans ce document sont établies en dehors d’éventuelles opérations futures de croissance externe qui pourraient venir modifier ces paramètres. Ces prévisions sont notamment fondées sur des données et hypothèses considérées comme raisonnables par le Groupe et dépendent de circonstances ou de faits susceptibles de se produire à l’avenir et dont certains échappent au contrôle du Groupe, et non pas exclusivement de données historiques. Les résultats réels pourraient s’avérer substantiellement différents de ces objectifs compte tenu de la matérialisation de certains risques ou incertitudes, et notamment qu’un nouveau produit peut paraître prometteur au cours d’une phase préparatoire de développement ou après des essais cliniques, mais n’être jamais commercialisé ou ne pas atteindre ses objectifs commerciaux, notamment pour des raisons réglementaires ou concurrentielles. Le Groupe doit faire face ou est susceptible d’avoir à faire face à la concurrence des produits génériques qui pourrait se traduire par des pertes de parts de marché. En outre, le processus de recherche et de développement comprend plusieurs étapes et, lors de chaque étape, le risque est important que le Groupe ne parvienne pas à atteindre ses objectifs et qu’il soit conduit à renoncer à poursuivre ses efforts sur un produit dans lequel il a investi des sommes significatives. Aussi, le Groupe ne peut être certain que des résultats favorables obtenus lors des essais pré cliniques seront confirmés ultérieurement lors des essais cliniques ou que les résultats des essais cliniques seront suffisants pour démontrer le caractère sûr et efficace du produit concerné. Il ne saurait être garanti qu'un produit recevra les homologations nécessaires ou qu'il atteindra ses objectifs commerciaux. Les résultats réels pourraient être sensiblement différents de ceux annoncés dans les déclarations prévisionnelles si les hypothèses sous-jacentes s'avèrent inexactes ou si certains risques ou incertitudes se matérialisent. Les autres risques et incertitudes comprennent, sans toutefois s'y limiter, la situation générale du secteur et la concurrence ; les facteurs économiques généraux, y compris les fluctuations du taux d'intérêt et du taux de change ; l'incidence de la réglementation de l'industrie pharmaceutique et de la législation en matière de soins de santé ; les tendances mondiales à l'égard de la maîtrise des coûts en matière de soins de santé ; les avancées technologiques, les nouveaux produits et les brevets obtenus par la concurrence ; les problèmes inhérents au développement de nouveaux produits, notamment l'obtention d'une homologation ; la capacité du Groupe à prévoir avec précision les futures conditions du marché ; les difficultés ou délais de production ; l'instabilité financière de l'économie internationale et le risque souverain ; la dépendance à l'égard de l'efficacité des brevets du Groupe et autres protections concernant les produits novateurs ; et le risque de litiges, notamment des litiges en matière de brevets et/ou des recours réglementaires. Le Groupe dépend également de tierces parties pour le développement et la commercialisation de ses produits, qui pourraient potentiellement générer des redevances substantielles ; ces partenaires pourraient agir de telle manière que cela pourrait avoir un impact négatif sur les activités du Groupe ainsi que sur ses résultats financiers. Le Groupe ne peut être certain que ses partenaires tiendront leurs engagements. A ce titre, le Groupe pourrait ne pas être en mesure de bénéficier de ces accords. Une défaillance d’un de ses partenaires pourrait engendrer une baisse imprévue de revenus. De telles situations pourraient avoir un impact négatif sur l’activité du Groupe, sa situation financière ou ses résultats. Sous réserve des dispositions légales en vigueur, le Groupe ne prend aucun engagement de mettre à jour ou de réviser les déclarations prospectives ou objectifs visés dans le présent communiqué afin de refléter les changements qui interviendraient sur les événements, situations, hypothèses ou circonstances sur lesquels ces déclarations sont basées. L'activité du Groupe est soumise à des facteurs de risques qui sont décrits dans ses documents d'information enregistrés auprès de l'Autorité des Marchés Financiers. Les risques et incertitudes présentés ne sont pas les seuls auxquels le Groupe doit faire face et le lecteur est invité à prendre connaissance du Document de Référence 2015 du Groupe, disponible sur son site web (www.ipsen.com).Comparaison des ventes consolidées des quatrièmes trimestres et des années 2016 et 2015 Le tableau suivant présente le chiffre d’affaires par domaines thérapeutiques et par produits pour les quatrièmes trimestres et années complètes 2016 et 2015 : Au quatrième trimestre 2016, les ventes de médecine de spécialité ont atteint 339,8 millions d’euros, en hausse de 17,8% d’une année sur l’autre, portées par la croissance de 27,0% des ventes en oncologie. En 2016, les ventes se sont élevées à 1 273,0 millions d’euros, en hausse de 16,1%, tirées par la croissance des ventes en oncologie de 22,1%, celles de neurosciences de 4,3%, et celles d’endocrinologie de 1,7%. Sur la période, le poids relatif de la médecine de spécialité a continué de progresser pour atteindre 80,3% des ventes totales du Groupe contre 77,2% un an plus tôt. En oncologie, les ventes ont atteint 247,3 millions d’euros au quatrième trimestre 2016, en hausse de 27,0% d’une année sur l’autre, tirées par la croissance continue de Somatuline® aux Etats-Unis et en Europe. En 2016, les ventes en oncologie ont atteint 904,8 millions d’euros, en hausse de 22,1%, et ont représenté 57,0% des ventes totales du Groupe contre 52,1% un an plus tôt. En neurosciences, les ventes de Dysport® ont atteint 71,2 millions d’euros au quatrième trimestre 2016, en baisse de 1,6% d’une année sur l’autre. Malgré une forte croissance des volumes en esthétique en Amérique du Nord avec Galderma, ainsi qu’en Russie et au Moyen-Orient, les ventes ont été affectées par des difficultés d’importation au Brésil suite à une annulation temporaire du certificat de bonnes pratiques de fabrication (BPF). Une licence d’importation exceptionnelle a été obtenue pour le marché public. En ce qui concerne le marché privé, Ipsen travaille en étroite collaboration avec les autorités réglementaires pour obtenir une licence d’importation exceptionnelle. La société estime qu’un nouveau certificat BPF sera délivré dans les prochains mois. En 2016, les ventes se sont élevées à 284,7 millions d’euros, en hausse de 4,0%, tirées par les bonnes performances en Russie, au Moyen-Orient et en Allemagne, ainsi que par les activités esthétiques en Amérique du Nord et en Europe avec le partenaire Galderma. Elles ont été cependant affectées par les difficultés d’importations au Brésil survenues au cours du second semestre 2016. Sur la période, les ventes en neurosciences ont représenté 18,1% des ventes totales du Groupe contre 19,4% un an plus tôt. En endocrinologie, les ventes de NutropinAq® ont atteint 14,0 millions d’euros au quatrième trimestre 2016, en baisse de 3,8% d’une année sur l’autre. En 2016, les ventes se sont élevées à 57,7 millions d’euros, en baisse de 3,5%, affectées par une baisse des volumes, notamment en Allemagne, en Italie et au Royaume-Uni, partiellement compensées par une bonne performance en France. Au quatrième trimestre 2016, les ventes d’Increlex® ont atteint 6,5 millions d’euros, en hausse de 1,5% d’une année sur l’autre, principalement tirées par les Etats-Unis. En 2016, les ventes se sont élevées 23,7 millions d’euros, en hausse de 16,9%. Sur la période, les ventes en endocrinologie ont représenté 5,1% des ventes totales du Groupe contre 5,6% un an plus tôt. Au quatrième trimestre 2016, les ventes de médecine générale ont atteint 90,4 millions d’euros, en hausse de 7,6% d’une année sur l’autre, tirées par les bonnes performances de Smecta® et Etiasa®. En 2016, les ventes se sont élevées à 311,6 millions d’euros, en baisse de 2,7%, principalement affectées par les ventes de Tanakan® en Russie. Sur