Marine  Bioprospec-on  

2nd  Caribbean  ABS  Workshop  

Dr,  Hartmut  Meyer  

Kingston,  Jamaica  

27.11.2013  

Renaissance  of  Natural  Products  in  Drug  Development  

•  Screening of existing libraries and combinatory chemistry is not achieving the hoped amount of more and new chemical entities

•  During the past 30 years, combinatory chemistry brought 1 de novo new chemical entity to the market (Nexavar®, antitumor)

•  From 1940s to 2010, 175 small molecules were approved for cancer treatment, of which 85 (49%) are natural products or direct derivatives (44 (34%) out of 128 since 1980)

•  Natural products exhibit a greater diversity and variability than libraries and combinatory chemistry

•  Marine organisms provide more unique and diverse compounds than terrestrial organisms

Newman & Cragg (2012)

Marine  Bioprospec-on  

•  Relatively young scientific field •  Accessibility of marine ecosystems increased steadily:

1970s Scuba diving 1980s Manned submersibles 1990s Remotely operated vehicles

•  Marine natural products in pharmaceutical pipeline (2011): FDA approved drugs 7 Clinical trials 11 Preclinical research 1458 Published marine natural products 8940 Mayer (2012)

•  136 of 183 marine molecules in (pre)clinical trials (2006) investigated for anticancer activities Glaser & Mayer (2009)

•  Estimation of value of marine anticancer drug discovery: 563 – 5690 bill USD Erwin et al (2010)

•  Relatively young scientific field •  Accessibility of marine ecosystems increased steadily:

1970s Scuba diving 1980s Manned submersibles 1990s Remotely operated vehicles

•  Marine natural products in pharmaceutical pipeline (2011): FDA approved drugs 7 Clinical trials 11 Preclinical research 1458 Published marine natural products 8940 Mayer (2012)

•  136 of 183 marine molecules in (pre)clinical trials (2006) investigated for anticancer activities Glaser & Mayer (2009)

•  Estimation of value of marine anticancer drug discovery: 563 – 5690 bill USD Erwin et al (2010)

New  Marine  Natural  Products  from  Invertebrates  

Costa Leal et al. (2012)

Costa Leal et al. (2012)

New  Marine  Natural  Products  from  Invertebrates  

7  Approved  Drugs  of  Marine  Origin  in  2012  

Substance (Drug)

Organism (production)

Country of Origin (collection/publication)

Indication (approval)

Cytarabine (Cytosar-U®, Depocyt®)

Theta crypta (sponge) (synthetic)

Florida, USA or Bimini Islands, Bahamas (1948)

leukaemia and lymphoma

(1969)

Vidarabine (Vira-A®)

Theta crypta (sponge) (synthetic)

Florida, USA or Bimini Islands, Bahamas (1948)

Herpes virus and others

(1976)

Keyhole Limpet Hemocyanin (Immucothel®)

Megathura crenulate (mollusk) (extraction)

California, USA bladder cancer (1997)

Ziconotide (Prialt®)

Conus magus (mollusk) (synthetic)

Philippines chronic severe pain (2004)

Petit & Biard (2013)

7  Approved  Drugs  of  Marine  Origin  in  2012  

Substance (Drug)

Organism (production)

Country of Origin (collection/publication)

Indication (approval)

Trabectidin (Yondelis®)

Ecteinascidia turbinata (tunicate) (hemisynthesis)

Panama, Colombia, Nicaragua, Honduras, Belize or Mexico (1978)

soft tissue sarcoma (2007) relapsed ova-rian carcinoma

(2009)

Eribulin mesylate (Halaven®)

Halichondria okadai (sponge) (synthetic)

Japan (1986) breast cancer (2010)

Brentuximab vedotin (Adcetris®)

Dolabella auricularia (mollusk) (synthetic)

Mauritius (1972) Hogkin

lymphoma (2011)

Petit & Biard (2013)

Marine  Drugs  in  U.S.  Clinical  Cancer  Tests  un-l  2011  

Drug (clinical phase)

Organism Country of Origin No. of trials (first record)

Cytarabine (Ara-C) (I – IV)

Theta crypta (sponge) Florida, USA & Bimini Islands, Bahamas

748 (1960s)

Eribulin mesylate (II-III)

Halichondria okadai (sponge) Japan 60

(2002) Keyhole Limpet Hemocyanin (I – III)

Megathura crenulate (mollusk)

California, USA 26 (1999)

Trabectidin * (I – III)

Ecteinascidia turbinata (tunicate)

Panama, Colombia, Nicaragua, Honduras, Belize, Mexico

24 (2005)

Plinabulin (II) Aspergillus ustus (fungus)

Japan 2 (2006)

Petit & Biard (2013)

Marine  Drugs  in  U.S.  Clinical  Cancer  Tests  un-l  2011  

Drug (clinical phase)

Organism Country of Origin No. of trials (first record)

Plitidepsin (I-II) * Trididemnum solidum (tunicate)

