Download The global marine pharmaceutical pipeline

The global marine pharmaceutical
pipeline
i li
Alejandro M. S. Mayer, Ph.D.
Midwestern University
Pharmacology Department, CCOM
Downers Grove,
Grove Illinois,
Illinois USA
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http://marinepharmacology.midwestern.edu/
The global marine pharmaceutical
pipeline
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FDA- approved
FDA
d marine
i pharmaceuticals
h
i l
The Clinical Pipeline
p
The Preclinical Pipeline
http://marinepharmacology.midwestern.edu/
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FDA –
approved: 7
Clinical Pipeline: 11
Preclinical Pipeline: 1,458
Chemistry Marine Natural Products: 8,940
Global Marine Pharmaceutical Pipeline in 2012
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The global marine pharmaceutical
pipeline
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•
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FDA- approved
pp
marine p
pharmaceuticals
The Clinical Pipeline
p
The Preclinical Pipeline
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The Odyssey of Marine Pharmaceuticals: a
Current Pipeline Perspective, Trend in
Pharmacological Sciences, 31: 255-265, 2010
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FDA- approved marine pharmaceuticals
http://marinepharmacology.midwestern.edu/
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Cytarabine Ara
Cytarabine,
Ara-C
C (Cytosar): FDA approval 1969
Arabinosylcytosine
or cytosine
arabinoside is a
synthetic pyrimidine
nucleoside
Caribbean sponge Tethya crypta,
source of spongothymidine, led to
synthesis of new class of arabinosyl
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nucleosides.
Cytarabine Ara
Cytarabine,
Ara-C
C (Cytosar): Cancer
•
Pharmacology: cytosine arabinoside is rapidly
converted into cytosine arabinoside triphosphate,
which inhibits the DNA polymerase by competing
with the physiologic substrate deoxycitidine
triphosphate
• Indications for use: induction and maintenance of
remission in acute non
non-lymphocytic
lymphocytic leukemia of
adults and children
• Also
Al used
d ffor: acute
t lymphocytic
l
h
ti lleukemia
k i and
d
chronic myelocytic leukemia
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Cytarabine, Ara-C (Cytosar): clinical trials
Downloaded from www.clinicaltrials.gov
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Cytarabine, Ara-C (Cytosar): Hospira, USA
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Downloaded from http://www.hospira.com/Products/cytarabine.aspx
Vidarabine Ara
Vidarabine,
Ara-A
A (Vira-A):
(Vira A): FDA approval 1976
Arabinofuranosyladenine
or adenine arabinoside is Caribbean sponge Tethya crypta,
source of spongouridine, led to
a synthetic purine
th i off new class
l
off arabinosyl
bi
l
synthesis
nucleoside
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nucleosides.
Vidarabine Ara
Vidarabine,
Ara-A
A (Vira-A):
(Vira A): Antiviral
• Ph
Pharmacology:
l
Vid bi iis converted
Vidarabine
t d iinto
t arabinoside
bi
id
triphosphate, and inhibits viral DNA polymerase and
DNA synthesis
• Indications for use: 3% ophthalmic ointment is used for
acute
t keratoconjunctivitis
k t
j
ti iti and
d recurrentt epithelial
ith li l
keratitis, caused by herpes simplex virus types 1 and 2
• Currently
C
tl discontinued
di
ti
d in
i th
the U
U.S.
