The global marine pharmaceutical i lipipeline

Alejandro M. S. Mayer, Ph.D.

Midwestern University Pharmacology Department, CCOM

Downers Grove Illinois USADowners Grove, Illinois, USA

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http://marinepharmacology.midwestern.edu/2

The global marine pharmaceutical pipeline

FDA d i h i l• FDA- approved marine pharmaceuticals• The Clinical Pipelinep• The Preclinical Pipeline

http://marinepharmacology.midwestern.edu/

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4

FDA –approved: 7

Clinical Pipeline: 11

Preclinical Pipeline: 1,458

Chemistry Marine Natural Products: 8,940

5Global Marine Pharmaceutical Pipeline in 2012

The global marine pharmaceutical pipeline

• FDA- approved marine pharmaceuticalspp p• The Clinical Pipeline• The Preclinical Pipelinep

• The Odyssey of Marine Pharmaceuticals: aThe Odyssey of Marine Pharmaceuticals: a Current Pipeline Perspective, Trend in Pharmacological Sciences, 31: 255-265, 2010

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FDA- approved marine pharmaceuticals

7http://marinepharmacology.midwestern.edu/

Cytarabine Ara C (Cytosar): FDA approval 1969Cytarabine, Ara-C (Cytosar): FDA approval 1969

Arabinosylcytosine or cytosine

arabinoside is a synthetic pyrimidine

Caribbean sponge Tethya crypta, source of spongothymidine, led to synthesis of new class of arabinosyl

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synthetic pyrimidine nucleoside

synthesis of new class of arabinosyl nucleosides.

Cytarabine Ara C (Cytosar): CancerCytarabine, Ara-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 triphosphatetriphosphate

• Indications for use: induction and maintenance of remission in acute non lymphocytic leukemia ofremission in acute non-lymphocytic leukemia of adults and children

Al d f t l h ti l k i d• Also used for: acute lymphocytic leukemia and chronic myelocytic leukemia

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Cytarabine, Ara-C (Cytosar): clinical trials

10Downloaded from www.clinicaltrials.gov

Cytarabine, Ara-C (Cytosar): Hospira, USA

11Downloaded from http://www.hospira.com/Products/cytarabine.aspx

Vidarabine Ara A (Vira A): FDA approval 1976Vidarabine, Ara-A (Vira-A): FDA approval 1976

ArabinofuranosyladenineArabinofuranosyladenine or adenine arabinoside is

a synthetic purine Caribbean sponge Tethya crypta, source of spongouridine, led to

th i f l f bi l12

nucleoside synthesis of new class of arabinosyl nucleosides.

Vidarabine Ara A (Vira A): AntiviralVidarabine, Ara-A (Vira-A): Antiviral

Ph l Vid bi i t d i t bi id• Pharmacology: Vidarabine is converted into arabinoside triphosphate, and inhibits viral DNA polymerase and DNA synthesisDNA synthesis

• Indications for use: 3% ophthalmic ointment is used for t k t j ti iti d t ith li lacute keratoconjunctivitis and recurrent epithelial

keratitis, caused by herpes simplex virus types 1 and 2C tl di ti d i th U S t d i FDA• Currently discontinued in the U.S. as noted in FDA Orange Book (3-2011)

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14Downloaded from http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm

Ziconotide (Prialt): FDA approval 2004Ziconotide (Prialt): FDA approval 2004

25 amino acid, polybasic peptide containing 3

Piscivorous marine snail Conus magus, source of the naturally occurring conopeptidepeptide containing 3

disulfide bridges and the FDA-approved drug

of the naturally occurring conopeptide

• Developed as a pain medication

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pp gPrialt®

Ziconotide (Prialt): clinical trials

16Downloaded from www.clinicaltrials.gov

Ziconotide (Prialt): Jazz Pharmaceuticals, Ireland

Downloaded from www.prialt.com

Omega 3 acid Ethyl Ester (Lovaza): FDA approval 2004Omega-3-acid Ethyl Ester (Lovaza): FDA approval 2004

ethyl esters of eicosapentaenoic acid (EPA) ethyl esters of docosahexaenoic acid (DHA)

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Downloaded from http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021654s023lbl.pdf

Omega-3-acid Ethyl Esters (Lovaza): clinical trials

19Downloaded from www.clinicaltrials.gov

Omega-3-acid Ethyl Esters (Lovaza): GlaxoSmithKline, UK

20Downloaded from http://www.gsk.com/products/prescription-medicines/lovaza.htm

Trabectedin, ET-743 (Yondelis®): cancer

Colonial ascidian Ecteinascidia turbinata(Phylum Chordata, Subphylum: Urochordata)

150

200175 PubMed 2000-07

50

100Pharmacology

Binds to the minor groove of DNA and interferes with cell division and the gene

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2000

2001

2002

2003

2004

2005

2006

2007

0

interferes with cell division and the gene transcription processes and repair machinery of the DNA.