Panama, Colombia, Nicaragua, Hondu-ras, Belize, Mexico

14 (2004)

Elisidepsin (I-II) * Elysia rufescens (mollusk)

Hawai’i, USA 4 (2006)

PM00104 (I-II) * Joruna funebris (nudibranchia)

Mexico 5 (2006)

PM01183 (I-II) * Ecteinascidia turbinata (tunicate)

Panama, Colombia, Nicaragua, Hondu-ras, Belize, Mexico

4 (2009)

ILX-651 (I-II) Dolabella auricularia (mollusk)

Mauritius 5 (2003)

TZT-1027 (I-II) Dolabella auricularia (mollusk)

Mauritius 4 (2003)

Petit & Biard (2013)

Marine  Drugs  in  U.S.  Clinical  Cancer  Tests  un-l  2011  

Drug (clinical phase)

Organism Country of Origin No. of trials (first record)

8 AB-conjugated compounds (I-II)

Dolabella auricularia (mollusk)

Mauritius 10 (2006)

3 AB-conjugated compounds (I)

Dolabella auricularia (mollusk)

Mauritius 2 (2009)

SalinosporamideA Salinospora tropica (actinomycete)

Bahamas 4 (2006)

PM060184 * Lithoplocamia lithistoides (sponge)

Madagascar (2005)

1 (2011)

Petit & Biard (2013)

*: PharmaMar, Spain

Marine  Bioprospec-on  and  ABS  

•  The legal debate on marine bioprospection concentrates on areas beyond national jurisdiction

•  The vast majority of marine excursions and collections are undertaken in national waters within the EEZs (200 nautical miles / 370 km out from the costal baseline)

•  The Caribbean Region is almost entirely covered by EEZs •  Marine ecosystems accessible for scuba divers (40m) are

within EEZs •  EEZs also cover deep sea ecosystems •  Our working assumption is that marine bioprospection in most

cases would be covered by the Nagoya Protocol and national legislation

Caribbean  EEZs  

Case  Study  1:  Pseudopterogorgia  elisabethae  

The Bahamas

Neptune's  Medicine  Chest  

In 1983, Bill Fenical discovered a sea fan off the Bahamas. From it, he isolated an agent that acted as an anti-inflammatory in humans. The substance, known as pseudopterosin, was patented by the university, and the cosmetic rights were sold to Estee Lauder for use in skin-care products. In fiscal 1994-95, the compound was among the UC system's top 10 patent royalty earners, bringing in $680,000. It was no small breakthrough. "Here, for the first time, was a scientifically proven marine product," Fenical says. He has published more than 300 scientific papers, helped found Nereus Pharmaceuticals — a private company licensed through UC San Diego to bring marine medical discoveries to market in the future...

Balzar (2006)

Country  of  Origin  in    Scien-fic  Publica-on  

Information on the country of origin: ”The expedition of the research Vessel Calanus (Univ. of Miami) took place in the central Bahama Island in June 1982. […] We acknowledge the government of the Bahama Islands for the kind permission to conduct research in their territorial waters.”

U.S.  Patent  of  UC  Berkeley  

Information on the country of origin: ”…shallow-water reefs of the West Indian region …”

Product  Factsheet  Lipo  Chemicals,  Inc.,  USA  

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Case  Study  2:  Plexaura  homomalla  

Cayman Islands

Case  Study  2:  Plexaura  homomalla  

1969: First discovery of prostaglandins in an invertebrate animal (Plexaura homomalla) from Florida

1970s: Harvest of P. homonalla (Black Sea Rod) with mammalian-identical prostaglandins from Cayman Islands

1980s: economically viable chemical synthesis of prostaglandines

2012: Maxey Cosmetics launches lash conditioner with Black Sea Rod Oil from Cayman Islands, distributed by Cayman Chemicals

"Maxeylash Cosmetics is also proud of their commitment to the Cayman Islands efforts in marine conservation and research, and proudly donate a royalty to the Cayman Islands Department of Environment"

Maxey Cosmetics (2012)

Sustainable  Harvest?  

Investigators are cautiously optimistic that the P. elisabethae populations can be sustained indefinitely with careful harvesting. Since the demand for the product is probably five times the current supply, expanded but properly managed harvesting of gorgonians could provide an economic incentive for community based conservation of coral reefs in other nations in the Caribbean.

Faulkner (2000)

•  early research concentrated on regrowth of biomass of individuals

•  later research took into account reproductivity of populations

Biomass  studies:  Regrowth  is  possible  

Although the pseudopterosins have not yet been developed as anti-inflammatory drugs, a partially purified extract of P. elisabethae is used as an additive in cosmetic products by Estée Lauder. This commercial development, which has resulted in the harvesting of more than 10 000 lbs of gorgonians, has provided the first real test of large scale harvesting of a marine invertebrate. The gorgonians, which occur between 45 and 75 ft. depth, are pruned by hand along an approximately 60-mile length of the Bahamas coastline. Diving is limited to about 60 ft., allowing the deep water specimens to provide a reservoir of breeding stock.