la période, les ventes en médecine générale ont représenté 19,6% des ventes totales du Groupe, contre 22,8% un an plus tôt. France – Au quatrième trimestre 2016, les ventes ont atteint 61,5 millions d’euros, en hausse de 14,1% d’une année sur l’autre, tirées par les premières ventes de Cabometyx®. En 2016, les ventes se sont élevées à 225,5 millions d’euros, en hausse de 6,2%, portées par la croissance soutenue de Somatuline® et Décapeptyl®, ainsi que par les premières ventes de Cabometyx® au cours du quatrième trimestre. Les ventes des produits de médecine générale étaient sables sur l’année, avec une bonne performance de Smecta®, compensée par le recul de Tanakan®, Adrovance®, et Nisis®/Nisisco®. Le poids relatif de la France dans les ventes consolidées du Groupe a continué de décroître et représente désormais 14,2% des ventes totales du Groupe contre 14,7% un an plus tôt. Allemagne – Au quatrième trimestre 2016, les ventes ont atteint 31,6 millions d’euros, en hausse de 5,4% d’une année sur l’autre. En 2016, les ventes se sont élevées à 123,2 millions d’euros, en hausse de 11,7%, portées par la forte croissance de Somatuline® et Dysport®, ainsi que par le lancement de Cabometyx® et de Cometriq® en novembre. Sur la période, les ventes en Allemagne ont représenté 7,8% des ventes totales du Groupe, contre 7,6% un an plus tôt. Italie – Au quatrième trimestre 2016, les ventes ont atteint 18,8 millions d’euros, en baisse de 3,4% d’une année sur l’autre. En 2016, les ventes se sont élevées à 81,2 millions d’euros, en hausse de 2,2%. La forte croissance de Somatuline® a été partiellement compensée par le recul des ventes de Dysport® et de NutropinAq®. Sur la période, les ventes en Italie ont représenté 5,1% des ventes totales du Groupe contre 5,5% un an plus tôt. Royaume-Uni – Au quatrième trimestre 2016, les ventes ont atteint 18,2 millions d’euros, en hausse de 12,6% d’une année sur l’autre. En 2016, les ventes se sont élevées à 72,8 millions d’euros, en hausse de 8,2%, portées par la croissance de Somatuline® et de Décapeptyl®. Sur la période, le Royaume-Uni a représenté 4,6% des ventes totales du Groupe, contre 5,3% un an plus tôt. Espagne – Au quatrième trimestre 2016, les ventes ont atteint 18,5 millions d’euros, en hausse de 6,0% d’une année sur l’autre. En 2016, les ventes se sont élevées à 69,2 millions d’euros, en hausse de 5,5%, tirées par la forte croissance des volumes de Décapeptyl® et de Somatuline®. Sur la période, les ventes en Espagne ont représenté 4,4% des ventes totales du Groupe, contre 4,5% un an plus tôt. Au quatrième trimestre 2016, le chiffre d’affaires généré dans les Autres pays d’Europe a atteint 97,7 millions d’euros, en hausse de 21,0% d’une année sur l’autre, tirées par le lancement de Cabometyx® en Autriche et la bonne performance de Dysport® en Russie. En 2016, les ventes se sont élevées à 349,2 millions d’euros, en hausse de 11,5%, tirées par la bonne performance de Somatuline® dans l’ensemble de la région ainsi que de Dysport® et Décapeptyl® notamment en Russie et en Ukraine, partiellement compensées par le recul de Tanakan® en Russie. Sur la période, les ventes dans la région ont représenté 22,0% des ventes totales du Groupe contre 22,3% un an plus tôt. Les autres produits et charges opérationnels ont représenté une charge de 6,8 millions d’euros avant impôt, principalement liée aux coûts du changement de gouvernance du Groupe et aux coûts liés au déménagement sur le nouveau site anglais de recherche et développement à Oxford. L’ensemble des coûts alloués à ces deux segments est présenté dans les indicateurs. Seuls les frais centraux partagés et les effets des couvertures de change ne sont pas alloués entre ces deux segments. Les frais de recherche et de développement sont désormais inclus dans les segments opérationnels ; ils étaient précédemment inclus en Non alloué. Les ventes de médecine de spécialité ont atteint 1 273,0 millions d’euros en 2016, en hausse de 14,2% par rapport à 2015 portées par les ventes en oncologie en augmentation de 20,2% à change courant. Le poids relatif des produits de médecine de spécialité a continué de progresser pour atteindre 80,3% des ventes totales du Groupe au 31 décembre 2016, contre 77,2% un an plus tôt. Le Résultat Opérationnel des activités de l’exercice 2016 s’est ainsi établi à 415,0 millions d’euros, incluant les dépenses de recherche et de développement, soit 32,6% du chiffre d’affaires, contre 328,9 millions d’euros, soit 29,5% l’an passé. Cette amélioration reflète la poursuite de la croissance des ventes de Somatuline® aux Etats-Unis et en Europe et le renforcement des investissements commerciaux notamment aux Etats-Unis pour Somatuline® ainsi qu’en Europe pour accompagner le lancement de Cabometyx®. Le Résultat Opérationnel des activités non alloué s'est élevé, pour l’exercice 2016, à (150,7) millions d'euros, à comparer aux (127,9) millions d'euros enregistrés en 2015. Il comprend essentiellement les frais centraux non alloués et les effets des couvertures de change. Les investissements opérationnels nets ont augmenté de 27,4 millions d’euros d’une année à l’autre et se sont élevés à 84,0 millions d’euros au 31 décembre 2016. En 2016, ils correspondent principalement à des investissements sur les sites industriels du Groupe en Irlande et en France nécessaires à l’accroissement des capacités de production et dans le nouveau centre de recherche et développement dédié aux toxines au Royaume-Uni. Les autres produits et charges opérationnels et charges de restructuration se sont établis à 20,8 millions d’euros et comprennent les coûts liés au changement de gouvernance du Groupe ainsi que des paiements liés aux plans de restructuration antérieurs. A fin décembre 2015, ces paiements de 28,9 millions d’euros étaient essentiellement liés aux décaissements de charges de restructurations ainsi qu’aux dépenses liées à l’arrêt du développement clinique du tasquinimod. Au 31 décembre 2016, les investissements financiers nets comprennent essentiellement 257 millions d’euros de paiement initial et de paiements d’étapes à Exelixis suite à la signature d’un accord exclusif de licence pour la commercialisation et le développement du cabozantinib, un paiement initial de 5 millions d‘euros à 3B Pharmaceuticals GmbH suite à la signature d'un contrat de licence exclusive pour de nouveaux produits radiopharmaceutiques en oncologie et un paiement d’étape de 5 millions d’euros lié à l’accord de licence avec Lexicon. (*) « Trésorerie nette » : trésorerie et équivalents de trésorerie sous déduction des concours et emprunts bancaires, autres passifs financiers et après réintégration des instruments dérivés. Le Groupe exerce son activité dans un environnement qui connaît une évolution rapide et fait naître de nombreux risques dont certains échappent à son contrôle. Les risques et incertitudes présentés ci-dessous ne sont pas les seuls auxquels le Groupe doit faire face et le lecteur est invité à prendre connaissance du Document de Référence 2015 du Groupe, disponible sur son site web (www.ipsen.com). 1 Croissance des ventes hors effets de change 2 Hors amortissements des immobilisations incorporelles (hors logiciels), plus ou moins-values de cession d’immobilisations, coûts liés à des restructurations, pertes de valeur ainsi que d’autres éléments non directement liés à l’activité 3 Une réconciliation entre le Résultat Opérationnel des activités et l’ancienne définition du Résultat Opérationnel Courant est présentée en page 3 4 Le Passage du Résultat net consolidé IFRS au Résultat net consolidé des activités est présenté en annexe 4 5 Trésorerie et équivalents de trésorerie sous déduction des concours et emprunts bancaires, autres passifs financiers et après réintégration des instruments dérivés 6 Modèle commercial mixte, à la fois de prescription et hors prescription 7 Objectifs financiers 2016 révisés et communiqués le 26 octobre 2016 8 Croissance d’une année sur l’autre hors effets de change 9 Nouvelle classification des ventes selon l'indication thérapeutique principale de chacun des produits