S as noted
t d iin FDA
Orange Book (3-2011)
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Downloaded from
http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm
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Ziconotide (Prialt): FDA approval 2004
25 amino acid, polybasic
peptide containing 3
disulfide bridges and the
FDA-approved
pp
drug
g
Prialt®
Piscivorous marine snail Conus magus, source
of the naturally occurring conopeptide
• Developed as a pain medication
15
Ziconotide (Prialt): clinical trials
Downloaded from www.clinicaltrials.gov
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Ziconotide (Prialt): Jazz Pharmaceuticals, Ireland
Downloaded from www.prialt.com
Omega 3 acid Ethyl Ester (Lovaza): FDA approval 2004
Omega-3-acid
ethyl esters of eicosapentaenoic acid (EPA)
ethyl esters of docosahexaenoic acid (DHA)
Downloaded from
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021654s023lbl.pdf
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Omega-3-acid Ethyl Esters (Lovaza): clinical trials
Downloaded from www.clinicaltrials.gov
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Omega-3-acid Ethyl Esters (Lovaza): GlaxoSmithKline, UK
Downloaded from http://www.gsk.com/products/prescription-medicines/lovaza.htm
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Trabectedin, ET-743 (Yondelis®): cancer
Colonial ascidian Ecteinascidia turbinata
(Phylum Chordata, Subphylum: Urochordata)
200
175
PubMed 2000-07
150
Pharmacology
100
50
0
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
Binds to the minor groove of DNA and
interferes with cell division and the gene
transcription processes and repair
machinery of the DNA.
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Trabectedin, ET-743 (Yondelis®): FDA approval 2005
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanP
roductDesignation/default.htm
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Trabectedin, ET-743 ((Yondelis®):
) FDA approval
pp
2005
Downloaded from
http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm
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Trabectedin, ET-743 (Yondelis®): clinical trials
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Downloaded from www.clinicaltrials.gov
Trabectedin, ET-743 (Yondelis®): Pharmamar, Spain
Downloaded from
http://www.pharmamar.com/yondelis.aspx
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Eribulin mesylate (Halaven®) : FDA approval 2010
Halichondrin B analogue
g E7389
(macrolide, polyketide)
Sponge Lissodendoryx sp.
(Phylum:Porifera
Ph l
P if ) Courtesy
C t
off John
J h Bl
Blunt,
t
Univ. of Canterbury, N. Zealand
Pharmacology
• Developed as an anticancer agent
• Microtubule interacting agent
• Developed by Eisai, Woodcliff Lake, NJ
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Eribulin mesylate Halaven®: clinical trials
Downloaded from www.clinicaltrials.gov
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Eribulin mesylate (Halaven®): Eisai Co., Ltd, Japan
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Downloaded from http://www.eisai.com/pdf/eir/epipeline.pdf
Brentuximab vedotin : FDA approval 2011
H2
N
H
N
O
HO
O
N
N
OMe O
OMe O
N
H
Monomethyl Auristatin E (peptide)
Dolabella auricularia (sea hare)
Phylum: Mollusca, Class: Gastropoda
Monomethyl auristatin E (MMAE) is a synthetic
anticancer agent
agent. Because of its toxicity
toxicity, it cannot be
used as a drug itself; instead, it is linked to a monoclonal
antibody (MAB) which directs it to the cancer cells.
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http://www.youtube.com/watch?v=WYuBjfJP84c
Brentuximab vedotin (SGN-35): cancer
mAb-linker-
H2
N
H
N
O
HO
O
N
N
OMe O
OMe O
N
H
Anti-CD30- Monomethyl Auristatin E (peptide)
Seattle Genetics’ proprietary technology
Pharmacology
• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets CD30, a
marker of Hodgkin lymphoma
lymphoma.
• The ADC is stable in the bloodstream, but releases MMAE, an antimicrotubule
agent, upon internalization into CD30-expressing tumor cells, resulting in a targeted
cell-killing effect.
Downloaded from http://www.seagen.com/product_pipeline_sgn35.shtml
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Brentuximab vedotin (SGN-35): clinical trials
Downloaded from www.clinicaltrials.gov
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Brentuximab vedotin (SGN-35): Seattle Genetics, USA
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Downloaded from http://www.seagen.com/product_pipeline.php
The global marine pharmaceutical
pipeline
•
•
•
FDA approved marine pharmaceuticals
FDAThe Clinical Pipeline
The Preclinical Pipeline
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The Marine Pharmaceutical Clinical Pipeline
http://marinepharmacology.midwestern.edu/
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FDA –
approved: 7
Clinical Pipeline: 11
Preclinical Pipeline: 1,458
Chemistry Marine Natural Products: 8,940
Global Marine Pharmaceutical Pipeline in 2012
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Marine pharmaceuticals in Phase 3
http://marinepharmacology midwestern edu/clinPipeline htm
http://marinepharmacology.midwestern.edu/clinPipeline.htm
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Plitidepsin (Aplidin®): Phase 3, cancer
OCH3
O
N
O
O
NH
N
CH3 O
O
O
O
O
O
O
N
H
OH
NH
CH3
N
O
N
O
O
Aplidium
p
albicans (seasquirt)
(
q )
Plitidepsin (depsipeptide)
(Phylum Chordata, Subphylum:Tunicata)
Pharmacology
• Extremely potent inducer of apoptosis with IC50 in the low nanomolar
range.
