THE PIPELINE AND THE FINISH LINE
Modern-day drug development fits a commercialization 'pipeline' analogy quite nicely. This imaginary pipeline contains the
various products currently under evaluation as potential commercial chemotherapies.
The operative word is potential. There is no guarantee that any of the compounds under development will see daylight at the
commercial end of the pipeline. Ideally, promising drug leads enter one end of the drug development pipeline as "New Chemical
Entities" (NCEs), and FDA-approved novel therapies emerge from the other end and are brought to market. That seems simple enough.
Remember, however, on average it takes more than a decade and several hundred million dollars to move drug candidates along the
pipeline. Also, bear in mind that for every new therapy that is granted FDA approval, thousands of others are abandoned somewhere
along the pipeline, either because they were found to be clinically ineffective or unsafe at therapeutically effective dosages.
The steps involved in bringing natural product-based drugs to market are briefly outlined here. For drugs developed from natural
products, the front end of the development pipeline usually consists of several years' worth of pre-clinical research. An NCE
that has been discovered by various research labs may be further screened for specific bioactivity against a defined battery of
cell lines. If results are encouraging, the compound may then be evaluated for efficacy and toxic side effects using animal
models and, more recently, in silico (computerized) simulations.
If the NCE continues to show potential, the research lab then usually looks for a partner within the pharmaceutical industry
interested in licensing the drug discovery in order to pursue clinical development. That partner informs the FDA of its
intentions to develop the drug by submitting an Investigational New Drug Application (IND). If the candidate drug performs well
in several years' worth of
human clinical trials, successfully meeting all clinical endpoints for safety and efficacy and
exhibiting acceptable ADME (absorption, digestion, metabolism, and elimination) criteria, the industry partner may then submit a New Drug Application (NDA) to the FDA. On
approval, the drug may be brought to market, concurrent with ongoing post-clinical studies to verify the absence of unanticipated
risks or side effects not detectable in the smaller study groups involved in clinical trials.
The First Wave of Marine-Derived Drugs
The first modern marine-derived drugs date back more than 50 years. Werner Bergman extracted the novel compounds spongothymidine
and spongouridine from the Caribbean sponge Tethya crypta in the early 1950s. These compounds were nucleosides
similar to those forming the building blocks of nucleic acids (DNA and RNA). They were unusual, however, in that they contained a
rare sugar called arabinose, rather than the typical ribose sugar of RNA. These natural nucleoside analogs were discovered to
have unexpected antiviral properties. Examination of their mode of action as reverse transcriptase inhibitors led to
the eventual synthesis of a number of important commercially available antiviral and anti-cancer drugs.
AZT (zidovudine), manufactured under the trade name Retrovir® by the drug company GlaxoSmithKline, was the first drug licensed for the
treatment of HIV infection. Acyclovir (Zovirax®) is another first-wave marine-derived antiviral commonly prescribed for treating
herpes. The arabinoside Ara-A (Vidarabine®) is also in clinical use as an antiviral (most often as an opthalmic ointment). A
related compound, Ara-C, is sold under the trade name Cytosar-U® by Pharmacia & Upjohn. It was FDA-approved for the treatment of
certain leukemias in 1969, making it the first such approved marine-derived drug for use in cancer chemotherapy.
Predating even these discoveries and product comercializations described above was the pioneering first wave MBT research of
Professor Guiseppe Brotzu of Italy. Brotzu cultured a seawater sample taken near a sewage outlet in the Mediterranean Sea in 1945.
Several bacterial and fungal isolates obtained from that sample were assayed for antibiotic potential. One of these isolates,
the fungus Cephalosporium acremonium, was shown to possess signiificant inhibitory activity when tested against a number of
bacterial strains. This finding marked the discovery of the first of the cephalosporin family of antibiotics, important additions to the fight against a range of bacterial infections.
The New Wave of MBT Drug Discovery
There is a significant (and growing) number of marine-derived compounds with pharmaceutical potential in the pipeline. The
accompanying table (modified from one included in Kijjoa and Sawangong 2004) presents the marine-derived potential therapeutic
compounds that are currently the focus of MBT drug discovery efforts. Many of these are still undergoing preclinical evaluation,
but several others are currently being administered to patients as part of clinical trials.
A sampling of some of the most exciting MBT-based drug discoveries currently undergoing clinical evaluation are briefly summarized below. A more
extensive overview of more than 30 marine-derived natural products is provided in this website's "Drugs From The Sea" Index.
- Bryostatin 1
For the last few years, many marine biomedical insiders have suggested that
Bryostatin 1 is leading the pack of marine-based natural products on track toward commercial drug approval as an anti-cancer therapy. This macrocyclic
lactone was first isolated from a California population of the fouling community bryozoan Bugula neritina. The
compound binds to and effectively modulates protein kinase C (PKC), an enzyme involved in the expression of certain types of
proteins. The apparent anti-cancer, anti-tumor, and immunostimulant bioactivity of the drug is related to this novel mechanism of
While bryostatin 1 may still be on its way toward drug approval, results reported from Phase II clinical trials have somewhat tempered
optimism derived from pre-clinical results showing significant anti-tumor activity against several cell lines and from early
clinical trials demonstrating effectiveness against some types of solid tumors. Nevertheless, there is at least some clinical
evidence that bryostatin 1 may be of synergistic benefit when used in combination with existing chemotherapies (e.g., paclitaxil
- The Didemnins
The Caribbean tunicate Trididemnun solidum was the source organism for a family of novel marine compounds called didemnins.