Ipsen (Euronext: IPN; ADR: IPSEY), a global specialty-driven pharmaceutical group, today announced financial results for the full year 2016. Commenting on the 2016 full year performance, David Meek, Chief Executive Officer of Ipsen, said: “The strong operating performance in 2016 serves as a solid foundation for the company in this new era of accelerated momentum and transformation. Sales grew by nearly 12% year-on-year, a record high for Ipsen, and core operating margin improved despite additional investments for the Cabometyx® launch in Europe.” David Meek added: “2016 was a very productive year for Ipsen with the Cabometyx® approval and launch for second line renal cell carcinoma in Europe, the launch of new indications for Dysport® in the U.S., a new corporate governance structure implemented, and most recently, the acquisition of Onivyde®, which reinforces our specialty oncology strategy. The focus for 2017 will be on building upon the strong momentum of the current business and the successful launch of Cabometyx®, which combined with the expected addition of Onivyde® and the new Primary Care products, will significantly contribute to the growth and profitability of the company in the coming years.” New definition of Core Financial Measures Ipsen has updated its definition of Core financial measures (Core Operating income, Core consolidated net profit, Core EPS) to exclude the amortization of intangible assets (excluding software) and the gain or loss on disposal of fixed assets. Core financial measures are the key performance indicators for understanding and measuring the performance of the Group. Ipsen believes that the updated financial indicators reflect with better clarity the Group’s underlying business trends and enable more meaningful comparisons year on year, as they exclude non-core items which may vary significantly. These performance indicators do not replace IFRS indicators, and should not be relied upon as such. Reconciliations between IFRS 2015/2016 results and the newly defined Core financial measures are presented in Appendix 4 and in the “Reconciliation from Core consolidated net profit to IFRS consolidated net profit” table on page 12. Note: Unless stated otherwise, all variations in sales are stated excluding foreign exchange impacts. Specialty Care sales reached €1,273.0 million, up 16.1%, driven by the strong growth of Somatuline® in North America, as well as a solid performance throughout Europe. Dysport® good sales performance in aesthetics in the U.S. through Galderma, and in Russia and the Middle East was offset by importation issues in Brazil that occurred in the second half of the year due to a temporary cancellation of the certificate of Good Manufacturing Practices (cGMP). Decapeptyl® sales reflect good volume growth in Europe and China offset by price pressure in the region. The Group booked during the fourth quarter the first sales of Cabometyx® in Europe, mainly in Germany, Austria and France following the product approval by EMA in September. Primary Care sales reached €311.6 million, down 2.7%, impacted by lower sales in Russia for Tanakan® and other Primary Care products, while Smecta® sales were slightly up driven by the implementation of the new OTx6 commercial model. Core Operating Income totaled €363.9 million, up 11.1%. Core operating margin reached 23.0%, up 0.3 points compared to 2015, mainly driven by strong business performance, partially offset by investments for the Cabometyx® launch and the adverse impact of foreign currencies. Core consolidated net profit was €263.6 million, up 12.8% over the period, compared to €233.8 million in 2015. Core earnings per share - fully diluted (see Appendix 4) grew by 13.0% year-on-year to reach €3.18 for 2016, compared to €2.82 in 2015. Free cash flow generated in 2016 reached €228.8 million, up by €52.5 million, driven by the strong operating performance and a good management of working capital and capital expenditures. Closing net cash reached €68.6 million at the end of the period, compared to €186.9 million in 2015, notably after payments to Exelixis for the original cabozantinib license and subsequent extension to Canada, as well as regulatory and commercial milestones, for a total of €257.3 million in 2016. IFRS Operating Income totaled €304.7 million, up 24.8% from €244.0 million in 2015, impacted by lower impairment charge, with an Operating margin at 19.2%, up 2.3 points compared to 2015. IFRS Consolidated net profit was €226.6 million, up 18.8% over the period, compared to €190.7 million in 2015 and fully diluted EPS at €2.73 in 2016, was up 18.7% from €2.30 in 2015. Comparison of 2016 performance with financial objectives The Group exceeded the raised guidance provided on 26 October 2016 for Specialty Care sales and Core operating margin and came in at the favorable end of revised guidance for Primary Care sales. The table below shows the comparison between the financial objectives provided on 26 October 2016 and 2016 actuals, both including the amortization of intangible assets. Below is a reconciliation of the Core Operating Income from the previous definition to the new reported definition: Dividend for the 2016 financial year proposed for the approval of Ipsen’s shareholders The Ipsen S.A. Board of Directors, which met on 22 February 2017, has decided to propose at the annual shareholders’ meeting on 7 June 2017 the payment of a dividend of €0.85 per share, stable year-on-year. The Group has set the following financial targets for 2017 assuming a successful closing of the Onivyde® transaction with Merrimack by the end of the first quarter 2017, and of the Consumer Healthcare transaction with Sanofi in the second quarter of 2017: Meeting, webcast and conference call for the press (in English) Ipsen will host a press conference on Thursday 23 February 2017 at 9:30 a.m. (Paris time, GMT +1) at Salons de l’hôtel des Arts et Métiers – 9 bis avenue d’Iéna – 75116 Paris (France). A conference call will take place and a web conference (audio and video webcast) will be available at www.ipsen.com. Participants should enter the call in approximately 5 to 10 minutes prior to its start. No reservation is required to participate in the conference call. A recording will be available for 7 days on Ipsen’s website and at the following numbers: France and continental Europe: +33 (0)1 70 99 35 29 UK: +44 (0)20 7031 4064 United States: +1 954 334 0342 Conference ID: 961391 Meeting, webcast and conference call (in English) for the financial community Ipsen will host an analyst meeting on Thursday 23 February 2017 at 2:30 p.m. (Paris time, GMT+1) at its headquarters in Boulogne-Billancourt (France). A conference call will take place and a web conference (audio and video webcast) will be available at www.ipsen.com. Participants should dial in to the call approximately 5 to 10 minutes prior to its start. No reservation is required to participate in the conference call. A recording will be available for 7 days on Ipsen’s website and at the following numbers: France and continental Europe: +33 (0)1 70 99 35 29 UK: +44 (0)20 7031 4064 United States: +1 954 334 0342 Conference ID: 961277 Ipsen is a global specialty-driven pharmaceutical group with total sales close to €1.6 billion in 2016. Ipsen sells more than 20 drugs in more than 115 countries, with a direct commercial presence in more than 30 countries. Ipsen’s ambition is to become a leader in specialty healthcare solutions for targeted debilitating diseases. Its fields of expertise cover oncology, neurosciences and endocrinology (adult & pediatric). Ipsen’s commitment to oncology is exemplified through its growing portfolio of key therapies improving the care of patients suffering from prostate cancer, neuro-endocrine tumors, renal cell carcinoma and pancreatic cancer. Ipsen also has a significant presence in primary care. Moreover, the Group has an active policy of partnerships. Ipsen's R&D is focused on its innovative and differentiated technological platforms, peptides and toxins, located in the heart of the leading biotechnological and life sciences hubs (Les Ulis/Paris-Saclay, France; Slough/Oxford, UK; Cambridge, US). In 2016, R&D expenditures exceeded €200 million. The Group has more than 4,900 employees worldwide. Ipsen’s shares are traded on segment A of Euronext Paris (stock code: IPN, ISIN code: FR0010259150) and are eligible to the “Service de Règlement Différé” (“SRD”). The Group is part of the SBF 120 index. Ipsen has implemented a Sponsored Level I American Depositary Receipt (ADR) program, which trades on the over-the-counter market in the United States under the symbol IPSEY. For more information on Ipsen, visit www.ipsen.com. The forward-looking statements, objectives and targets contained herein are based on the Group’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. All of the above risks could affect the Group’s future ability to achieve its financial targets, which were set assuming reasonable macroeconomic conditions based on the information available today. Use of the words "believes," "anticipates" and "expects" and similar expressions are intended to identify forward-looking statements, including the Group’s expectations regarding future events, including regulatory filings and determinations. Moreover, the targets described in this document were prepared without taking into account external growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by the Group. