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Faculdade de Farmácia da Universidade de Lisboa iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences)

Rogério Sá GasparFaculdade de Farmácia da Universidade de Lisboa e

iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences, http://www.imed.ul.pt )

NanomedicineNanomedicine: : R&D R&D afterafter 30 30 yearsyears ofof clinicalclinical experienceexperienceandand thethe issueissue ofof accessaccess to to newnew technologiestechnologies

http://imed.ul.pt


Lisbon approach to 3Ds: iMed.UL

NanomedicineNanomedicine & & DDSDDS


Oncology & InflamationLLiposomesiposomes

NanoparticlesNanoparticlesPolymericPolymeric TherTher..

InfectiousInfectiousDiseasesDiseasesLiposomesLiposomes

NanoparticlesNanoparticlesVaccinesVaccines

DermalDermal ResearchResearch PulmonaryPulmonaryDeliveryDelivery andand

macromolecularmacromolecularcomplexationcomplexation

Projects

Coordination

Rogério Gaspar

NANOMEDICINE & NANOMEDICINE & DrugDrug DeliveryDelivery SystemsSystems

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National & InternationalColaborations

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Summary

• Nanomedicine: Nanotechnology in Health

• Current critical issues in pharmaceuticals development

• The access to new technologies

• Future developments and major challenges


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 2008. 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): 534-536


Build On Existing European Landscape ?Build On Existing European Landscape ?

01‐02‐2010 7Faculdade de Farmácia da Universidade de Lisboa iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences)


Technology Classesin clinical trial market

PolymerConjugates

Bioactive Synthetic Polymers/Vesicles

Block copolymermicelles

"Nanoparticles"

Nano‐sized drug crystals

lipidic, protein or polymeric, inorganic drug non

covalentlyor covalent bound

nanocapsule, nanoshell

multilayerednanoparticle

metallic:‐ gold, silver, Q dots, iron oxide (polymer coatings used to stabilise)

(NB many nanoparticles are not round)

Protein/AbConjugates

Crosslinked (Nano) Gels

lipidic drug mixtures

1 drug

2 drugs

LiposomalLiposomal‐‐ lipidiclipidic

PEG (polymer)‐protein ‐aptamer conjugates

polymer‐drug conjugates ±

targeting/imaging agents

± targeting and imaging agents

combinationtherapy

drug maybe entrapped or covalently bound

± targeting groups

60‐200

20‐200

5‐25 10‐20

60‐200


Nanopharmaceuticals: overall view of particulate carriers translation


R. Duncan, Nature Reviews Cancer, September 2006R. Duncan, Nature Reviews Cancer, September 2006

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 |

Cancer, EPR and Intracellular trafficking

10


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


Amphotericin B

Abelcet

AmphocilAmbisome

12


Doxil/Caelyx: Stealth® Liposomes

CaelyxCaelyx isis indicatedindicated::

•• As As monotherapymonotherapy for for patientspatients withwith metastaticmetastatic breastbreast cancercancer, , wherewhere therethere isis anan increasedincreased cardiaccardiac riskrisk..

•• For For treatmenttreatment ofof advancedadvanced ovarianovarian cancercancer inin womenwomen whowho havehavefailedfailed a a firstfirst--lineline platinumplatinum--basedbased chemotherapychemotherapy regimenregimen..

•• For For treatmenttreatment ofof AIDSAIDS--relatedrelated KaposiKaposi’’ss sarcomasarcoma (KS) (KS) inin patientspatientswithwith lowlow CD4 CD4 countscounts (< 200 CD4 (< 200 CD4 lymphocyteslymphocytes/mm3) /mm3) andandextensiveextensive mucocutaneousmucocutaneous oror visceral visceral diseasedisease. . –– CaelyxCaelyx maymay bebe usedused as as firstfirst--lineline systemicsystemic chemotherapychemotherapy, , oror as as

secondsecond lineline chemotherapychemotherapy inin AIDSAIDS--KS KS patientspatients withwith diseasedisease thatthat hashasprogressedprogressed withwith, , oror inin patientspatients intolerantintolerant to, prior to, prior combinationcombinationsystemicsystemic chemotherapychemotherapy comprisingcomprising atat leastleast twotwo ofof thethe followingfollowingagentsagents: a vinca : a vinca alkaloidalkaloid, , bleomycinbleomycin andand standard standard doxorubicindoxorubicin ((ororotherother anthracyclineanthracycline).).


