Conferencia - PDF RogerioGaspar

Nanomedicine:
R&D after 30 years of clinical experience

and the issue of access to new technologies
Rogrio S Gaspar
Faculdade de Farmcia da Universidade de Lisboa e
iMed.UL (Research Institute for Medicines and Pharmaceutical Sciences, http://www.imed.ul.pt )
FaculdadedeFarmciadaUniversidadedeLisboa
iMed.UL (Research Institute forMedicines and Pharmaceutical Sciences)
Lisbon approach to 3Ds: iMed.UL
Nanomedicine &
DDS
NANOMEDICINE&Drug Delivery Systems
Coordination
RogrioGaspar
National &International
Colaborations
Projects
1 2 3 4
Oncology & Infectious Dermal Research Pulmonary
Inflamation Diseases Delivery and
Liposomes Liposomes macromolecular
Nanoparticles Nanoparticles complexation
Polymeric Ther.
Ther. Vaccines
Therapeutic activity
( a m a s t ig o t e s /5 0 0 n u c le i) x liv e r w e ig t h x 2 x 1 0 5
300
of Trifluralin Liposomes
250
200
150
100
50
0
Negative
1
Control
P ositive
2
Control (Sb)
Liposomal
3
TFL Team
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 JanuaryJuly 2008. Location on the axes in this KamadaKawai 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 ?
01022010 FaculdadedeFarmciadaUniversidadedeLisboa 7
iMed.UL(ResearchInstituteforMedicinesandPharmaceuticalSciences)
targetingand
Liposomal imagingagents Polymer polymerdrug TechnologyClasses
lipidic Conjugates
conjugates
targeting/imaging inclinicaltrialmarket
agents
1drug
PEG(polymer) Protein/Ab
protein
aptamerconjugates Conjugates
2drugs
combination
therapy
Block
lipidicdrugmixtures
00

525 copolymer
10
2
60
micelles

20
nm 602
0 0
20
<1,
200
000 drugmaybeentrapped
5
20 orcovalentlybound
0
<1,000
targetinggroups
metallic: gold,
lipidic,proteinor
drugnon silver,Qdots,iron
polymeric,inorganic
covalently oxide(polymer
orcovalent coatingsusedto
bound stabilise)
Crosslinked
multilayered
(Nano)Gels
nanoparticle
Bioactive
nanocapsule,
nanoshell (NBmany
Nanosized Synthetic
nanoparticles drugcrystals Polymers/Vesicles
arenotround)
"Nanoparticles" iMed.UL (Research Institute forMedicines and RuthDuncan,EMAAdhocExpertGroup,December2009
Pharmaceutical Sciences)
Nanopharmaceuticals:
overall view of particulate carriers translation
Cancer, EPR and Intracellular trafficking
Nanocarriersasanemergingplatformforcancertherapy,
D.Peer,J.M.Karp,S.Hong,O.C.Farokhzad,R.Margalitand
RobertLanger,naturenanotechnology|VOL2|DECEMBER2007|
R. Duncan, Nature Reviews Cancer, September 2006
FaculdadedeFarmciadaUniversidadedeLisboa 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)
Amphotericin B
Abelcet
Amphocil
Ambisome
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 Kaposis 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).
Comparison of Clinical Pharmacokinetics for Different Micellar
Nanocarriers and Corresponding Commonly Used Formulations
Sutton et al,
al, 2007-
2007- Pharmaceutical Research
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),
SmPC), 2007
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-TNF 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 791791 UCB Pharma Phase II (PEGylated anti-
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-
HPMA-platinate
Cancer IT-
IT-101: CYCLOSERT
CYCLOSERT-Insert Therapeutics Phase I Enhanced Camptothecin
Constipation NKTR-118 Nektar Phase I (oral PEG-naloxol)
Colorectal cancer NKTR-
NKTR-102 Nektar Phase I (PEG-
(PEG-irinotecan)
irinotecan)
and other solid tumors
Advanced PEG-
PEG-SN38 Enzon Phase I (irinotecan analogue)
solid tumors and lymphoma
Solid tumors CYT-
CYT-6091 Cytimmune Sciences Phase I PEG-
PEG-gold-
gold-TNF
Micelles
Resistant cancers SP1049C (Dox
(Dox)) Supratek Phase II
Cancer NK-
NK-105 NanoCarrier Phase I Paclitaxel micelle
NK-
NK-6004 NanoCarrier Phase I
Cancer Platinate micelle
Nanoparticles
Cancer Abraxane Abraxis FDA/EMA Approved
Dendrimers
HIV Prevention Vivagel StarPharma Phase I/II
Nanocarriers asanemergingplatformforcancertherapy,
D.Peer,J.M.Karp,S.Hong,O.C.Farokhzad,R.Margalit andRobertLanger,naturenanotechnology|VOL2|DECEMBER2007|
Diagnostics & Therapeutics
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
InvestmentEscalationperSucessful Compound
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
Icarus(Matisse)
lack of sustained innovation incentives are ingredients
of what we could coin as an Icarus-model
model
Hubert G. Leufkens, 2008 (UIPS, Utrecht University)
CzerepakEAetal.NatRevDrugDisc2008;7:531.
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
Pharma 2020:Thevision,PriceWaterhouseCoopers
2020:Thevision,PriceWaterhouseCoopers,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)
Prof. Dr. Gunter 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.
KaplanMeier 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
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
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,
The following conclusions are possible assuming that the NHS is willing
to pay up to 20,00040,000 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,
K Facey, I Bradbury, G Laking and E Payne
Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers
In vivo nano-
nano-imaging of membrane dynamics in metastatic tumor cells using quantum
quantum dots.
Future 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
developments
Major challenges
PPPs like Innovative Medicines Initiative by 2013-2017 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

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Nanomedicine:

R&D after 30 years of clinical experience

Nanomedicine: Nanotechnology in Health

Current critical issues in pharmaceuticals

The access to new technologies

Future developments and major challenges

Where does nanotechnology belong in the map of science?

As monotherapy for patients with metastatic breast cancer,

For treatment of advanced ovarian cancer in women who have

For treatment of AIDS-related Kaposis sarcoma (KS) in patients

Polymer-Drug Conjugates and Polymeric Carriers

The spiral of increased competition in pharma, the

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

Source: Strategic Research Agenda - IMI

overall platinum sensitive

PLDH appears to be cost-effective compared with topotecan and

The cost-effectiveness results for the base-case analysis were

For platinum-sensitive patients, the combination of paclitaxel and

Incorporation of multifunctional platforms capable of integrating diagnostics

Increase in costs of health care have to engage society in search of solutions

Building social consensus with involvement of patients, health professions,

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