The global marine pharmaceutical pipeline

Alejandro M. S. Mayer, Ph.D.

Pharmacology Department, CCOMMidwestern University

Downers Grove, Illinois 60565, USA

1

Merci Beaucoup! • "Rendez-vous de Concarneau committee

Torger Borresen (Denmark) Laura Giuliano (Monaco) Claire Hellio (UK) - ChairPhilippe Lebaron (France) Daniel Pardo (France)

• Concarneau Local CommitteeDaniel Sellos (MNHN France)Yves Le Gal (MNHN France)Stéphanie Bordenave (MNHN France)Françoise Denis (MNHN France)Daniel Pardo (CNRS/MNHN France)Rachel Sellin (Pôle Mer Bretagne Fabienne Guérard (IUEM Brest)

• French Embassy, Washington D.C.2

Chicago, Illinois, USA

3

Basic Sciences building, Midwestern University, Downers Grove, Illinois, USA 4

http://marinepharmacology.midwestern.edu/

The global marine pharmaceutical pipeline

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

http://marinepharmacology.midwestern.edu/

Chemistry Marine Natural Products: 8,940

Preclinical Pipeline: 1,458

Clinical Pipeline: 14

FDA –approved: 5

Global Marine Pharmaceutical Pipeline in 20117

8

The global marine pharmaceutical pipeline

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

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

9

http://marinepharmacology.midwestern.edu/clinPipeline.htm August 201111

FDA- approved marine pharmaceuticals

http://marinepharmacology.midwestern.edu/clinPipeline.htm August 2011 12

Cytarabine, Ara-C (Cytosar®)

Arabinosylcytosine or cytosine

arabinoside is a synthetic pyrimidine

nucleoside 13

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

Cytarabine, Ara-C (Cytosar®): clinical trials

Downloaded 8/1/2011 from www.clinicaltrials.gov14

15Downloaded 8/1/2011 from http://www.hospira.com/Products/cytarabine.aspx

Ziconotide (Prialt®)

25 amino acid, polybasic peptide containing 3

disulfide bridges and the FDA-approved drug

Prialt®

Piscivorous marine snail Conus magus, source of the naturally occurring conopeptide

http://www.youtube.com/watch?v=gsfPHGWvzvo16

17

Ziconotide (Prialt®): clinical trials

Downloaded 8/1/2011 from www.clinicaltrials.gov18

19

Downloaded 8/1/2011 from www.prialt.com

Eribulin mesylate (E7389) Halaven®

Halichondrin B analogue E7389 (macrolide, polyketide)

Pharmacology

• Microtubule interacting agent

• Developed as an anticancer agent

• Developed by Eisai, Woodcliff Lake, NJ

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

20

Eribulin mesylate (E7389) Halaven®: FDA- approval 2010

Downloaded 8/1/2011 from http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp 21

Eribulin mesylate (E7389) Halaven®: clinical trials

Downloaded 8/1/2011 from www.clinicaltrials.gov22

Eribulin mesylate (E7389) Halaven®

23

Downloaded 8/1/2011 from http://www.eisai.com/pdf/eir/epipeline.pdf

Omega-3-acid Ethyl Esters (Lovaza®)

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

Downloaded 8/5/2011 from http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021654s023lbl.pdf 24

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

Downloaded 8/1/2011 from http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp 25

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

Downloaded 8/1/2011 from www.clinicaltrials.gov26

http://www.lovaza.com/romDownloaded 8/1/2011 from

Trabectedin, Ecteinascidin-743 (Yondelis®)

28

2000

2001

2002

2003

2004

2005

2006

2007

0

50

100

150

200175 PubMed 2000-07

Pharmacology

Binds to the minor groove of DNA and interferes with cell division and the gene transcription processes and repair machinery of the DNA.

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

29http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm

Downloaded 8/2/2011 fromhttp://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm

30

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

31Downloaded 8/2/2011 from www.clinicaltrials.gov

The global marine pharmaceutical pipeline

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

32

33

Chemistry Marine Natural Products: 8,940

Preclinical Pipeline: 1,458

Clinical Pipeline: 14

FDA –approved: 5

Global Marine Pharmaceutical Pipeline in 201134

Marine pharmaceuticals in Phase III

http://marinepharmacology.midwestern.edu/clinPipeline.htm August 2011

35

Brentuximab vedotin (SGN-35)

H2N

HN

NN

OMeO

O

ONH

HO

OMe O

Monomethyl Auristatin E (peptide)

mAb-linker-

Pharmacology

Anti-CD30-

Dolabella auricularia (sea hare)

Phylum: Mollusca, Class: Gastropoda

• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets CD30, a marker of Hodgkin lymphoma. • The ADC is stable in the bloodstream, but releases MMAE, an antimicrotubuleagent, upon internalization into CD30-expressing tumor cells, resulting in a targeted cell-killing effect.

Seattle Genetics’ proprietary technology

Downloaded 8/7/2011 from http://www.seagen.com/product_pipeline_sgn35.shtml36

Brentuximab approved August 19, 2011!