• It triggers Rac 1 activation, together with MPK-1 downregulation, and
sustained JNK activation.
• Ongoing
O
i efforts
ff t seekk to
t identify
id tif the
th primary
i
cellular
ll l ttarget.
t
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Mayer et al. TIPS 2010
Plitidepsin (Aplidin®): Phase 3, clinical trials
Downloaded from www.clinicaltrials.gov
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Plitidepsin (Aplidin®): Pharmamar, Spain
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Marine pharmaceuticals in Phase 2
http://marinepharmacology.midwestern.edu/clinPipeline.htm
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PM00104 (Zalypsis®): Phase 2, cancer
OCH3
CH3
HO
AcO
H
H3C
N
CH3
N
O
O
OH
NH
O
CF3
Jorunna funebris (sea slug)
(Phylum: Mollusca,
Mollusca Class: Gastropoda)
(Zalypsis®) alkaloid
Pharmacology
• New DNA-binding alkaloid isolated from the skin and mucus of the Pacific
nudibranch Joruna funebris.
• Zalypsis® binds to guanines in selected DNA triplets, DNA adducts
eventually give rise to double strand breaks, S-phase arrest and apoptosis in
cancer cells.
Mayer et al. TIPS 2010
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PM00104 (Zalypsis®): Phase 2, clinical trials
Downloaded from www.clinicaltrials.gov
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PM00104 (Zalypsis®): Pharmamar, Spain
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Glembatumumab vedotin (CDX-011) : Phase 2, cancer
H2
N
H
N
O
HO
O
N
N
OMe O
OMe O
N
H
Monomethyl Auristatin E (peptide)
Dolabella auricularia (sea hare)
Phylum: Mollusca, Class: Gastropoda
Monomethyl auristatin E (MMAE) is a synthetic
anticancer agent
agent. Because of its toxicity
toxicity, it cannot be
used as a drug itself; instead, it is linked to a monoclonal
antibody (MAB) which directs it to the cancer cells.
44
Glembatumumab vedotin (CDX-011) : Phase 2, cancer
mAb-linker-
H2
N
H
N
O
HO
O
N
N
OMe O
OMe O
N
H
Anti-NMB- Monomethyl Auristatin E (peptide)
Seattle Genetics’ proprietary technology
Pharmacology
• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets
glycoprotein NMB
NMB, a marker of breast cancer
cancer.
• The ADC is stable in the bloodstream, but releases MMAE, an antimicrotubule
agent, upon internalization into NMB-expressing tumor cells, resulting in a targeted
cell-killing effect.
