i3du - PhD Programme in Medicines and Pharmaceutical Innovation First Report January 2015 June 2016 Faculty of Pharmacy, Universidade de Lisboa

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1 i3du - PhD Programme in Medicines and Pharmaceutical Innovation First Report January 2015 June 2016 Faculty of Pharmacy, Universidade de Lisboa 1. Summary description 2. Activities 3. Facts and numbers 4. Conclusion and outlook to the future 1. Summary description The mission of the i3du Programme ( is to translate research into knowledge and innovation with tangible benefits for society. Focusing on translational research in target discovery, drug design, pre-clinical development, and drug safety, the i3du Programme will deliver accomplished scientists and professionals to academic research institutions, pharmaceutical companies and healthcare systems, in their bid to rationalize discovery and development of innovative products and technologies. The unique organization into fields of study ensures that Faculty and students across the host institutions share ideas and work together freely and without undue administrative barriers. Faculty members are often involved in more than one field, further increasing mentorship options for students. The i3du Programme is supported by the most qualified researchers and educators from the universities of Lisbon (ULisboa) and Porto (UPorto), and from pharmaceutical companies and biotechs. Both universities award the PhD degrees (accredited by A3ES) that anchor the i3du Programme. The consortium involves the Faculties of Pharmacy at ULisboa (FFULisboa) and U.Porto (FFUPorto), and the Research Centers imed.ulisboa at ULisboa, and REQUIMTE and IBMC.INEB at U.Porto, in collaboration with Hovione and Novartis as major industry partners. In the 2014 call for applications, 4 candidates among 94 applicants were selected to receive the PhD fellowship. In the 2015 call, 48 applications were received, and 4 additional fellowships were awarded. Currently, 8 PhD students receiving a fellowship from the FCT PhD Programme are enrolled into the i3du. A rigorous selection procedure was undertaken by the evaluation panel resulting in all cases in recruitment of high quality students with a track record of publications unusual for this stage in their career. Importantly, a larger number of students holding individual FCT fellowships or supported by others sources, such as the pharma industry, have also joined the i3du Programme. Of note, FFUPorto was recently awarded 4 additional fellowships to be attributed to i3du students through the NORTE2020 programme, call NORTE Advanced Training Doctoral 1

2 Programmes, which will duplicate the overall number of fellowships awarded by the Programme in The 2016 call is currently open. 2. Activities The i3du Programme is student-centred. A full training i3du Programme consists of elective advanced core courses, laboratory rotations and seminars, in parallel with research activities, during the first year, followed by a 3-year interdisciplinary research project leading to an original doctoral thesis. Each PhD student has dedicated supervisors and a PhD Thesis Committee. Particular attention is given to each personal career development plan. All educational and training activities fall within the scope of A3ESaccredited doctoral fields of studies from the Faculties of Pharmacy, both at ULisboa and UPorto. This document reports on i3du activities throughout the first 1.5 years. Core Courses The following core courses have been organized: Biomarkers and Assay Development This course covers critical aspects of biomarkers from identification to validation, to impact on diagnosis and prognosis of disease states. The training programme is aimed at PhD students and has slots allocated to seminars and workshops, including discussions with lecturers and companies involved in biomarker development and diagnosis. It welcomes the participation of external academic and scientific communities. This course took place in September 14-18, 2015, hosted several international speakers and was attended by close to 100 participants, including PhD students (46%), postdocs (17%), and professionals. Eighteen i3du PhD students attended this course. Students were evaluated by the preparation of an interdisciplinary