Rogério Sá Gaspar. Faculdade de Farmácia da Universidade de Lisboa

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1 Nanomedicine: R&D after 30 years of clinical experience and the issue of access to new technologies Rogério Sá Gaspar e imed.ul (Research Institute for Medicines and Pharmaceutical Sciences, )

2 Lisbon approach to 3Ds: imed.ul Nanomedicine & DDS

3 NANOMEDICINE & Drug Delivery Systems Coordination Rogério Gaspar Projects National & International Colaborations 1 Oncology & Inflamation Liposomes Nanoparticles Polymeric Ther Infectious Dermal Research Diseases Liposomes Nanoparticles Vaccines Pulmonary Delivery and macromolecular complexation Therapeutic activity 300 of Trifluralin Liposomes 250 (am astigotes/500 nuclei) x liver w eigth x 2x Negative Positive Liposomal Control 1 Control 2 (Sb) TFL 3 Team

4 Summary Nanomedicine: Nanotechnology in Health Current critical issues in pharmaceuticals development The access to new technologies Future developments and major challenges

5 The position of nanoscience and nanotechnology over a base map of science. Each node in this map15 is one of the 175 subject categories in the SCI. The size of each node is proportional to the number of nanopapers published in journals in each subject category during the period January July Location on the axes in this Kamada Kawai algorithm representation has no inherent meaning: the connecting arcs and proximity reflect similarity based on cross-citation patterns, reinforced by colouring to reflect the clustering of subject categories into macrodisciplines Where does nanotechnology belong in the map of science? Alan L. Porter and Jan Youtie, Nature Nanotechnology, (September 2009):

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7 Build On Existing European Landscape?

8 Liposomal lipidic 1 drug ± targeting and imaging agents Polymer Conjugates polymer drug conjugates ± targeting/imaging agents Technology Classes in clinical trial market PEG (polymer) protein aptamer conjugates Protein/Ab Conjugates 2 drugs combination therapy lipidic drug mixtures Block copolymer micelles nm5 200 <1,000 <1,000 drug maybe entrapped or covalently bound ± targeting groups lipidic, protein or polymeric, inorganic drug non covalently or covalent bound metallic: gold, silver, Q dots, iron oxide (polymer coatings used to stabilise) nanocapsule, nanoshell "Nanoparticles" multilayered nanoparticle (NB many nanoparticles Nano sized drug crystals Bioactive Synthetic Polymers/Vesicles Crosslinked (Nano) Gels are not Faculdade round) de Farmácia da Universidade de Lisboa imed.ul (Research Institute for Medicines and Ruth Pharmaceutical Duncan, EMA Sciences) Adhoc Expert Group, December 2009

9 Nanopharmaceuticals: overall view of particulate carriers translation

10 Cancer, EPR and Intracellular trafficking Nanocarriers as an emerging platform for cancer therapy, D.Peer, J. M. Karp,S. Hong, O. C. Farokhzad,R. Margalit and Robert Langer, nature nanotechnology VOL 2 DECEMBER 2007 R. Duncan, Nature Reviews Cancer, September

11 Clinical Development of Nanopharmaceuticals Amphotericin B lipid formulations (fungal systemic infections) DaunoXome Doxil/Caelyx Myocet Abraxane MRI agents PEGylated proteins Mylotarg HPMA polymeric conjugates Xyotax /Opaxio Dendrimers Micelles Targeted liposomes Nanosystems for the delivery of nucleic acids (e.g. sirna) 11

12 Amphotericin B Abelcet Ambisome Amphocil 12

13 Doxil/Caelyx: Stealth Liposomes Caelyx is indicated: As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk. For treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen. For treatment of AIDS-related related Kaposi s sarcoma (KS) in patients with low CD4 counts (< 200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease. Caelyx may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: : a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).

14 Comparison of Clinical Pharmacokinetics for Different Micellar Nanocarriers and Corresponding Commonly Used Formulations Sutton et al,, Pharmaceutical Research

15 Myocet Myocet, in combination with cyclophosphamide, is indicated for the first line treatment of metastatic breast cancer in women. EMEA, European Public Assessment Report (EPAR), Summary of Product Characteristics (SmPC), 2007

16 Polymer products PEGylated-Proteins Hepatoma Zinostatin Stimaler Yamanouchi Japan Approved SMANCS SCID Adagen Enzon FDA Approved ALL Oncaspar Enzon FDA Approved PEG-L-asparaginase Neutropenia Neulasta (pegfilgrastim), Amgen FDA Approved Crohn's disease Cimzia UCB Pharma Approved in CH but not EU, PEG-anti-TNFα antibody fragment Macular Degeneration, Macugen (pegaptanib sodium) (OSI)-Eyetech FDA Approved Filed in EU Acromegaly Somavert (pegvisomant)pfizer FDA Approved Hepatitis C PEGASYS Roche FDA Approved (peginterferon alfa-2a) Hepatitis C PEG-INTRON Schering-Plough FDA Approved (peginterferon alfa-2 Solid tumours CDP 791 UCB Pharma Phase II (PEGylated anti-gfr antibody fragment (VEGFR) Polymer-Drug Conjugates and Polymeric Carriers NSCLC XYOTAX/OPAXIO Cell Therapeutics Phase III Cancer Prolindac Access Pharmaceuticals Phase II HPMA-platinate Cancer IT-101: CYCLOSERT -Insert Therapeutics Phase I Enhanced Camptothecin Constipation NKTR-118 Nektar Phase I (oral PEG-naloxol) Colorectal cancer NKTR-102 Nektar Phase I (PEG-irinotecan irinotecan) and other solid tumors Advanced PEG-SN38 Enzon Phase I (irinotecan analogue) solid tumors and lymphoma Solid tumors CYT-6091 Cytimmune Sciences Phase I PEG-gold gold-tnf Micelles Resistant cancers SP1049C (Dox( Dox) Supratek Cancer NK-105 NanoCarrier NK-6004 NanoCarrier Cancer Platinate micelle Phase II Phase I Phase I Paclitaxel micelle Nanoparticles Cancer Abraxane Abraxis FDA/EMA Approved Dendrimers HIV Prevention Vivagel StarPharma Phase I/II 16