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Downloaded from http://www.celldextherapeutics.com/wt/page/cancer
Glembatumumab vedotin (CDX-011) : Phase 2, clinical trials
Downloaded from www.clinicaltrials.gov
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Glembatumumab vedotin: CellDex Therapeutics, USA
Downloaded from http://www.celldextherapeutics.com/wt/page/pipeline_redirect
http://www celldextherapeutics com/wt/page/pipeline redirect
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Marine pharmaceuticals in Phase 1
http://marinepharmacology.midwestern.edu/clinPipeline.htm
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Marizomib (Salinosporamide A): Phase 1, Cancer
H
OH
H
N
O
O
O
CH3
Cl
Salinosporamide A is a betalactone-gamma-lactam
lactone
gamma lactam
Pharmacology
gy
Salinospora tropica, a marine bacteria
(Phylum: Actinobacteria). Courtesy of Ray Lam,
Nereus Pharmaceuticals
Preclinical and Clinical research
• Covalent modification of the
• Developed as an Anticancer agent
active site threonine residues of
the 20S proteasome,
proteasome a multimulti
subunit enzyme complex that
degrades ubiquitin-tagged
proteins in eukaryotic cells
• Developed by Nereus Pharmaceuticals,
San Diego, CA
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Marizomib (Salinosporamide A): Phase 1, clinical trials
Downloaded from www.clinicaltrials.gov
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Salinosporamide A (NPI-0052): Nereus, USA
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Downloaded from http://www.nereuspharm.com/overview.shtml
The global marine pharmaceutical pipeline
•
•
•
FDA approved marine pharmaceuticals
FDAThe Clinical Pipeline
The Preclinical Pipeline
52
FDA –
approved: 7
Clinical Pipeline: 11
Preclinical Pipeline: 1,458
Chemistry Marine Natural Products: 8,940
Global Marine Pharmaceutical Pipeline in 2012
http://marinepharmacology.midwestern.edu/
Marine pharmaceutical preclinical
pipeline
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•
•
•
•
For the period 1998-2008
13 marine pharmacology reviews
p
1,458 compounds
Global research enterprise
Multiple pharmacological classes
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The global marine pharmaceutical preclinical pipeline
Global research involving investigators in 32 countries & US
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in the period 2007-2008
Marine pharmaceutical preclinical
pipeline
•
•
•
•
•
For the period 1998-2008
13 marine pharmacology reviews
p
1,458 compounds
Global research enterprise
Multiple pharmacological classes
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The marine pharmaceuticals preclinical pipeline in
2007-2008: 197 compounds
•
•
•
•
•
•
•
Antitumor
Antibacterial
Antifungal
Antiviral
Antimalarial
Antituberculosis
Antiprotozoal
•
•
•
•
•
•
Anticoagulant
Cardiovascular
Anti-inflammatory
Immune system
Nervous system
Variety of molecular
targets: eg. enzymes,
receptors
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The global marine pharmaceutical pipeline: conclusions
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•
•
•
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Biodiversity
Bi
di
it off marine
i organisms
i
and
d chemistry
h i t
FDA-approved agents in several therapeutic areas
Active clinical pipeline: Phase 1, 2, 3
Biotechnology: FDA-approved, Phase 1 & 2 MABs
Preclinical pipeline could be larger if $$ increases
US, European & Japanese companies involved
Large markets for pharmaceuticals in cancer, etc.
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Acknowledgements
Global Marine Pharmaceutical Clinical Pipeline:
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•
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•
•
•
•
•
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J. Michael Macintosh, M.D., University of Utah
David Newman, Ph.D., National Cancer Institute
Keith Glaser, Ph.D., Abbott Laboratories
Robert Jacobs,, Ph.D.,, U.C. Santa Barbara
Daniel Little, Ph.D., U.C. Santa Barbara
William Kem, Ph.D., University of Florida
Barbara Potts,
Potts Ph
Ph.D.,
D Nereus Pharmaceuticals
Dale Shuster, Ph.D., Eisai Pharmaceuticals
Maria del Carmen Cuevas Marchante, Ph.D., PharMamar, Spain
Global Marine Pharmaceutical Preclinical Pipeline reviews
•
•
•
•
•
Roberto Berlinck,, Ph.D.,, Universityy of Sao Paulo. Brasil
Mark Hamann, Ph.D., University of Mississippi, USA
Abimael Rodriguez, Ph.D., University of Puerto Rico, USA
Nobuhiro Fusetani,
Fusetani Ph.D.,
Ph D Hokkaido University
University, Japan
Kirk Gustafson, Ph.D., National Cancer Institute, USA
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New developments in the marine
pharmaceutical clinical and preclinical
pipeline will be posted @
htt //
http://marinepharmacology.midwestern.edu
i
h
l
id
t
d /
[email protected]
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