research project by groups of students with diverse background. Discussion groups and topics were previously organized by the teaching staff; specific time was allocated to interaction and discussion throughout the week. Quality of the sessions and networking were highlighted by students as the 2 most important aspects of the course. Biopharmaceuticals and Advanced Therapies This course covers critical aspects of biopharmaceuticals and advanced therapies from discovery methods to development of therapies, with emphasis on success cases of antibodies, gene therapy and cell therapy. The aim of this training course is to delivery not only state-of-the-art information but also to give training on the different aspects of biopharmaceuticals, including preclinical and clinical trials of biopharmaceuticals, regulatory aspects and entrepreneurship in innovative therapies. As the functions of biopharmaceuticals are fully explored and utilized, they will become increasingly relevant to the drug development community. Case studies were discussed and fully explored as part of the course evaluation. This course 2

3 took place in September 28-October 2, Eleven i3du PhD students attended this course. Medicinal Chemistry This course covers the critical aspects of drug discovery ranging from target identification to lead identification and lead optimization strategies. Hands-on training using state-of-the-art molecular simulation software is included. In addition, a unique overview of the drug discovery process in the pharmaceutical industry is also provided with invited lecturers from pharmaceutical industry. The students have prepared very high quality research projects, as part of the evaluation process. This course took place in February 15-19, Twelve i3du PhD students attended this course. Advanced Drug Delivery This course trains students in the development of advanced medicinal products, covering crucial aspects that determine the fate of drugs in the human or animal body, from their fundamentals to the advanced strategies to overcome the physiological barriers, including innovative technological and therapeutic applications. The faculty, including key international speakers contributed to high quality discussions and supported the students throughout the case studies as part of the evaluation process. This course took place in March 14-18, Twenty-three i3du PhD students attended this course. Non-clinical Efficacy and Safety The course includes interactive lectures addressing pharmacology, pharmacokinetic and safety studies to support first in human studies on any experimental molecule, and a number of case studies in the areas referred, which demand interpretation of results and solution building. Work group will take into account the relevant international guidelines on experimental data to support clinical studies. Special relevance will be given to the choice of relevant experimental models. Evaluation is continuous through interaction between faculty and students, and includes also a case study. The course took place in April 15-29, Twelve i3du PhD students attended this course. Pharmacoepidemiology and Pharmacovigilance This course will cover key issues in pharmacoepidemiology and drug safety research. Special topics will be addressed including bias and confounding, impact of variability of drug exposures in clinical outcomes and molecular pharmacoepidemiology. Recent published papers and Pharmacovigilance Directive in European Union will be presented and discussed. Selected case studies are the basis to expand the concepts. Each participant has to develop in a day-by-day basis a protocol to address his/her own research question. The course took place in May 18-June 4, 2016 and was attended by 9 i3du PhD students. Laboratory rotations, short courses and workshops In addition to the core courses, students have been engaged in several laboratory rotations and seminars, according to each career development 3