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties, notably the fact that a promising product in early development phase or clinical trial may end up never being launched on the market or reaching its commercial targets, notably for regulatory or competition reasons. The Group must face or might face competition from generic products that might translate into a loss of market share. Furthermore, the Research and Development process involves several stages each of which involves the substantial risk that the Group may fail to achieve its objectives and be forced to abandon its efforts with regards to a product in which it has invested significant sums. Therefore, the Group cannot be certain that favorable results obtained during pre-clinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the product concerned. There can be no guarantees a product will receive the necessary regulatory approvals or that the product will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Other risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the Group's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the Group’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The Group also depends on third parties to develop and market some of its products which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to the Group’s activities and financial results. The Group cannot be certain that its partners will fulfil their obligations. It might be unable to obtain any benefit from those agreements. A default by any of the Group’s partners could generate lower revenues than expected. Such situations could have a negative impact on the Group’s business, financial position or performance. The Group expressly disclaims any obligation or undertaking to update or revise any forward looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. The Group’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers. The risks and uncertainties set out are not exhaustive and the reader is advised to refer to the Group’s 2015 Registration Document available on its website (www.ipsen.com). Comparison of Consolidated Sales for the Fourth Quarter and Full Year 2016 and 2015: Sales by therapeutic area and by product9 Note: Unless stated otherwise, all variations in sales are stated excluding foreign exchange impacts. The following table shows sales by therapeutic area and by product for the fourth quarter and full year 2016 and 2015: In the fourth quarter of 2016, sales reached €430.2 million, up 15.5%, led by the 17.8% growth of Specialty Care sales, while Primary Care sales grew by 7.6%. In 2016, sales amounted to €1,584.6 million, up 11.8%, driven by the 16.1% growth of Specialty Care sales, while Primary Care sales declined by 2.7%. In the fourth quarter of 2016, sales of Specialty Care products of €339.8 million, were up 17.8% year-on-year driven by Oncology sales growth of 27.0%. In 2016, sales of Specialty Care products of €1,273.0 million, were up 16.1% fueled by Oncology sales growth of 22.1%, Neurosciences sales growth of 4.3%, and Endocrinology sales growth of 1.7%. Over the period, the relative weight of Specialty Care continued to increase to reach 80.3% of Group sales, compared to 77.2% in 2015. In Oncology, sales reached €247.3 million in the fourth quarter of 2016, up 27.0% year-on-year, driven by the continued growth of Somatuline® in the United States and in Europe. In 2016, Oncology sales amounted to €904.8 million, up 22.1% and represented 57.0% of total Group sales, compared to 52.1% in 2015. Somatuline® – In the fourth quarter of 2016, sales reached €146.5 million, up 34.1%. In 2016, sales amounted to €538.3 million, up 35.5%. Somatuline®’s improved performance was driven by strong volumeand market share growth in North America and by a strong performance in most European countries, notably in the United Kingdom, France and Germany. Decapeptyl® – In the fourth quarter of 2016, sales totaled €88.0 million, up 8.5% year-on-year. In 2016, sales amounted to €339.8 million, up 4.2%. Decapeptyl®’s good performance across Europe, notably in France, Spain and UK was negatively impacted by price pressure in China which offset local volume growth. Cabometyx® – In the fourth quarter of 2016, sales reached €8.3 million, including sales recognized in France under the Cabometyx® Managed Access Program (ATU or Temporary Use Authorization). Other Oncology – In the fourth quarter of 2016, Hexvix® sales amounted to €4.5 million, up 6.6% year-on-year. In 2016, sales of Hexvix® reached €18.3 million, up 7.1%, mainly driven by the good performance in Germany, which accounts for the majority of product sales. The Group also registered first sales of Cometriq® of €1.2 million in the fourth quarter 2016. In Neurosciences, sales of Dysport® reached €71.2 million in the fourth quarter of 2016, down 1.6% year-on-year. Despite strong volume growth in the aesthetics business in North America with Galderma, and in Russia and the Middle East, sales were negatively impacted by importation issues in Brazil due to a temporary cancellation of the certificate of Good Manufacturing Practices (cGMP). An exceptional import license has been secured for the public market. For the private market, Ipsen is working closely with regulatory authorities on obtaining an exceptional import license. The company expects a new GMP certificate to be issued in the coming months. In 2016, sales amounted to €284.7 million, up 4.0%, driven by the good performance in Russia, the Middle East and in Germany as well as by the strong aesthetics business in North America and in Europe with Ipsen’s partner Galderma and despite the negative impact of importation issues in Brazil that arose in the second half of 2016. Over the period, Neurosciences sales represented 18.1% of total Group sales, compared to 19.4% in 2015. In Endocrinology, sales of NutropinAq® reached €14.0 million in the fourth quarter of 2016, down 3.8% year-on-year. In 2016, sales amounted to €57.7 million, down 3.5%, impacted by lower volumes, especially in Germany, Italy and the UK, and partly offset by a good performance in France. In the fourth quarter of 2016, sales of Increlex® reached €6.5 million, up 1.5% year-on-year, mostly driven by the United States. In 2016, sales amounted to €23.7 million, up 16.9%. Over the period, Endocrinology sales represented 5.1% of total Group sales, compared to 5.6% in 2015. In the fourth quarter of 2016, Primary Care sales reached €90.4 million, up 7.6% year-on-year, driven by the good performance of Smecta® and Etiasa®. In 2016, sales amounted to €311.6 million, down 2.7%, impacted by lower Tanakan® sales in Russia. Over the period, Primary Care sales represented 19.6% of total Group sales, compared to 22.8% in 2015. In the fourth quarter of 2016, Gastroenterology sales reached €63.7 million, up 9.6% year-on-year led by Smecta®. In 2016, sales amounted to €219.1 million, in line with 2015, driven by higher Smecta® sales in Russia and France but offset by negative inventory trends in Asia and the delisting of Bedelix® in Algeria. Smecta® – In the fourth quarter of 2016, sales reached €31.6 million, up 25.5% year-on-year, driven by a favorable basis of comparison in China. In 2016, sales amounted to €111.0 million, up 0.6% with a good performance in Russia and France, driven by the implementation of the OTC commercial model, and slightly offset by the negative stocking impact in China. Etiasa® – In the fourth quarter of 2016, sales reached €11.5 million up 38.6% year-on-year. In 2016, sales amounted to €29.3 million, up 19.5%. Forlax® – In the fourth quarter of 2016, sales reached €10.2 million, down 4.9% year-on-year. In 2016, sales amounted to €39.3 million, up 0.5%, supported by a good performance in France, Russia and China, as well as by Ipsen’s partners who distribute Macrogol®, the generic version of Forlax®, and offset by the sales decline in Algeria and in Italy. Fortrans® – In the fourth quarter of 2016, sales reached €7.3 million, down 0.4% year-on-year. In 2016, sales amounted to €23.2 million, up 2.7% due to the good performance in China. In the Cognitive Disorders area, sales of Tanakan® reached €15.8 million in the fourth quarter of 2016, up 7.1% year-on-year, driven by a rebound in Russia. Sales in 2016 amounted to €43.6 million, down 14.3%, impacted by continued market challenges in Russia and the market decrease in France. Sales of Other Primary Care products reached €5.4 million in the fourth quarter of 2016, up 8.3% year-on-year. In 2016, sales amounted to €23.5 million, down 10.0%, mainly affected by the underperformance of Adrovance®, which was down 15.5% over the period. In the fourth quarter of 2016, Drug-related Sales (active ingredients and raw materials) reached €5.4 million, down 11.6% year-on-year, mostly affected by import difficulties in Algeria. In 2016, sales amounted to €25.5 million, up 4.9% driven by solid sales to the Group partner Schwabe. Group sales by geographical area in the fourth quarter and full year 2016 and 2015: In the fourth quarter of 