The global marine pharmaceutical piliipeline
Alejandro M. S. Mayer, Ph.D.
Midwestern University Pharmacology Department, CCOM Downers Grove , Illinois , USA
1 2 http://marinepharmacology.midwestern.edu/ The global marine pharmaceutical pipeline
• FDA- approvedihd marine pharmaceut ilicals • The Clinical Pipeline • The Preclinical Pipeline
http://marinepharmacology.midwestern.edu/
3 4 FDA – approved: 7
Clinical Pipeline: 11
Preclinical Pipeline: 1,458
Chemistry Marine Natural Products: 8,940
Global Marine Pharmaceutical Pipeline in 2012 5 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
6 FDA- approved marine pharmaceuticals
http://marinepharmacology.midwestern.edu/ 7 Cytarabine, Ara-C(CytosarC (Cytosar): FDA approval 1969
Arabinosylcytosine or cytosine Caribbean sponge Tethya crypta, arabinoside is a source of spongothymidine, led to synthetic pyrimidine synthesis of new class of arabinosyl nucleoside nucleosides. 8 Cytarabine, Ara-C(CytosarC (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-lymphocytic leukemia of adults and children • Also use d for: acutlte lymp hocy tiltic leu kem ia an d chronic myelocytic leukemia
9 Cytarabine, Ara-C (Cytosar): clinical trials
Downloaded from www.clinicaltrials.gov 10 Cytarabine, Ara-C (Cytosar): Hospira, USA
11 Downloaded from http://www.hospira.com/Products/cytarabine.aspx Vidarabine, Ara-A(ViraA (Vira-A): FDA approval 1976
Arabinofuranosyladenine or adenine arabinoside is Caribbean sponge Tethya crypta, a synthetic purine source of spongouridine, led to nucleoside synthesi s o f new c lass o f ara binosy l 12 nucleosides. Vidarabine, Ara-A(ViraA (Vira-A): Antiviral
• Pharmaco logy: Vidara bine is conver tditted into ara binos ide triphosphate, and inhibits viral DNA polymerase and DNA synthesis • Indications for use: 3% ophthalmic ointment is used for acute k erat oconj uncti viti s an d recurren t ep ithe lia l keratitis, caused by herpes simplex virus types 1 and 2 • CtlCurrently discon tinue d ithUSin the U.S. as no tdiFDAted in FDA Orange Book (3-2011)
13 Downloaded from http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm 14 Ziconotide (Prialt): FDA approval 2004
25 amino acid, polybasic Piscivorous marine snail Conus magus, source peptide containing 3 of the naturally occurring conopeptide disulfide bridges and the FDA-approved dru g • Developed as a pain medication
Prialt® 15 Ziconotide (Prialt): clinical trials
Downloaded from www.clinicaltrials.gov 16 Ziconotide (Prialt): Jazz Pharmaceuticals, Ireland
Downloaded from www.prialt.com Omega-3-acid Ethyl Ester (Lovaza ): FDA approval 2004
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 18 Omega-3-acid Ethyl Esters (Lovaza): clinical trials
Downloaded from www.clinicaltrials.gov 19 Omega-3-acid Ethyl Esters (Lovaza): GlaxoSmithKline, UK
Downloaded from http://www.gsk.com/products/prescription-medicines/lovaza.htm 20 Trabectedin, ET-743 (Yondelis®): cancer
Colonial ascidian Ecteinascidia turbinata (Phylum Chordata, Subphylum: Urochordata)
200 175 PubMed 2000-07
150 Pharmacology 100 Binds to the minor groove of DNA and 50 interferes with cell division and the gene transcription processes and repair 0 21 machinery of the DNA. 1 4 5 7 00 03 06 0 0 0 2 200 2002 2 200 200 2 200 Trabectedin, ET-743 (Yondelis®): FDA approval 2005
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanP 22 roductDesignation/default.htm Trabectedin, ET-743 (Yondelis®): FDA approval 2005
Downloaded from http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm 23 Trabectedin, ET-743 (Yondelis®): clinical trials
24 Downloaded from www.clinicaltrials.gov Trabectedin, ET-743 (Yondelis®): Pharmamar, Spain
Downloaded from http://www.pharmamar.com/yondelis.aspx 25 Eribulin mesylate (Halaven®) : FDA approval 2010
Halichondrin B analogue E7389 Sponge Lissodendoryx sp. (Phy lum: Por ifera) CtCourtesy o fJhBltf John Blunt, (macrolide, polyketide) Univ. of Canterbury, N. Zealand Pharmacology • Developed as an anticancer agent
• Microtubule interacting agent • Developed by Eisai, Woodcliff Lake, NJ
26 Eribulin mesylate Halaven®: clinical trials
Downloaded from www.clinicaltrials.gov 27 Eribulin mesylate (Halaven®): Eisai Co., Ltd, Japan
28 Downloaded from http://www.eisai.com/pdf/eir/epipeline.pdf Brentuximab vedotin : FDA approval 2011
HO O H N N H2 N N H N O OMe O OMe 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 be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells.