4 plan. Short courses such as Library Search: PubMed, Scopus and Web of Science, Scientific Journal Evaluation, Introduction do EndNote X7, Scientific Writing of Original and Revision Papers, Design of Experiments in Pharmaceutical Sciences Research, Computational drug design, Statistics in Scientific Research took place at FFUPorto and FFUlisboa, often organized by the students according to their identified needs. Annual Meeting The annual meeting of PhD students took place in Lisbon, on July 15-16, 2015, as a forum to discuss PhD projects and interactions with the pharmaceutical industry. Representatives of the pharmaceutical industry (Hovione, Bial), regulators (Infarmed IP) and biotechs (Technophage, Kemin) were present to discuss potential PhD subprojects and rotations. A keynote lecture was delivered by invited speaker Jorge Ruas (Karolinska Institute, Sweden) talking about regulation of behaviour and metabolism by musclederived signals. The meeting was fully organized by the Postgraduate Students Commission in straight collaboration with the i3du Executive Board. In 2016, PhD students will discuss their projects in the annual meeting taking place in Lisbon, July 14-15, Oral presentations and posters will foster interaction and future collaborations. Already successful ongoing collaborative projects will be discussed. Invited speaker Hans Peter Wessel, Section Head Infrastructure and Administration (Discovery Chemistry) at F.Hoffmann-La Roche Ltd in Basel, Switzerland until 2013 and current member of the i3du Programme External Advisory Committee will discuss the topic of lead generation in pharmaceutical research. Non-canonical pathways after PhD studies will be discussed on round-table format. The detailed programme is attached to this report. i3du committees including the External Evaluation Committee will meet in Lisbon on July 15, 2016, and progress reports will be prepared. Ongoing PhD projects Enrollment in the i3du PhD Programme in has been very successful. More than 30 research projects have been approved (Table 1). In many cases, PhD students are main drivers and have promoted interdisciplinary projects between research areas within research units and with the industry, often contributing to the internationalization of the i3du PhD Programme. Table 1 Students, topics and supervisors in the i3du PhD Programme in PhD Student Topic Supervisors Ana Cláudia Rodrigues Fonseca Ana Ester Limede e Ventura Membrane permeability and aquaporin modulation: pharmacological targets in chronic diseases Implication of stress stimuli-derived ceramides on cell membrane biophysical properties: understanding the molecular mechanisms of ceramides action Graça Soveral (FFULisboa) Liana Silva (FFULisboa); Manuel Prieto (IST); Anthony Futerman (Weizmann Institute Science, Israel) 4

5 André Daniel Lopes Simão Ângelo Filipe Almeida Monteiro Cátia Sofia Vicente Gomes Diana Alexandra Santana da Silva Fernandes Gustavo Adolfo Lopes Ferreira da Silva Hugo Miguel de Sousa e Brito Inês Margarida Vieira da Silva Jaime Conceição Joana Sofia de Almeida Pimentel Cavaco Labib Abdulrasool Abdulrazak Al- Mousawe Luís Miguel Afonso Ramos de Carvalho Mara Diana Saavedra Cardoso Doria Márcia Filipa Cabedal da Mata Marco Calvinho Cavaco Maria Filipe Canas de Matos e Oliveira Ribeiro Marianna Katz Marta Alexandra Bogalho Rodrigues Carvalho Oluwatomide Adeoye Patrícia Filipa Alves Serra Pedro Elói Antunes Dionísio Priscila Costa Ribeiro Quintino Malú Role of mitofusin 2 in non-alcoholic fatty liver disease and targeting by micrornas Modulation of the p53 pathway by novel small molecules through inhition of p53 protein-protein interactions Novel therapeutic approach to amyotrophic lateral sclerosis: targeting neurotoxic astrocytes before transplantation Biopharmaceuticals formulations for dry powder inhalers Discovery of novel quinolone-based antimalarials using the Winterfeldt chemistry New drugs to treat fatty liver and progression to cancer Aquaporins in metabolic syndrome: new targets for drug discovery Formulations of oral solid drugcyclodextrin complexes Combinatory approach for advance breast cancer chemoresistance modulation Improving medication adherence in patients with diabetes mellitus type 2 using pharmacotherapy plan Activity-based Probes for Biomarker discovery in chronic obstructive pulmonary disease Risk analysis approach to microbiological environmental monitoring in a pharmaceutical facility Risk management in medicines life cycle Dual strategy for lung cancer: cleaning the primary compartment while eradicating brain metastasis Probing and targeting mitochondria bioenergetics in neurodegeneration