Trabectedin, ET-743 (Yondelis®): FDA approval 2005

22http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm

Trabectedin, ET-743 (Yondelis®): FDA approval 2005( ) pp

Downloaded from

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Downloaded fromhttp://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm

Trabectedin, ET-743 (Yondelis®): clinical trials

24Downloaded from www.clinicaltrials.gov

Trabectedin, ET-743 (Yondelis®): Pharmamar, Spain

25Downloaded from http://www.pharmamar.com/yondelis.aspx

Eribulin mesylate (Halaven®) : FDA approval 2010

Halichondrin B analogue E7389 Sponge Lissodendoryx sp. (Ph l P if ) C t f J h Bl t

g(macrolide, polyketide)

Pharmacology

(Phylum:Porifera) Courtesy of John Blunt, Univ. of Canterbury, N. Zealand

• Microtubule interacting agent

• Developed as an anticancer agent

• Developed by Eisai, Woodcliff Lake, NJ

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Eribulin mesylate Halaven®: clinical trials

27Downloaded from www.clinicaltrials.gov

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

HN

NN

O

NH

HO

N OMeO O HOMe O

Monomethyl Auristatin E (peptide)

Dolabella auricularia (sea hare)

Phylum: Mollusca, Class: Gastropoda

Monomethyl auristatin E (MMAE) is a synthetic anticancer agent Because of its toxicity it cannot beanticancer agent. Because of its 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.

29http://www.youtube.com/watch?v=WYuBjfJP84c

Brentuximab vedotin (SGN-35): cancer

H2N

HN

NN

OMeO

O

ONH

HO

OMe OmAb-linker-

Monomethyl Auristatin E (peptide)Anti-CD30-Seattle Genetics’ proprietary technology

Pharmacology

• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets CD30, a marker of Hodgkin lymphomamarker of Hodgkin 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.

30Downloaded from http://www.seagen.com/product_pipeline_sgn35.shtml

Brentuximab vedotin (SGN-35): clinical trials

31Downloaded from www.clinicaltrials.gov

Brentuximab vedotin (SGN-35): Seattle Genetics, USA

32Downloaded from http://www.seagen.com/product_pipeline.php

The global marine pharmaceutical pipeline

• FDA- approved marine pharmaceuticalsFDA approved marine pharmaceuticals• The Clinical Pipeline• The Preclinical Pipeline

33

The Marine Pharmaceutical Clinical Pipeline

34http://marinepharmacology.midwestern.edu/

FDA –approved: 7

Clinical Pipeline: 11

Preclinical Pipeline: 1,458

Chemistry Marine Natural Products: 8,940

Global Marine Pharmaceutical Pipeline in 201235

Global Marine Pharmaceutical Pipeline in 2012

Marine pharmaceuticals in Phase 3Marine pharmaceuticals in Phase 3

http://marinepharmacology midwestern edu/clinPipeline htmhttp://marinepharmacology.midwestern.edu/clinPipeline.htm

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Plitidepsin (Aplidin®): Phase 3, cancer

OOCH3

N

ONH O

O

ONCH3

ONCH3O

Aplidium albicans (seasquirt)O

ONH

OH

ONH

N

ON

OO

O

Plitidepsin (depsipeptide)p ( q )

(Phylum Chordata, Subphylum:Tunicata)

Pharmacology

• Extremely potent inducer of apoptosis with IC50 in the low nanomolarExtremely 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.

O i ff t k t id tif th i ll l t t37

• Ongoing efforts seek to identify the primary cellular target.

Mayer et al. TIPS 2010

Plitidepsin (Aplidin®): Phase 3, clinical trials

38Downloaded from www.clinicaltrials.gov

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

CH3

OCH3

AcOHO

H3CCH3

AcO

NN

OHO

O

H

CF3

OHONH

O Jorunna funebris (sea slug)(Phylum: Mollusca Class: Gastropoda)

Pharmacology(Zalypsis®) alkaloid

(Phylum: Mollusca, Class: Gastropoda)

• 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.