Initial evaluation of bioactivity in these compounds, classified as cyclic depsipeptides [def], led to the selection of didemnin B as the most promising drug candidate. The compound was shown to
be an effective inhibitor of nucleotide and protein synthesis. Preclinical trials revealed anti-tumor activity in an array of tumor models as
well as a moderate overall toxicity profile. These positive results led to the selection of didemnin B as the first marine natural product to be placed into
clinical human trials. Phase I trials were promising, but larger Phase II trials reported poorer response rates when the drug was
administered at low doses, and excessive toxicity when dosages were increased. Clinical development of didemnin B was halted in
the mid-1990s based on clinical results.
Fortunately, the related compound aplidine (Aplidin®, dehydrodidemnin B) was isolated from an unrelated tunicate species
(the Mediterranean species Aplidium albicans). Like didemnin B, aplidine interferes with DNA and protein synthesis, leading to
target arrest in the G1-G2 phase of the cell cycle . Moreover, aplidine has been shown to inhibit specific enzymes essential to
the formation, growth, and vascularization of tumors. Aplidin®, a wholly synthetic analog of the drug owned by the marine pharmaceutical
company PharmaMar, has performed positively in preclinical and Phase I clinical trials and is currently in Phase II trials for the treatment of
solid tumors. Preliminary research findings also suggest in vitro activity in acute lymphoid and myeloid leukemias.
- The Dolastatins
The dolastatins are a family of peptides isolated from the
Indian Ocean sea hare Dollabella auricularia. Dolastatins are
antiproliferative agents, inhibiting the growth and reproduction of target cells and inducing apoptosis ("cell suicide" or programmed cell
death) in a variety of malignant cell types. The MOA of the dolastatins is based on interaction with tubulin, an important structural and
organizational cellular component. As a result of this interaction, normal microtubule
function is disrupted and mitotic cell division ceases.
Two natural dolastatins, dolastatin 10 and dolastatin 15, were selected for drug development based on their superior
antiproliferative bioactivity. Phase I and Phase II clinical trials with dolastatin 10 revealed acceptable toxicity levels, but
failed to demonstrate significant clinical activity against solid tumors. However, the drug did exhibit synergistic antitumor
activity when administered in tandem with with bryostatin 1 or vinca alkaloids, so it remains a viable candidate for combination
The pursuit of synthetic dolastatin analogs has led to the development of LU103793, a dolastatin 15 analog that exhibits improved
stability and water solubility over that of its natural counterpart. Bioactivity against a range of tumor types has been reported
from a number of Phase I studies, and Phase II trials are ongoing for breast, lung, ovarian, prostate and colon cancers.
Preliminary findings suggesting LU103793 treatment may not lead to certain toxicity side-effects common to other tubulin
interactive agents (including natural dolastatins) is encouraging.
- Ectenaisdin 743 (ET-743, Yondelis®)
The ecteinascidins are a family of alkaloid compounds isolated from a Caribbean mangrove tunicate species, Ectenaiscidia
turbinata. One particular compound, ecteinascidin 743 , exhibited both a high degree of bioactivity and a high
concentration in the source organism (relative to other ecteinascidins). The relative abundance and ease of collection of E.
turbinata also played a role in selection of this natural product as a drug development candidate.
The MOA of this potent antitumor compound is based on its ability to mediate the interaction between cellular DNA and various
transcription factors and other proteins. ET-743 is also affective as an inhibitor of DNA synthesis, capable of arresting the
cell cycle and inducing p53-independent apoptosis in target cells. The compound also exhibits tubulin
interactive bioactivity. Preclinical in vitro screens indicated ET-743 was most active against cancers in colon, breast, lung,
brain, and ovarian cell lines.
Phase I clinical trials recorded moderate side-effects and antitumor activity in cases of advanced and drug-resistant tumors in
ovarian, breast, and mesenchyme tissues. Phase II trials confirmed the drug effectiveness against these and other drug-resistant
tumors (e.g., soft tissue sarcomas), and also helped establish baseline parameters to identify patients likely to tolerate this
very strong drug. Phase III trials comparing treatment with ET-743 to current drug therapies have not yet been published will
help to determine the true therapeutic potential of WT-743.
Discodermolide is a macrolide [def] originally isolated in 1987
from the Caribbean sponge Discodermia dissoluta. Compound
development as an immunosuppressant (e.g., for organ transplant recipients) was initially pursued. But discodermolide proved to
be too toxic at the dosages required for effective immune system suppression and development as a potential intiocancer agent was
taken up. The drug has since proven very potent against certain cancers, and development efforts are ongoing.