Continuous development methodologies to enhance pharmaceutical R&D productivity Advanced therapy medicinal products: new strategies for clinical applications of cell and gene therapy Lopinavir-cyclodextrin nanoparticles for controlled oral delivery Viral surface glycoproteins as potential drug targets against HIV-1 and HIV-2 infections Systems analysis of inflammation and neuronal demise in neurodegenerative diseases Food supplements in patients with malignant neoplasia submitted to pelvic radiotherapy Ethnopharmacologic study of African medicinal plants Rui Castro (FFULisboa); Cecília Rodrigues (FFULisboa); Antonio Zorzano (Institute for Research in Biomedicine, Barcelona, Spain) Maria Santos (FFULisboa); Cecília Rodrigues (FFULisboa); Lucília Saraiva (FFUPorto) Dora Brites (FFULisboa); António Salgado (FCS Uminho); Brian Kaspar (Ohio State University, USA) Maria Luisa Corvo (FFULisboa); Eunice Costa (Hovione) Rui Moreira (FFULisboa); Artur Silva (UAveiro); Maria Santos (FFULisboa) Cecília Rodrigues (FFULisboa); Rui Castro (FFULisboa) Graça Rodrigues (FFULisboa); Maria Irene Jesus (FFUPorto); Joana Miranda (FFULisboa) José Manuel Sousa Lobo (FFUPorto); Helena Marques (FFULisboa) Mafalda Videira (FFULisboa); Cristina Sampayo (FFULisboa) Ana Paula Martins (FFULisboa); Hélder Mota (FFULisboa) Rui Moreira (FFULisboa); Susana Dias Lucas (FFULisboa); Deborah Penque (INSA) José Cardoso Meneses (IST); Ana Quinto (OMPharma); António Almeida (FFULisboa) Ana Paula Martins (FFULisboa) Mafalda Videira (FFULisboa) Susana Solá (FFULisboa); Cecília Rodrigues (FFULisboa) Carlos Afonso (FFULisboa); Maria Santos (FFULisboa); Nuno Matos (Hovione) Ana Paula Martins (FFULisboa); Bruno Sepodes (FFULisboa) Helena Marques (FFULisboa); Nuno Taveira (ISCS Egas Moniz) Rita Guedes (FFULisboa); Nuno Taveira (Egas Moniz) Joana Amaral (FFULisboa); Cecília Rodrigues (FFULisboa); Tiago Outeiro (University Medical Center Goettingen, Germany) Maria Eduardo Figueira (FFULisboa), Bruno Sepodes (FFULisboa); Paula Alves (IPO) Olga Silva (FFULisboa); Maria Beatriz da Silva Lima (FFULisboa); 5

6 Romina Paula de Aguiar Guedes Rosa Alexandrina de Sousa Couto Rosa Fernandes Direito Sara Daniela de Sousa Reis Sérgio José Póvoas Camões Sofia Leonor Afonso Domingos Tânia da Cunha Branco dos Santos Tânia Isabel Rodrigues Genebra Trajano Felipe Barrabas Xavier da Silva Yvonne Bessem Ojong Targeting the proteasome in anticancer therapy by a computational based drug discovery approach Development and application of an innovative disposable sensor for Novel Psychoactive Substances (NPSs) based on electrochemistry Role of the Diospyros kaki L. extract in preventing inflammation and cancer Neuroprotection by histone acetyltransferase modulators: activation or inhibition? Modulating mesenchymal stem cells to overcome impaired wound healing Pharmacological modulators of Parkinson s disease-associated proteins Biological and biophysical properties of atypical sphingolipids: implications to physiology and pathophysiology Targeting mitochondrial bioenergetics to improve aging-impaired neurogenesis Comparative analysis of graphical presentation of textual content, pictorial and functional ergonomics package inserts of drugs and health products leaflets of the community member countries of Portuguese Speaking Countries (CPLP) Treatment monitoring models in cancer radiotherapy Rita Serrano (FFULisboa) Rita Guedes (FFULisboa); Jorge Salvador (FFUCoimbra); Riccardo Gavioli (Universidade de Ferrara, Italy) Maria Beatriz Junqueiro (FFUPorto); Cecilia Rodrigues (FFULisboa) Maria Eduardo Figueira (FFULisboa); Maria do Rosário Bronze ( FFULisboa) Jorge Oliveira (FF/UPorto); Cecilia Rodrigues (FFULisboa); Paulo Oliveira (UCoimbra) Joana Miranda (FFULisboa); Jorge Santos (ECBio S.A.); Félix Carvalho (FFUPorto) Rui Moreira (FFULisboa); Lucília Borralho (FFUPorto); Maria Teresa Duarte (IST) Thorsten Hornemann (University Hospital Zurich); Liana Silva (FFULisboa); Manuel Prieto (IST) Susana Solá (FFULisboa); Cecília Rodrigues (FFULisboa); Jorge Oliveira (FFUPorto) Afonso Cavaco (FFULisboa) e Carla Spinillo (Universidade Federal do Paraná, Brasil) Ana Paula Martins (FFULisboa); Hélder Mota (FFULisboa) 3. Facts and numbers The implementation of this Programme has visibly increased the dynamics around the PhD in