41Mayer et al. TIPS 2010

PM00104 (Zalypsis®): Phase 2, clinical trials

42Downloaded from www.clinicaltrials.gov

PM00104 (Zalypsis®): Pharmamar, Spain

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Glembatumumab vedotin (CDX-011) : Phase 2, cancer

H2

HN

NN

O

NH

HO

N OMeO O HOMe O

Monomethyl Auristatin E (peptide)

Dolabella auricularia (sea hare)

Phylum: Mollusca, Class: Gastropoda

Monomethyl auristatin E (MMAE) is a synthetic anticancer agent Because of its toxicity it cannot beanticancer agent. Because of its 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

H2N

HN

NN

OMeO

O

ONH

HO

OMe OmAb-linker-

Monomethyl Auristatin E (peptide)Anti-NMB-Seattle Genetics’ proprietary technology

Pharmacology

• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets glycoprotein NMB a marker of breast cancerglycoprotein NMB, a marker of breast 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.

45Downloaded from http://www.celldextherapeutics.com/wt/page/cancer

Glembatumumab vedotin (CDX-011) : Phase 2, clinical trials

46Downloaded from www.clinicaltrials.gov

Glembatumumab vedotin: CellDex Therapeutics, USA

Downloaded from http://www celldextherapeutics com/wt/page/pipeline redirect

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Downloaded from http://www.celldextherapeutics.com/wt/page/pipeline_redirect

Marine pharmaceuticals in Phase 1

48http://marinepharmacology.midwestern.edu/clinPipeline.htm

Marizomib (Salinosporamide A): Phase 1, Cancer

OHH

HN

O

O

OO

CH3

Salinosporamide A is a beta-lactone-gamma-lactam

Salinospora tropica, a marine bacteria (Phylum: Actinobacteria). Courtesy of Ray Lam,

Cl

lactone gamma lactam

Pharmacology Preclinical and Clinical research

Nereus Pharmaceuticals

gy• Covalent modification of the active site threonine residues of the 20S proteasome a multi-

• Developed as an Anticancer agent

• Developed by Nereus Pharmaceuticals,

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the 20S proteasome, a multisubunit enzyme complex that degrades ubiquitin-tagged proteins in eukaryotic cells

San Diego, CA

Marizomib (Salinosporamide A): Phase 1, clinical trials

50Downloaded from www.clinicaltrials.gov

Salinosporamide A (NPI-0052): Nereus, USA

51Downloaded from http://www.nereuspharm.com/overview.shtml

The global marine pharmaceutical pipelineThe global marine pharmaceutical pipeline

• FDA- approved marine pharmaceuticalsFDA approved marine pharmaceuticals• The 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 preclinicalpipeline

• For the period 1998-2008• 13 marine pharmacology reviews• 1,458 compoundsp• Global research enterprise• Multiple pharmacological classesMultiple pharmacological classes

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The global marine pharmaceutical preclinical pipeline

56Global research involving investigators in 32 countries & US in the period 2007-2008

Marine pharmaceutical preclinicalpipeline

• For the period 1998-2008• 13 marine pharmacology reviews• 1,458 compoundsp• Global research enterprise• Multiple pharmacological classesMultiple pharmacological classes

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The marine pharmaceuticals preclinical pipeline in 2007-2008: 197 compounds

• Antitumor• Antibacterial

• Anticoagulant • Cardiovascular

• Antifungal• Antiviral

• Anti-inflammatory• Immune system

• Antimalarial• Antituberculosis

• Nervous system• Variety of molecular

• Antiprotozoal targets: eg. enzymes, receptors

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The global marine pharmaceutical pipeline: conclusionsThe global marine pharmaceutical pipeline: conclusions

Bi di it f i i d h i t• Biodiversity of marine organisms and chemistry• 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 involvedUS, European & Japanese companies involved• Large markets for pharmaceuticals in cancer, etc.

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AcknowledgementsGlobal Marine Pharmaceutical Clinical Pipeline:• 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 Ph D Nereus Pharmaceuticals• Barbara Potts, Ph.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., University of Sao Paulo. Brasil, , y• Mark Hamann, Ph.D., University of Mississippi, USA • Abimael Rodriguez, Ph.D., University of Puerto Rico, USA• Nobuhiro Fusetani Ph D Hokkaido University Japan

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• Nobuhiro Fusetani, Ph.D., Hokkaido University, Japan• Kirk Gustafson, Ph.D., National Cancer Institute, USA

New developments in the marine pharmaceutical clinical and preclinical

pipeline will be posted @pipeline will be posted @

htt // i h l id t dhttp://marinepharmacology.midwestern.edu/

amayer@midwestern.edu

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