Comparison of Clinical Pharmacokinetics for Different Micellar Nanocarriers and Corresponding Commonly Used Formulations

Sutton Sutton etet alal, 2007, 2007-- PharmaceuticalPharmaceutical ResearchResearch


Myocet

MyocetMyocet, , inin combinationcombination withwith cyclophosphamidecyclophosphamide, , isis indicatedindicated for for thethe firstfirst lineline treatmenttreatment ofof metastaticmetastatic breastbreast cancercancer inin womenwomen..

EMEA, EMEA, EuropeanEuropean PublicPublic AssessmentAssessment ReportReport (EPAR), (EPAR), SummarySummary ofof ProductProduct CharacteristicsCharacteristics ((SmPCSmPC), 2007), 2007


Polymer productsPEGylated-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 Solid tumourstumours CDP 791CDP 791®® UCB UCB PharmaPharma Phase IIPhase II ((PEGylatedPEGylated antianti--GFR antibody fragment (VEGFR)GFR antibody fragment (VEGFR)

Polymer-Drug Conjugates and Polymeric Carriers•• NSCLCNSCLC XYOTAX/OPAXIOXYOTAX/OPAXIO Cell TherapeuticsCell Therapeutics Phase IIIPhase III•• CancerCancer ProlindacProlindac Access Pharmaceuticals Access Pharmaceuticals Phase IIPhase II HPMAHPMA--platinateplatinate•• CancerCancer ITIT--101:101: CYCLOSERTCYCLOSERT™™--Insert TherapeuticsInsert Therapeutics Phase IPhase I Enhanced Enhanced CamptothecinCamptothecin• Constipation NKTR-118 Nektar Phase I (oral PEG-naloxol)•• Colorectal cancerColorectal cancer NKTRNKTR--102 102 NektarNektar Phase IPhase I (PEG(PEG--irinotecanirinotecan))

and other solid tumorsand other solid tumors•• Advanced Advanced PEGPEG--SN38 SN38 EnzonEnzon Phase I Phase I ((irinotecanirinotecan analogue)analogue)

solid tumors and lymphomasolid tumors and lymphoma•• Solid tumorsSolid tumors CYTCYT--60916091 CytimmuneCytimmune SciencesSciences Phase IPhase I PEGPEG--goldgold--TNFTNF

Micelles•• Resistant cancersResistant cancers SP1049C (SP1049C (DoxDox)) SupratekSupratek Phase IIPhase II•• CancerCancer NKNK--105105 NanoCarrierNanoCarrier Phase IPhase I PaclitaxelPaclitaxel micellemicelle

NKNK--60046004 NanoCarrierNanoCarrier Phase IPhase I•• CancerCancer PlatinatePlatinate micellemicelle

Nanoparticles•• CancerCancer AbraxaneAbraxane AbraxisAbraxis FDA/EMA ApprovedFDA/EMA Approved

Dendrimers• HIV Prevention Vivagel StarPharma Phase I/II

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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 |


DiagnosticsDiagnostics & & TherapeuticsTherapeutics


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. GERBERnature nanotechnology | VOL 1 | DECEMBER 2006


Investment Escalation per Investment Escalation per SucessfulSucessful CompoundCompound

20


Current trends in the pharma/bio model for DDD

• “The spiral of increased competition in The spiral of increased competition in pharmapharma, the , the decline of the decline of the ''blockbusterblockbuster' ' paradigmparadigm, , greatgreat pressurespressuresto to meetmeet investorsinvestors‘‘ expectationsexpectations, , heavyheavy marketing marketing andandoffoff--label use, societal mistrust, short term goals and label use, societal mistrust, short term goals and lack of sustained lack of sustained innovationinnovation incentives are incentives are ingredientsingredientsof what we could coin as an of what we could coin as an IcarusIcarus--modelmodel”Hubert G. Leufkens, 2008 (UIPS, Utrecht University)

21

Czerepak EA et al. Nat Rev Drug Disc 2008; 7: 531.