Pharmacy and Pharmaceutical Sciences awarded by ULisboa and UPorto, respectively. In a period when the number of fellowships attributed through the FCT-centred call for individual fellowships have dropped dramatically, we have increased the number of PhD students. At the Faculty of Pharmacy in Lisbon, the number of students evolved from 47 in 2011, to 101 in 2015 (Table 2). From these, many students are individual fellowship holders, others have received a PhD fellowship through the i3du Programme, and almost 5% are funded by the pharmaceutical industry or biotechs. Approximately 70% of the students are originally from other organic units at ULisboa or from outside ULisboa. This current attractiveness is strongly linked to improvement of the curriculum achieved with the implementation of the i3du PhD Programme, aided by favourable employment rates. Of note, similar trends are evident at the Faculty of Pharmacy at UPorto, partner in the i3du PhD Programme. 6

7 Table 2 Number of PhD students enrolled in the i3du Programme, and number of theses produced First year students Total number of students PhD theses A strong participation of industry, including SMEs, is a crucial added value for successful implementation and high impact of the i3du Programme. As such, the enhancement of academia-industry cooperation in terms of research training, career development and knowledge sharing, taking into account the protection of intellectual property rights, will continue to be strongly encouraged. Complementary aspects of training such as entrepreneurship, creativity and innovation are also stimulated in partnership with pharma and biotechs. The number of students in industrial environment is expected to continue increasing (Tables 3 and 4). Table 3 Level of interaction with industry and internationalization of the i3du Programme. Number and relative percentage of PhD students are indicated. Interaction with industry (4%) 3 (2%) 0 (0%) 1 (1%) 5 (5%) Internationalization 10 (21%) 8 (7%) 1 (1%) 1 (1%) 12 (12%) Table 4 Ongoing industry-associated research projects involving i3du faculty. PhD Student Márcia Filipa Cabedal da Mata Sérgio José Póvoas Camões Beatriz Noriega Fernandes Diana Alexandra Santana da Silva Fernandes Marianna Katz Joana Henriques Ministro Topic Risk management in medicines life cycle Modulating mesenchymal stem cells to overcome impaired wound heading Dissolution of dry powder inhaler formulations: in vitro/in vivo correlations Biopharmaceuticals formulations for dry powder inhalers Continuous development methodologies to enhance pharmaceutical R&D productivity Development of a new biological combination for the treatment of hospital- Pharmaceutical companies and biotechs Laboratórios Pfizer, Lda. ECBio, S.A. Hovione FarmaCiência, S.A. Hovione FarmaCiência, S.A. Hovione FarmaCiência, S.A. TechnoPhage, S.A. 7

8 Madalena Zinke Reis Fernandes Cipriano acquired bacterial pneumonia Development of three-dimensional umbilical cord-derived mesenchymal stem cell culture for differentiation into hepatocyte-like cells: a potencial breakthrough in toxicological drug screening ECBio, S.A. The international dimension as a fundamental component in R&D in Portugal is addressed in the i3du Programme in terms of career development. i3du is taking advantage of strategic partnerships with other universities, research centers and companies, at national and international levels, to widen the focus in education, research and innovation, promoting further mobility and internationalization (Table 1). In 2015, 12% of the new students are from abroad or have foreign supervisors (Table 3). Many more students spend training periods in laboratories outside of Portugal; ideally, all students should have an international experience throughout the i3du PhD programme. Here we highlight the leadership of the FCT i3du PhD Programme in partnership with UPorto, research institutes and pharmaceutical industry. Important is also the participation of FFULisboa and FFUPorto in seven other FCT doctoral programmes. i3du faculty members are involved in two Marie Skłodowska-Curie Innovative Training Networks, and in SafeSciMET and PharmaTrain international courses supported by the EU and Innovative Medicines Initiative, respectively, with an extensive network of national and international