2016, sales in the Major Western European countries reached €148.6 million, up 8.6% year-on-year. In 2016, sales in the Major Western European countries amounted to €571.9 million, up 6.9%. Over the period, sales in the Major Western European countries represented 36.1% of total Group sales, compared to 37.7% in the previous year. France – In the fourth quarter of 2016, sales reached €61.5 million, up 14.1% year-on-year, driven by the first sales of Cabometyx®. In 2016, sales amounted to €225.5 million, up 6.2%, driven by the sustained growth of Somatuline® and Decapeptyl®, as well as the first sales of Cabometyx® in the fourth quarter. Primary Care sales were stable over the year with a good performance of Smecta®, offset by the decrease of Tanakan®, Adrovance®, and Nisis®/Nisisco®. The relative weight of France in the Group’s consolidated sales has continued to decrease to represent 14.2% of total Group sales, compared to 14.7% in the previous year. Germany – In the fourth quarter of 2016, sales reached €31.6 million, up 5.4% year-on-year. In 2016, sales amounted to €123.2 million, up 11.7%, driven by strong growth of Somatuline® and Dysport® as well as the commercial launch of Cabometyx® and Cometriq® in November. Over the period, sales in Germany represented 7.8% of total Group sales, compared to 7.6% in the previous year. Italy – In the fourth quarter of 2016, sales reached €18.8 million, down 3.4% year-on-year. In 2016, sales amounted to €81.2 million, up 2.2%. The solid growth of Somatuline® was partly offset by the sales decline of Dysport® and NutropinAq®. Over the period, sales in Italy represented 5.1% of total Group sales, compared to 5.5% in the previous year. United Kingdom – In the fourth quarter of 2016, sales reached €18.2 million, up 12.6% year-on-year. In 2016, sales amounted to €72.8 million, up 8.2%, driven by Somatuline® and Decapeptyl®. Over the period, the United Kingdom represented 4.6% of total Group sales, compared to 5.3% in the previous year. Spain – In the fourth quarter of 2016, sales reached €18.5 million, up 6.0% year-on-year. In 2016, sales amounted to €69.2 million, up 5.5%, driven by strong volume growth of Decapeptyl® and Somatuline®. Over the period, sales in Spain represented 4.4% of total Group sales, compared to 4.5% in the previous year. In the fourth quarter of 2016, sales in Other European countries reached €97.7 million, up 21.0% year-on-year, driven by the launch of Cabometyx® in Austria and the good performance of Dysport® in Russia. In 2016, sales amounted to €349.2 million, up 11.5%, supported by the strong performance of Somatuline® across the region as well as Dysport® and Decapeptyl®, notably in Russia and Ukraine, partly offset by the Tanakan® slowdown in Russia. Over the period, sales in the region represented 22.0% of total Group sales compared to 22.3% in the previous year. In the fourth quarter of 2016, sales generated in North America reached €83.3 million, up 69.4% year-on-year. In 2016, sales amounted to €273.0 million, up 72.5%, supported by the growth of Somatuline® and the growth of Dysport® mainly driven by the strong growth in aesthetics through the Galderma partnership. Over the period, sales in North America represented 17.2% of total Group sales, compared to 10.9% in the previous year. In the fourth quarter of 2016, sales in the Rest of the World reached €100.5 million, down 3.9% year-on-year mainly impacted by Dysport® in Brazil. In 2016, sales amounted to €390.5 million, down 4.4%. Sales were impacted by importation issues in Brazil which negatively impacted Dysport®, as well as the delisting of Bedelix® in Algeria. Over the period, sales in the Rest of the World represented 24.6% of total Group sales, compared to 29.1% in the previous year. Comparison of Core consolidated income statement for 2016 and 2015 Core financial measures are performance indicators. Reconciliation between these indicators and IFRS headings is presented in Appendix 4 “Bridges from IFRS consolidated net profit to Core consolidated net profit”. In 2016, the Group's consolidated sales came to €1,584.6 million, up 9.7% year-on-year, and up 11.8% excluding the impact of foreign exchange. Other revenues for the financial year 2016 totaled €86.5 million, up 13.4% versus €76.3 million generated in 2015. This change was attributable to higher royalties received from Group partners (mainly Galderma for Dysport® and Menarini for Adenuric®), the new distribution model for Etiasa® in China, partially offset by the recognition in 2015 of an upfront payment of €3.4 million received from the sale of Ginkor Fort® licensing rights to Tonipharm. In 2016, cost of goods sold amounted to €353.3 million, representing 22.3% of sales compared to €336.8 million, or 23.3% of sales in 2015. The improvement in cost of goods sold as a percentage of sales was primarily due to a favorable product mix arising from the growth of the Specialty Care business associated with productivity efforts deployed at manufacturing sites. In 2016, selling expenses came to €608.4 million, representing 38.4% of sales, up 12.4% versus 2015. The increase reflected the investments to support Cabometyx®’s launch in Europe as well as commercial efforts deployed to support Somatuline®'s growth and to launch Dysport® in spasticity indications in the United States. For the financial year 2016, research and development expenses totaled €208.9 million, compared with €192.1 million in the same period in 2015. Main expenditures were committed to continue managing the lifecycle of Dysport® and Somatuline® as well as developing new oncology programs based on peptide receptor radionuclide therapy. In 2016, the research tax credit amounted to €29.6 million, up €1.5 million versus 2015. In 2016, general and administrative expenses came to €129.4 million, compared to €122.9 million in 2015. This increase resulted primarily from some limited additional support functions costs in accordance with sales growth priorities and the impact of the Group's outperformance on bonus pay. In 2016, other core operating expenses totaled €7.1 million, compared with other core operating income of €0.7 million in 2015. This evolution is mainly due to the impact of the currency hedging policy. Core Operating Income in 2016 came to €363.9 million, representing 23.0% of sales, compared with €327.7 million in Core Operating Income in 2015, representing 22.7% of sales. The continued good performance of Somatuline® in the United States and Europe, along with the strengthening partnership with Galderma, enabled the Group to intensify its commercial investments, notably to support the launch of Cabometyx® in Europe, while maintaining its profitability. The growth of the Core Operating Income between December 2015 and December 2016 reached 11.1%. In 2016, the Group had net financial expense of €14.3 million, versus net financial expense of €11.3 million in 2015. In 2016, core income tax expense of €88.0 million resulted from a core effective tax rate of 25.2% on pre-tax profit. That compares with a core effective rate of 26.9% in 2015. For the year ended 31 December 2016, Core consolidated net profit increased by 12.8% to €263.6 million, with €262.9 million attributable to Ipsen S.A. shareholders. This compares to consolidated net profit of €233.8 million, with €232.9 million attributable to Ipsen S.A. shareholders in 2015. In 2016, Core EPS fully diluted (see Appendix 4) came to €3.18, up 13.0% versus €2.82 per share in 2015. From Core financial measures to IFRS reported figures Reconciliations between IFRS 2015/2016 results and the newly defined Core financial measures are presented in Appendix 4. In 2016, the main reconciling items between Core consolidated net income and IFRS consolidated net income were: Amortization of intangible assets (excluding software) for 2016 amounted to €7.7 million before tax, compared with €4.7 million before tax in 2015. This variance consisted mainly of the amortization of the cabozantinib intangible assets starting with the first sales of the product. Other operating expenses for 2016 amounted to €6.8 million before tax and consisted mainly of the costs from the change in the Group’s corporate governance and the costs from the move to the new UK research and development site in Oxford. In 2015, those expenses totaled €7.2 million before tax. They corresponded mainly to the amount booked following the discontinuation of the tasquinimod studies for prostate cancer. In 2016, restructuring costs came to €1.9 million before tax, compared with €6.7 million before tax in 2015. In 2016, Ipsen recorded a €42.9 million impairment charge (before tax) on intangible assets related to OctreoPharm for €28.9 million (delayed development), to MCNA for €8.0 million (after the termination of the Telesta Therapeutics partnership), and to Canbex Therapeutics for €5.4 million (purchase option). In 2015, the Group recorded a €57.0 million loss before tax to impair all intangible assets related to the tasquinimod program, and a €7.6 million impairment loss before tax, resulting from the full write-down of an Ipsen BioInnovation Ltd. intangible asset. In 2016, Ipsen received €5.3 million of dividends from Rhythm Holding and €2.4 million of dividends from InnoBio