Discodermolide is a tubulin interactive agent with an MOA similar to that of the dolastatins and the commercial anticancer drug
Taxol® (paclitaxel) Importantly, discodermolide has demonstrated potency against some treatment-resistant cancers that are not
responsive to paclitaxel. Discodermolide also exhibits better water solubility, facilitating patient delivery. Perhaps
most exciting is the recent finding that combination treatment with
discodermolide and Taxol® combats tumor growth in certain cancers (e.g., lung cancer) with several times the efficacy of either
drug administered on its own. By synergistically altering the dynamic instability of microtubules, the combination drug treatment
freezes cancer cells in the G2-M stage of the cell cycle, preventing DNA replication and cell division, and ultimately leading to
Discodermolide is progressing through Phase I human clinical trials and continues to show promise in combating pancreatic cancer
and other drug-resistant cancers. Despite the complexity of the molecule, a number of gram-scale laboratory syntheses have been
elucidated. Larger scale synthesis by means of a 39-step
pathway developed by licenseholder Novartis has also yielded sufficient material for
current clinical trials. Simpler synthetic routes, or possibly the use of recombinant DNA strategies (see "Alternate Sources" companion section) will likely be required if drug approval creates a
commercial-scale demand for this drug.
- Neovastat® (AE-941)
Neovastat (AE-941) is a standardized liquid extract derived from shark cartilage. Unlike raw dried shark
cartilage for which anticancer claims remain unsubstantiated based on results of human use
studies, AE-941 is a defined standard extract (comprising the < 500 kDa mass extract fraction) with significant positive early
clinical evidence of its efficacy.
Although the substance exhibits multiple mechanisms of action, it is the anti-angiogenic (blood vessel formation) aspects of AE-941 that make it extraordinary.
AE-941 essentially thwarts the demands of tumors for new capillaries,
depriving them of oxygen and nutrition they need to continue growing.
AE-941 is now in international Phase III trials for renal cell carcinoma and non-small-cell lung cancer. It has received more
recent attention as a possible treatment against metastatic prostate and breast cancer. The anti-angiogenic MOA further suggests
potential as a therapy against blood diseases like multiple myeloma.
Another promising marine-based anti-angiogenic agent is the compound squalamine. It is an aminosterol obtained
from the spiny dogfish (Squalus acanthus) a common New England coastal shark. Commercialization of this compound, like AE-941, must be
approached prudently to avoid further damaging already heavily impacted global shark populations.
- And the First to Cross the Finish Line... Ziconotide (Prialt®)
ziconotide is a synthetic form of a peptide extracted from the venom of predatory
tropical cone snails (Conus spp.). This drug is
a member of a newly described chemical family called the conopeptides that has garnered a great deal of attention as a potential option for pain management.
The MOA of ziconotide revolves around the compound's ability to target and block specific neuron presynaptic ion channels,
effectively short-circuiting the nerves that normally transmit pain signals. The precisely targeted mode of action carries an
important advantage over currently available opioid drugs with more system-wide suppressive effects such as sedation and
In December 2004, the FDA granted Irish pharmaceutical company Elan Corporation approval
to market its product Prialt® for pain management in a select subset of patients. Approval to market the compound in the EU was
subsequently granted by the European Commission in February 2005. The drug is currently available in the United States for
the treatment of severe, chronic pain in patients who require intrathecal (IT) analgesia. Intrathecal medication is delivered directly into the space around
the spinal cord, allowing chronic pain to be managed while still allowing the patient to maintain body muscle control. So far, Prialt is only approved
for delivery to IT patients by means of specific internal (surgically implanted) or external programmable microinfusion and catheter systems. The target
population for the drug is patients suffering from severe chronic pain such as
that in some patients with neuropathic pain, cancer, and AIDS, and who have been shown to be intolerant of or resistant to other
Amador, M.L., Jimeno, J., Paz-Ares, L., Cortes-Funes, H., and M. Hidalgo. 2003. Progress in the development and acquisition of
anticancer agents from marine sources. Annals of Oncology 14:1607-1615.
Bergmann W and RJ Feeney. 1951. Contributions to the study of marine products. XXXII. The nucleosides of sponges. J Org Chem
Bergmann W and DC Burke. 1955. Contributions to the study of marine products. XXXIX. The nucleosides of sponges. III.
Spongothymadine and spongouridine. J Org Chem 20:1501-1507.
Erba E, Bergamaschi D, Bassano L et al. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action.
Eur J Cancer 2001; 37: 97-105.
Kijjoa A and P Sawangwong. 2004. Drugs and cosmetics from the sea (review paper). Mar. Drugs 2004:73-82.
Mayer MS. 1999. Marine Pharmacology in 1998: Antitumor and Cytotoxic Compounds. The Pharmacologist 41:159-164.
Newman DJ, and GM Cragg. 2004. Advanced preclinical and clinical trials of natural products and related compounds from marine
sources. Current Medicinal Chemistry 11:1693-1713.
Davy Jones' Medicine Chest (1994 Omni Magazine article):
What is p53?