Icarus (M

atisse)


Number of new drugs, small number of companies involved in generating new medicines

B.Munos, Nature Reviews in Drug Discovery (December 2009)


Source:Pharma 2020, PWC


Current trends in the pharma/bio model for DDD

24

PharmaPharma 2020: The vision, 2020: The vision, PriceWaterhouseCoopersPriceWaterhouseCoopers, 2007, 2007


Key Bottlenecks in the Pharmaceutical R&D Process

Source: Strategic Research Agenda - IMI


Health Technologies Assessment (HTA)and incremental cost per QALY gained (ICER)

Rawlins MD, Culyer AJ. National Institute for Clinical Excellence and its value judgments. BMJ (Clinical research ed). 2004(329):224-7.

Prof. Dr. Günter Neubauer and Philip Lewis, Medical innovations in the EU - investing in health, value for society, Health First Europe, 2050 Health Odyssey, 2007


Kaplan–Meier survival curves for PLDH versus topotecan(C. Main et al, Health Technology Assessment 2006; Vol. 10: No. 9)

overall

platinum-refractory

platinum sensitive

progression-free


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.

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

(WTP-willingness to pay)


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)


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 30-57. Incorporating the results of trial 30-57 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.


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


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


FutureFuturedevelopmentsdevelopments

In vivo In vivo nanonano--imaging of membrane dynamics in metastatic tumor cells using quaimaging of membrane dynamics in metastatic tumor cells using quantum dotsntum 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 http://, www.jbc.org/cgi/doi/10.1074/jbc.M109.075374


Major challenges• PPPs like Innovative Medicines Initiative by 2013-2017 need to deliver better

integration between basic research and clinical needs, allowing for fasterdevelopment of new drugs without compromising patient safety (biomarkers, imaging, adequacy of preclinical models, better understanding andmanagement of pharmacogenetic variability)

• Incorporation of multifunctional platforms capable of integrating diagnosticsand therapeutics in critical diseases (nanotheranostics in metastatic cancer)

• Increase in costs of health care have to engage society in search of solutionsthat allow better treatments with affordable costs (better management andaccountability of health care systems, critical and transparent assesment oftechnologies 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 betweenstakeholders not for confrontation

Nanomedicine: �R&D after 30 years of clinical experience and the issue of access to new technologiesLisbon approach to 3Ds: iMed.ULSummaryNanopharmaceuticals: �overall view of particulate carriers translationClinical Development of NanopharmaceuticalsAmphotericin BDoxil/Caelyx: Stealth® LiposomesComparison of Clinical Pharmacokinetics for Different Micellar Nanocarriers and Corresponding Commonly Used FormulationsMyocetPolymer productsDiagnostics & TherapeuticsRapid and label-free nanomechanical detection of biomarker transcripts in human RNA �J. ZHANG, H. P. LANG, F. HUBER, A. BIETSCInvestment Escalation per Sucessful CompoundCurrent trends in the pharma/bio model for DDDNumber of new drugs, small number of companies involved in generating new medicinesCurrent trends in the pharma/bio model for DDDKey Bottlenecks in the Pharmaceutical R&D ProcessHealth Technologies Assessment (HTA)�and incremental cost per QALY gained (ICER)Kaplan–Meier survival curves for PLDH versus topotecan�(C. Main et al, Health Technology Assessment 2006; Vol. 10: No. 9)PLDH has a 69% probability of being the most cost-effective treatment strategy, rising to 90% at a WTP of £30,000 per QALY �anRelative risks for response rates for PLDH versus topotecan sub-group analysis stratified by platinum sensitivity (C. Main et Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovLung 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 sFuture �developmentsMajor challenges

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