fund as well as Spirogen earn-out payment, while in 2015 the Group received a €4.9 million final earn-out from the sale of PregLem shares. In 2016, Operating Income totaled €304.7 million, up 24.8% from €244.0 million in 2015, impacted by a lower impairment charge, with an Operating margin at 19.2%, up 2.3 points compared to 2015. Consolidated net profit was €226.6 million, up 18.8% over the period, compared to €190.7 million in 2015. Fully diluted EPS was €2.73 in 2016, up 18.7% from €2.30 in 2015. Segment information is presented according to the Group's two operating segments: Specialty Care and Primary Care. All costs allocated to these two segments are presented in the key performance indicators. Only corporate overhead costs and the impact of the currency hedging policy are not allocated to the two operating segments. Research and development costs are allocated to operating segments, while formerly included in Unallocated. The Group uses Core Operating Income to measure its segment performance and to allocate resources. Sales, revenue and Core Operating Income are presented by therapeutic area for the 2016 and 2015 financial years in the following table. In 2016, Specialty Care sales grew to €1,273.0 million, up 14.2% over 2015, driven by oncology sales that advanced 20.2% at current rates. The relative weight of Specialty Care products continued to increase, reaching 80.3% of total consolidated sales at 31 December 2016, versus 77.2% a year earlier. In 2016, Core Operating Income for Specialty Care amounted to €415.0 million, including research and development costs, representing 32.6% of sales. That result compared to €328.9 million in 2015, representing 29.5% of sales. The improvement reflected Somatuline®'s continued sales growth in the United States and Europe, along with increased commercial investments, notably in the United States for Somatuline® and in Europe to support the Cabometyx® launch. In 2016, sales of Primary Care products came to €311.6 million, down 5.5% year on year, mainly related to continued market challenges in Russia for Tanakan® and lower other Primary Care sales. In 2016, Core Operating Income for Primary Care amounted to €99.6 million, representing 32.0% of sales. In 2016, unallocated Core Operating Income came to a negative €150.7 million, compared with a negative €127.9 million in 2015. These expenses consisted mainly of unallocated corporate expenses and of the impact from the currency hedging policy. In 2016, the Group had a decrease in net cash of €118.4 million, bringing closing net cash to €68.6 million. In 2016, Operating Cash Flow totaled €307.1 million, up €64.0 million versus 31 December 2015. The increase was driven by higher Core Operating Income and by the improvement in working capital requirement partially offset by higher net capital expenditures (excluding milestones paid). The working capital requirement for operating activities increased by €2.8 million at 31 December 2016, compared with an increase of €53.2 million at 31 December 2015. The change at 31 December 2016 stemmed mainly from the following: In 2016, other working capital requirement decreased by €12.1 million, compared with a €7.4 million increase in 2015, mainly due to the reimbursement in 2016 of French R&D tax credit amounts. Net capital expenditure grew by €27.4 million year-on-year to €84.0 million at 31 December 2016. In 2016, these investments included projects in the Group’s manufacturing sites in Ireland and in France to increase production capacity, as well as in the new R&D toxin center in the UK. In 2016, Free Cash Flow came to €228.8 million, up €52.5 million versus 31 December 2015. This evolution was mainly driven by the Operating Cash Flow improvement. Other operating income and expenses and restructuring costs amounted to €20.8 million including the impact of the change in the Group’s corporate governance, as well as payments for earlier restructuring plans. At the end of December 2015, €28.9 million of such payments were primarily comprised of restructuring costs and expenses arising from discontinuing clinical trials of tasquinimod. The €3.1 million in financial income paid at the end of December 2016 resulted mainly from hedging costs and realized exchange losses, partially offset by the collection of dividends on Rhythm Holding participation, as well as by an earnout payment related to the sale of Spirogen shares and dividends from Innobio Fund. In comparison, the €4.7 million in financial expense, at the end of December 2015, were derived from a €4.9 million earnout payment from the PregLem shares that was partially offset by an unfavorable foreign exchange effect. The change in current income tax stemmed from the change in the effective tax rate. At 31 December 2016, the dividend payout to Ipsen S.A. shareholders amounted to €70.0 million. Net investments at 31 December 2016 mainly encompassed a €257 million upfront and milestones payment to Exelixis, following the signature of an exclusive licensing agreement to commercialize and develop cabozantinib, a €5 million upfront payment to 3B Pharmaceuticals GmbH, following the signature of an exclusive licensing agreement for new radiopharmaceutical products in oncology and a €5 million milestone paid in relation with the Lexicon license agreement. These amounts are partially offset by regulatory milestone payments received from Acadia (€7 million) and Radius (€3 million) and by scheduled payments related to the agreement signed with Galderma in December 2015 for Asia-Pacific markets (collection of a net €6 million). At 31 December 2015, net investments primarily included the €31.4 million acquisition of OctreoPharm Sciences GmbH and the purchase of a €6.0 million call option to acquire Canbex Therapeutics. Reconciliation of cash and cash equivalents and net cash (*) Net cash / (debt): cash and cash equivalents, less bank overdrafts, bank loans and other financial liabilities and excluding financial derivative instruments. (**) Financial liabilities mainly exclude €18.2 million in derivative instruments in 2016, compared with €4.5 million in derivative instruments in 2015. On 16 June 2016, Ipsen S.A. issued a €300 million unsecured seven-year public bond loan with an annual interest rate of 1.875%. In addition, €300 million of bilateral long term bank loans were contracted with a maximum maturity of 6.5 years from June 2016. At 31 December 2016, none of these bank loans had been tapped. On 24 June 2016, Ipsen S.A. amended its multiple-currency Revolving Credit Facility to reduce it to €300 million and to remove its financial covenants. This credit line remained undrawn at 31 December 2016. Ipsen S.A. has also a €300 million short term commercial paper program of which €30 million were issued at 31 December 2016. (a) Milestones paid correspond to payments subject to the terms and conditions set out in the Group's partnership agreements. The €257.3 million in upfront and milestones paid to Exelixis accounted for the majority of the milestones paid at 31 December 2016. The amounts paid were recorded as an increase in intangible assets on the consolidated balance sheet. The transactions were included in the "Acquisition of intangible assets" line item in the consolidated statement of cash flow (see Appendix 3.1). (b) Milestones received are amounts collected by Ipsen from its partners. Of the €20.7 million in milestones received at 31 December 2016, €10.5 million were paid by Galderma in accordance with the partnership agreement signed in December 2015 for the Asia Pacific region. The amounts were recorded as deferred income in the consolidated balance sheet and then recognized in the income statement as "Other revenues". Milestones received were included in the "Net change in other operating assets and liabilities" line item in the consolidated statement of cash flow (see Appendix 3.1). The reconciliation items between Core consolidated net profit and IFRS consolidated net profit are described in the paragraph “From Core financial measures to IFRS reported figures”. The Group operates in an environment which is undergoing rapid change and exposes its operations to a number of risks, some of which are outside its control. The risks and uncertainties set out below are not exhaustive and the reader is advised to refer to the Group’s 2015 Registration Document available on its website (www.ipsen.com). 1 Year-on-year growth excluding foreign exchange impacts 2 Excludes amortization of intangible assets (excluding software), gain or loss on disposal of fixed assets, restructuring costs, impairment losses and other non-core items 3 Reconciliation between this new definition of Core Operating Income and the previous definition is presented on page 3 4 Bridges from IFRS consolidated net profit to Core consolidated net profit are presented in appendix 4 5 Cash and cash equivalents, less bank overdrafts, bank loans and other financial liabilities and excluding financial derivative instruments 6 OTx: Combination of prescription and over-the-counter 7 2016 revised financial objectives communicated on 26 October 2016 8 Year-on-year growth excluding foreign exchange impacts 9 New sales reporting according to main therapeutic indication of each product