Faulkner (2000)

Although the pseudopterosins have not yet been developed as anti-inflammatory drugs, a partially purified extract of P. elisabethae is used as an additive in cosmetic products by Estée Lauder. This commercial development, which has resulted in the harvesting of more than 10 000 lbs of gorgonians, has provided the first real test of large scale harvesting of a marine invertebrate. The gorgonians, which occur between 45 and 75 ft. depth, are pruned by hand along an approximately 60-mile length of the Bahamas coastline. Diving is limited to about 60 ft., allowing the deep water specimens to provide a reservoir of breeding stock. Studies indicate that regrowth occurs in about 18 months and the test population of gorgonians is now being pruned for the fourth time (W. Fenical, pers. comm.).

Faulkner (2000)

Although the pseudopterosins have not yet been developed as anti-inflammatory drugs, a partially purified extract of P. elisabethae is used as an additive in cosmetic products by Estée Lauder. This commercial development, which has resulted in the harvesting of more than 10 000 lbs of gorgonians, has provided the first real test of large scale harvesting of a marine invertebrate.

Faulkner (2000)

Although the pseudopterosins have not yet been developed as anti-inflammatory drugs, a partially purified extract of P. elisabethae is used as an additive in cosmetic products by Estée Lauder.

Faulkner (2000)

Biomass  studies:  Regrowth  is  possible  

Sea Whip Extract is also a completely renewable resource: “Colonies of Sea Whip Coral have been researched by independent scientists since before 1990, and consistently monitored since 1996. Their studies, as well as the records of the exclusive harvester show that the coral extract has been collected in a sustainable manner that has consistently resulted in complete re-growth.“

ermis LABS (2010)

Reproduc-on  and  popula-on  studies:  Fecundity  suffers  

•  Experimentally induced tissue loss to male colonies reduced spermary production.

•  Female colonies harvested 4 years earlier had lower fecundity than uninjured colonies.

•  Energy reallocation in injured colonies persists years after the damage has healed.

Page & Lasker (2012)

•  The effects of the harvesting were site specific ranging from a 38 to 67% reduction in the density of mature colonies.

•  Severe depression of adult abundances coupled with local recruitment can create a negative feedback and lead to the decline of local populations.

Lasker (2013)

Outlook  

•  Marine bioprospection is a major activity in the Caribbean, carried out by institutions and companies from the U.S. and the EU

•  Utilisation of Caribbean marine genetic resources is a rapidly advancing field

•  Several subscription drugs for major indications have been approved during the last 10 years

•  Most Caribbean countries still run research permit systems without ABS provision (20 years after CBD entered into force)

•  Marine bioprospection has not yet received adequate attention in the ABS discussion

•  The ABS Initiative plans to bring the topic under the spotlight in the next 2 years with the support of the countries of the region

References  

Balzar J. 2006. Neptune’ medicine chest. Los Angeles Times, 18 May 2006 Costa Leal M et al. 2010. Trends in the discovery of new marine natural products from invertebrates over the last two

decades – Where and what are we bioprospecting? PLoS ONE 7(1) e30580 ermis LABS (2010) New acne treatment product, Coral Actives, launched by Ermis Labs. Press release, 31.08.2010 Erwin P M et al. 2010. The pharmaceutical value of marine biodiversity for anti-cancer drug discovery. Ecological

Economics 70(2): 445-451 Faulkner D J. 2000. Marine pharmacology. Antonie van Leeuwenhoek 77: 135-145 Glaser K B, A M S Mayer. 2009. A renaissance in marine pharmacology: from preclinical curiosity to clininal reality.

Biochemical Pharmacology 78(5): 440-448 Lasker H R. 2013. Recruitment and resilience of a harvested Caribbean octocoral. PLoS ONE 8(9) e74587 Mayer A M S. 2012 The global marine pharmaceutical pipeline. OECD Forum on Marine Biotechnology, 30-31 May

2012 http://www.oecd.org/sti/biotech/forumonmarinebiotechnology30-31may2012agendaandpresentations.htm Mayer A M S et al. 2010. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends in

Pharmacological Sciences 31: 255-265 Maxey Cosmetics. 2012. Lusher lashes with Caribbean conditioner, TV spot

http://www.thebalancingact.com/story/3883/you_moisturize_your_face_moisturize_your_eyelashes_too Newman D J, G M Cragg. 2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010.

Journal of Natural Products 75: 311-335 Ngo D-H et al. (2013) Biological activities of marine bioactive peptides. In: Marine Proteins and peptides: Biological

activities and applications (Kim S-K, ed.) p. 509-518 Page C A, H R Lasker. 2012. Effects of tissue loss, age and size on fecundity in the octocoral Pseudopterogorgia

elisabethae. Journal of Experimental Marine Biology and Ecology 434/435: 47-52 Petit K, J-F Biard. 2013. Marine natural products and related compounds as anticancer agents: an overview of their

clinical status. Anti-cancer Agents in Medicinal Chemistry 13: 603-631