partners. Other opportunities are expected through the involvement in newly created consortia that seek funding opportunities in science, education and entrepreneurship in H2020 initiatives, IMI, Twining, Teaming and EIT Health (Table 5). These dynamic range of initiatives will strengthen research institutional policy and create synergies for the educational models that are being implemented. Table 5 Ongoing international research projects led or participated by i3du faculty. Programme Title Investigator A training network for the chemical siteselective modification of proteins: Preparation of the next-generation of Pedro Góis therapeutic chemically-defined protein conjugates Marie Sklodowska-Curie Innovative Training Networks Marie Skłodowska-Curie Innovative Training Networks Innovative Medicines Initiative Innovative Medicines Initiative Bioenergetic remodeling in the pathophysiology and treatment of nonalcoholic fatty liver disease Safety sciences for medicines (SafeSciMET) Medicines development (PharmaTrain) Cecília Rodrigues Beatriz Silva Lima Beatriz Silva Lima 8

9 LIFE Environment and Resource Efficiency ERANet EuroNanoMed2 European Innovative Research & Technological Development Projects in Nanomedicine ERANet EuroNanoMed2 European Innovative Research & Technological Development Projects in Nanomedicine ERANet JPco-fuND EU Joint Programme - Neurodegenerative Disease Research ERANet-LAC Latin America Caribbean and European Union Harvard Medical School- Portugal Program in Translational Research and Information Research Scholars Program in Liver Diseases Gilead Sciences International Academic Drug Discovery Consortium - AstraZeneca Intercept Investigator- Initiated Research National PKU Alliance (NPKUA), USA Swedish Research Council in Medicine and Health Drugs Policy Initiative (EU) Joint Programming Initiative on Water challenges for a changing world (EU) European Society of Clinical Microbiology and Infectious Diseases Improving current barriers for controlling pharmaceutical compounds in urban wastewater treatment plants Targeting tumor microenvironment by a translational multivalent nanomedicine: towards na effective anticancer combination immunotherapy (Nano) systems with active targeting to sensitize colorectal cancer stem cells to antitumoral treatment (Target4Cancers) Generation of Improved cellular and animal models for identification of disease phenotype and new therapeutic targets of Alzheimer's Disease Integrated valorization of lignocellulosic agroindustrial waste to furan based building blocks Treat liver diseases by targeting hepatocyte necroptosis Role of mitofusin 2 in non-alcoholic fatty liver disease and targeting by mirnas High throughput screening with AstraZeneca's compound library Targeting the NAFLD-HCC continuum with bile acid-activated receptor agonists and mirnas Human phenylanine hyrdoxylase and nanobiomaterials: a novel enzyme reposition therapy approach to PKU Patient-specific induced pluripotent stem cells to study synucleinopathies Identification and assessment of new psychoactive substances: a European network Bioorganic novel approaches for food process in waste water treatment and valorization: lupanine case study Transcription profiling of clinical Mycobacterium tuberculosis strains: global transcriptomic response towards Cristina Almeida Rogério Gaspar Mafalda Videira Dora Brites Carlos Afonso Cecília Rodrigues Rui Castro Cecília Rodrigues Rui Castro Paulo Roque Lino Dora Brites Dora Brites Carlos Afonso João 9

10 drug exposure and metabolic shift towards latency Perdigão The total budget for the i3du PhD Programme is 3.6 M over a 8-year period, including funding from FCT and NORTE2010. In 2015, the budget was close to 400 k (Figure 1). Figure 1 i3du budget in 2015 and provisional for the period , including scholarships and other expenses. 4. Conclusion and outlook to the future The i3du PhD programme received almost 150 applications in the 2014 and 2015 calls. As an indicator of this dynamics, the number of students enrolled in the 1st year of the PhD degree at FFULisboa increased from less than 15 in 2013 and 2014 to 40 in Similar trends were seen in FFUPorto. Therefore, training efficiency and number of graduates is expected to steadily increase in the i3du Programme in the coming years. 10