Patent
Baxter International, 3B Pharmaceuticals Gmbh and Baxter Healthcare S.A. | Date: 2011-02-11

The invention provides peptides that bind Tissue Factor Pathway Inhibitor (TFPI), including TFPI-inhibitory peptides, and compositions thereof. The peptides may be used to inhibit a TFPI, enhance thrombin formation in a clotting factor-deficient subject, increase blood clot formation in a subject, treat a blood coagulation disorder in a subject, purify TFPI, and identify a TFPI-binding compound.


Dockal M.,Baxter Innovations GmbH | Hartmann R.,Baxter Innovations GmbH | Fries M.,Baxter Innovations GmbH | Thomassen M.C.L.G.D.,Maastricht University | And 9 more authors.
Journal of Biological Chemistry | Year: 2014

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slowtight binding mechanism and tissue factor-activated FVII (TFFVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ∼1 nM). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-Å resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an γ-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal α-helix that is anchored to K1 at its reactive center loop and two-stranded β-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nM) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nM). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Daumer M.P.,University of Bonn | Daumer M.P.,Institute of Immunology and Genetics | Schneider B.,University of Bonn | Giesen D.M.,University of Bonn | And 10 more authors.
Medical Microbiology and Immunology | Year: 2011

Monoclonal antibody (MAb) 2c, specific for glycoprotein B of herpes simplex virus (HSV), had been shown to mediate clearance of infection from the mucous membranes of mice, thereby completely inhibiting mucocutaneous inflammation and lethality, even in mice depleted of both CD4+ and CD8+ cells. Additionally, ganglionic infection was highly restricted. In vitro, MAb 2c exhibits a potent complement-independent neutralising activity against HSV type 1 and 2, completely inhibits the viral cell-to-cell spread as well as the syncytium formation induced by syncytial HSV strains (Eis-Hübinger et al. in Intervirology 32:351-360, 1991; Eis-Hübinger et al. in J Gen Virol 74:379-385, 1993). Here, we describe the mapping of the epitope for MAb 2c. The antibody was found to recognise a discontinuous epitope comprised of the HSV type 1 glycoprotein B residues 299 to 305 and one or more additional discontinuous regions that can be mimicked by the sequence FEDF. Identification of the epitope was confirmed by loss of antibody binding to mutated glycoprotein B with replacement of the epitopic key residues, expressed in COS-1 cells. Similarly, MAb 2c was not able to neutralise HSV mutants with altered key residues, and MAb 2c was ineffective in mice inoculated with such mutants. Interestingly, identification and fine-mapping of the discontinuous epitope was not achieved by binding studies with truncated glycoprotein B variants expressed in COS cells but by peptide scanning with synthetic overlapping peptides and peptide key motif analysis. Reactivity of MAb 2c was immensely increased towards a peptide composed of the glycoprotein B residues 299 to 305, a glycine linker, and a C-terminal FEDF motif. If it could be demonstrated that antibodies of the specificity and bioactivity of MAb 2c can be induced by the epitope or a peptide mimicking the epitope, strategies for active immunisation might be conceivable. © 2010 Springer-Verlag.