17 Nanocarriers as an emerging platform for cancer therapy, D.Peer, J. M. Karp,S. Hong, O. C. Farokhzad,R. Margalit and Robert Langer, nature nanotechnology VOL 2 DECEMBER 2007

18 Diagnostics & Therapeutics

19 Rapid and label-free nanomechanical detection of biomarker transcripts in human RNA J. ZHANG, H. P. LANG, F. HUBER, A. BIETSCH, W. GRANGE, U. CERTA, R. McKENDRY, H.-J. GU NTHERODT, M. HEGNER AND CH. GERBER nature nanotechnology VOL 1 DECEMBER 2006

20 Investment Escalation per Sucessful Compound 20

21 Current trends in the pharma/bio model for DDD The spiral of increased competition in pharma,, the decline of the 'blockbuster' paradigm, great pressures to meet investors expectations, heavy marketing and off-label use, societal mistrust, short term goals and lack of sustained innovation incentives are ingredients of what we could coin as an Icarus-model model Hubert G. Leufkens, 2008 (UIPS, Utrecht University) Icarus (Matisse) Czerepak EA et al. Nat Rev Drug Disc 2008; 7:

22 Number of new drugs, small number of companies involved in generating new medicines B.Munos, Nature Reviews in Drug Discovery (December 2009)

23 Source: Pharma 2020, PWC

24 Current trends in the pharma/bio model for DDD Pharma 2020: The vision, PriceWaterhouseCoopers,,

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26 Key Bottlenecks in the Pharmaceutical R&D Process Source: Strategic Research Agenda - IMI

27 Health Technologies Assessment (HTA) and incremental cost per QALY gained (ICER) Prof. Dr. Gu nter Neubauer and Philip Lewis, Medical innovations in the EU - investing in health, value for society, Health First Europe, 2050 Health Odyssey, 2007 Rawlins MD, Culyer AJ. National Institute for Clinical Excellence and its value judgments. BMJ (Clinical research ed). 2004(329):224-7.

28 Kaplan Meier survival curves for PLDH versus topotecan (C. Main et al, Health Technology Assessment 2006; Vol. 10: No. 9) overall platinum sensitive platinum-refractory progression-free

29 PLDH has a 69% probability of being the most cost-effective treatment strategy, rising to 90% at a WTP of 30,000 per QALY and 92% at a WTP of 50,000 per QALY. (WTP-willingness to pay) C Main, L Bojke, S Griffin, G Norman, M Barbieri, L Mather, D Stark, S Palmer, and R Riemsma, Health Technology Assessment 2006; Vol. 10: No. 9

30 Relative risks for response rates for PLDH versus topotecan sub-group analysis stratified by platinum sensitivity (C. Main et al, Health Technology Assessment 2006; Vol. 10: No. 9)

31 Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation, C Main, L Bojke, S Griffin, G Norman, M Barbieri, L Mather, D Stark, S Palmer, and R Riemsma, Health Technology Assessment 2006; Vol. 10: No. 9 The following conclusions are possible assuming that the NHS is willing to pay up to 20,000 40,000 per additional QALY: PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of trial Incorporating the results of trial gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost effective.

32 Lung cancer FDG-PET/CT scan K Facey, I Bradbury, G Laking and E Payne, Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers, Health Technology Assessment 2007; Vol. 11: No. 44

33 K Facey, I Bradbury, G Laking and E Payne Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers Health Technology Assessment 2007; Vol. 11: No. 44

34 Future developments In vivo nano-imaging of membrane dynamics in metastatic tumor cells using quantum dots. Gonda K, Watanabe TM, Ohuchi N, Higuchi H. (Tohoku University, Sendai, Japan) J.Biol.Chem. Papers in Press. Published on November 16, 2009 as Manuscript

35 Major challenges PPPs like Innovative Medicines Initiative by need to deliver better integration between basic research and clinical needs, allowing for faster development of new drugs without compromising patient safety (biomarkers, imaging, adequacy of preclinical models, better understanding and management of pharmacogenetic variability) Incorporation of multifunctional platforms capable of integrating diagnostics and therapeutics in critical diseases (nanotheranostics in metastatic cancer) Increase in costs of health care have to engage society in search of solutions that allow better treatments with affordable costs (better management and accountability of health care systems, critical and transparent assesment of technologies and drugs) Building social consensus with involvement of patients, health professions, health industry (including insurance companies) and governments The needs of the current moment are pledging for dialogue between stakeholders not for confrontation