29 http://www.youtube.com/watch?v=WYuBjfJP84c Brentuximab vedotin (SGN-35): cancer
HO O H N N mAb-linker- H2 N N H N O OMe O OMe O
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. • 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 30 Brentuximab vedotin (SGN-35): clinical trials
Downloaded from www.clinicaltrials.gov 31 Brentuximab vedotin (SGN-35): Seattle Genetics, USA
32 Downloaded from http://www.seagen.com/product_pipeline.php The global marine pharmaceutical pipeline
• FDA- approved marine pharmaceuticals • The Clinical Pipeline • The Preclinical Pipeline
33 The Marine Pharmaceutical Clinical Pipeline
http://marinepharmacology.midwestern.edu/ 34 FDA – approved: 7
Clinical Pipeline: 11
Preclinical Pipeline: 1,458
Chemistry Marine Natural Products: 8,940
Global Marine Pharmaceutical Pipeline in 2012 35 Marine pharmaceuticals in Phase 3
http://marinepharmacology. midmidwesternwestern. edu/clinPipeline. htm
36 Plitidepsin (Aplidin®): Phase 3, cancer
OCH3 O N O N O CH O NH 3 O O CH3 O N O N N O OH H O O NH O O App(lidium albicans (seasqq)uirt) 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. • OiOngoing e fftktidtifthifforts seek to identify the primary cell lllttular target. 37 Mayer et al. TIPS 2010 Plitidepsin (Aplidin®): Phase 3, clinical trials
38 Downloaded from www.clinicaltrials.gov Plitidepsin (Aplidin®): Pharmamar, Spain
39 Marine pharmaceuticals in Phase 2
http://marinepharmacology.midwestern.edu/clinPipeline.htm
40 PM00104 (Zalypsis®): Phase 2, cancer
OCH3 HO CH3 AcO H H3C N CH3 N O O OH NH CF O 3 Jorunna funebris (sea slug) (Phylum: 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 41 PM00104 (Zalypsis®): Phase 2, clinical trials
Downloaded from www.clinicaltrials.gov 42 PM00104 (Zalypsis®): Pharmamar, Spain
43 Glembatumumab vedotin (CDX-011) : Phase 2, cancer
HO O H N N H2 N N H N O OMe O OMe 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 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
HO O H N N mAb-linker- H2 N N H N O OMe O OMe O
Anti-NMB- Monomethyl Auristatin E (peptide) Seattle Genetics’ proprietary technology
Pharmacology
• Brentuximab vedotin is an antibody-drug conjugate (ADC) that targets glycoprotein 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.
45 Downloaded from http://www.celldextherapeutics.com/wt/page/cancer Glembatumumab vedotin (CDX-011) : Phase 2, clinical trials
Downloaded from www.clinicaltrials.gov 46 Glembatumumab vedotin: CellDex Therapeutics, USA
Downloaded from http://www.celldextherapeutics .com/wt/page/pipeline com/wt/page/pipeline_ redirect
47 Marine pharmaceuticals in Phase 1
http://marinepharmacology.midwestern.edu/clinPipeline.htm 48 Marizomib (Salinosporamide A): Phase 1, Cancer
H OH H O N O O
CH3
Cl Salinospora tropica, a marine bacteria Salinosporamide A is a beta- (Phylum: Actinobacteria). Courtesy of Ray Lam, lactone-gamma-lactam Nereus Pharmaceuticals
Pharmacology Preclinical and Clinical research •Covalent modification of the • Developed as an Anticancer agent active site threonine residues of • Developed by Nereus Pharmaceuticals, the 20S proteasome , amultia multi- subunit enzyme complex that San Diego, CA degrades ubiquitin-tagged 49 proteins in eukaryotic cells Marizomib (Salinosporamide A): Phase 1, clinical trials
Downloaded from www.clinicaltrials.gov 50 Salinosporamide A (NPI-0052): Nereus, USA
51 Downloaded from http://www.nereuspharm.com/overview.shtml The global marine pharmaceutical pipeline
• FDA- 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 preclinical pipeline
• For the period 1998-2008 • 13 marine pharmacology reviews • 1,458 compounds • Global research enterprise • Multiple pharmacological classes
55 The global marine pharmaceutical preclinical pipeline
Global research involving investigators in 32 countries & US56 in the period 2007-2008 Marine pharmaceutical preclinical pipeline
• For the period 1998-2008 • 13 marine pharmacology reviews • 1,458 compounds • Global research enterprise • Multiple pharmacological classes
57 The marine pharmaceuticals preclinical pipeline in 2007-2008: 197 compounds
• Antitumor • Anticoagulant • Antibacterial • Cardiovascular • Antifungal • Anti-inflammatory • Antiviral • Immune system • Antimalarial • Nervous system • Antituberculosis • Variety of molecular • Antiprotozoal targets: eg. enzymes, receptors
58 59 The global marine pharmaceutical pipeline: conclusions
• Biodi versit y o f mar ine organ isms an d c hem is try • 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.
60 Acknowledgements Global 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 • 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 • 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 61 New developments in the marine pharmaceutical clinical and preclinical pipeline will be posted @
http:// mari neph armacol ogy.mid west ern.ed u/
62