Horiya S.,Brandeis University | Bailey J.K.,Brandeis University | Temme J.S.,Brandeis University | Guillen Schlippe Y.V.,Massachusetts General Hospital | And 2 more authors.
Journal of the American Chemical Society | Year: 2014

Herein, we report a method for in vitro selection of multivalent glycopeptides, combining mRNA display with incorporation of unnatural amino acids and "click" chemistry. We have demonstrated the use of this method to design potential glycopeptide vaccines against HIV. From libraries of ∼1013 glycopeptides containing multiple Man9 glycan(s), we selected variants that bind to HIV broadly neutralizing antibody 2G12 with picomolar to low nanomolar affinity. This is comparable to the strength of the natural 2G12-gp120 interaction, and is the strongest affinity achieved to date with constructs containing 3-5 glycans. These glycopeptides are therefore of great interest in HIV vaccine design. © 2014 American Chemical Society.


Witney T.H.,Stanford University | Witney T.H.,University College London | James M.L.,Stanford University | Shen B.,Stanford University | And 13 more authors.
Science Translational Medicine | Year: 2015

Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [11C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor-associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis.


Patent
3B Pharmaceuticals GmbH | Date: 2014-06-11

The present invention is related to neurotensin receptor antagonists of formula (I):R^(1) is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl;AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;R^(2) is selected from the group consisting of (C_(1)-C_(6))alkyl, (C_(3)-C_(8))cycloalkyl, (C_(3)-C_(8))cycloalkylmethyl, halogen, nitro and trifluoromethyl;ALK is (C_(2)-C_(5))alkylidene;R^(3), R^(4) and R^(5) are each and independently selected from the group consisting of hydrogen and (C_(1)-C_(4))alkyl under the proviso that one of R^(3), R^(4) and R^(5) is of the following formula (II)ALK is (C_(2)-C_(5))alkylidene;R^(6) is selected from the group consisting of hydrogen and (C_(1)-C_(4))alkyl; andR^(7) is selected from the group comprising H, Acceptor, -[Acceptor-Effector], -[Linker-Acceptor], and -[Linker-Acceptor-Effector], wherein Acceptor is a moiety which mediates linking of an Effector to the N atom of formula (II) or which mediates linking of the Effector to the Linker,Effector is selected from the group comprising a diagnostically active agent and a therapeutically active agent,Linker is a moiety which links the Acceptor to the N atom of formula (II),-[Acceptor-Effector] is a moiety where the Effector is complexed or covalently bound to the Acceptor,-[Linker-Acceptor] is a moiety where the Linker is conjugated to the Acceptor, and-[Linker-Acceptor-Effector] is a moiety where the Linker is conjugated to the Acceptor, whereby the Effector is complexed or covalently bound to the Acceptor;or a pharmacologically acceptable salt, solvate or hydrate thereof.


Patent
3B Pharmaceuticals GmbH | Date: 2015-12-16

The present invention is related to a conjugate comprising a structure of general formula (1)[TM1] - [AD1] - [LM] - [AD2] - [TM2](1),whereinTM1 is a first targeting moiety, wherein the first targeting moiety is capable of binding to a first target,AD1 is a first adapter moiety or is absent,LM is a linker moiety or is absent,AD2 is a second adapter moiety or is absent, andTM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target;wherein the first targeting moiety and/or the second targeting moiety is a compound of formula (2):R^(1) is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl;AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;R^(2) is selected from the group consisting of (C_(1)-C_(6))alkyl, (C_(3)-C_(8))cycloalkyl, (C_(3)C_(8))cycloalkylmethyl, halogen, nitro and trifluoromethyl;ALK is (C_(2)-C_(5))alkylidene;R^(3), R^(4) and R^(5) are each and independently selected from the group consisting of hydrogen and (C_(1)-C_(4))alkyl under the proviso that one of R^(3), R^(4) and R^(5) is of the following formula (3)ALK is (C_(2)-C_(5))alkylidene;R^(6) is selected from the group consisting of hydrogen and (C_(1)-C_(4))alkyl; andR^(7) is a bond;or a pharmacologically acceptable salt, solvate or hydrate thereof.

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