37

38http://www.seagen.com/product_pipeline.phpDownloaded 8/24/2011 from

Brentuximab vedotin (SGN-35): clinical trials

Downloaded 8/5/2011 from www.clinicaltrials.gov39

Plitidepsin (Aplidin®)

N

ONH

O

O

ONH

OH

O

ONH

ON

OCH3

CH3O

NCH3

ON

OO

O

O

Aplidium albicans (seasquirt)

(Phylum Chordata, Subphylum:Tunicata)Plitidepsin (depsipeptide)

Pharmacology

• Extremely potent inducer of apoptosis with IC50 in the low nanomolarrange. • It triggers Rac 1 activation, together with MPK-1 downregulation, and sustained JNK activation. • Ongoing efforts seek to identify the primary cellular target.

Mayer et al. TIPS 201040

41

Downloaded 8/1/2011 from

Plitidepsin (Aplidin®): clinical trials

42Downloaded 8/5/2011 from www.clinicaltrials.gov

Marine pharmaceuticals in Phase II

http://marinepharmacology.midwestern.edu/clinPipeline.htm August 2011

43

DMXBA (GTS-21)

Proboscis worm Paranemertesperegrina (Phylum Nemertea). W. Kemet al. Toxicon 9, 15-22, 1971

DMXB-A: 3-(2,4-dimethoxybenzylidene)-anabaseine, GTS-21alkaloid

PharmacologyGTS-21 acts as a partial

agonist at neural nicotinic acetylcholine receptors, binds to both the

44

α4β2 and α7 subtypes, but only activates α7

Preclinical and Clinical research• Developed for Alzheimers, Attention

Deficit Hyperactivity Disorder, and Schizophrenia

DMXBA (GTS-21)

Downloaded 8/5/2011 from www.clinicaltrials.gov 45

46

DMXBA (GTS-21)

PM00104 (Zalypsis®)

Pharmacology

H3C

CH3

CH3

OCH3

AcO

CF3

NN

HO

OHO

ONH

O

H

Jorunna funebris (sea slug)

• 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. • Cell lines with mutant p53 or lacking p53 are more sensitive to the treatment with Zalypsis than cell lines with wild type p53.

Mayer et al. TIPS 2010

(Zalypsis®) alkaloid(Phylum: Mollusca, Class: Gastropoda)

47

PM00104 (Zalypsis®)

Downloaded 8/5/2011 from www.clinicaltrials.gov 48

49Downloaded 8/1/2011 from

Marine pharmaceuticals in Phase I

http://marinepharmacology.midwestern.edu/clinPipeline.htm August 201150

Bryostatin-1

Colonial Bugula Neritina (Phylum Bryozoa) Downloaded from http://ucsdnews.ucsd.edu/

Macrolide lactone(Polyketide)

Preclinical and Clinical research

• Developed as an Anticancer agent

• 38 clinical trials

Pharmacology• protein kinase C inhibitor

51

Bryostatin-1

Downloaded 8/5/2011 from www.clinicaltrials.gov 52

Marizomib (Salinosporamide A, NPI-0052)

Salinosporamide A is a beta-lactone-gamma-lactam

53

Pharmacology• Covalent modification of the active site threonine residues of the 20S proteasome, a multi-subunit enzyme complex that degrades ubiquitin-tagged proteins in eukaryotic cells

Preclinical and Clinical research

• Developed as an Anticancer agent

• Developed by Nereus Pharmaceuticals, San Diego, CA

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

HN

O

O

O

CH3

OHH

Cl

Salinosporamide A (NPI-0052)

Downloaded 8/5/2011 from www.clinicaltrials.gov 54

Salinosporamide A (NPI-0052)

55Downloaded 8/1/2011 from

56

The global marine pharmaceutical pipeline

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

57

Chemistry Marine Natural Products: 8,940

Preclinical Pipeline: 1,458

Clinical Pipeline: 14

FDA –approved: 5

Global Marine Pharmaceutical Pipeline in 201158

59

Chemistry Marine Natural Products: 8,940

Preclinical Pipeline: 1,458

Clinical Pipeline: 14

FDA –approved: 5

Global Marine Pharmaceutical Pipeline in 201160

Marine pharmaceuticals preclinicalpipeline

• Last ten years: 1,458 compounds• Global research enterprise• Multiple pharmacological classes

http://marinepharmacology.midwestern.edu/61

62

The global marine pharmaceutical preclinical pipeline2007-8

Global research involving investigators in 26 countries & US

Marine pharmaceutical preclinical pipeline

• Last ten years: 1,458 compounds• Global research enterprise• Multiple pharmacological classes

http://marinepharmacology.midwestern.edu/63

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

• Anticoagulant • Cardiovascular• Anti-inflammatory• Immune system• Nervous system• Variety of molecular

targets: eg. enzymes, receptors

• Antitumor• Antibacterial• Antifungal• Antiviral• Antimalarial• Antituberculosis• Antiprotozoal

64

65

66

67

Acknowledgements

68

Global Marine Pharmaceutical Clinical Pipeline: TIPS 2010 article• 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• Dale Shuster, Ph.D., Eisai Pharmaceuticals• Maria del Carmen Cuevas Marchante, Ph.D., PharMamar, SpainGlobal Marine Pharmaceutical Preclinical Pipeline 1998-2008

reviews• Roberto Berlinck, Ph.D., University of Sao Paulo. Brasil• Mark Hamann, Ph.D., University of Mississippi, USA • Abimael Rodriguez, Ph.D., University of Puerto Rico, USA• Nobuhiro Fusetani, Ph.D., Hokkaido University, Japan• Kirk Gustafson, Ph.D., National Cancer Institute, USA

http://marinepharmacology.midwestern.edu/

or

Google: marine pharmacology

amayer@midwestern.edu

69