Natural Products in Clinical Trials: Volume 1

By Bentham Science Publishers

Natural products continue to play a key role in drug development. A recent analysis of the drug market in the developed world revealed that 40% of total clinically approved drugs were either unmodified natural products or their semi-synthetic derivatives.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Mar 2, 2018
• ISBN: 9781681082134

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Clinical Trials for Deriving Bioactive Compounds from Marine Invertebrates

Ana R. Gomes¹, *, Ana C. Freitas¹, ², ³, Armando C. Duarte¹, ², Teresa A.P. Rocha-Santos¹, ²

¹ Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal

² CESAM, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal

³ ISEIT/Viseu, Instituto Piaget, Estrada do Alto do Gaio, Galifonge, 3515-776 Lordosa, Viseu, Portugal

Abstract

Natural products have been the greatest source of novel medicines currently used in the treatment of several human diseases. In past decades, a notable quantity of natural molecules has been obtained from several marine sources. The huge biodiversity existing in the marine environment, from among which marine invertebrates stand out as a major contributors to the discovery of new molecules, has encouraged investigators from all over the world to identify new marine natural compounds with therapeutic potential. With the discovery of cytarabine and vidarabine in 1974 promising natural products isolated from marine invertebrates became part of the pharmacopeia used in human therapeutic. In 2004, ziconotide was approved for moderate to severe pain treatment and in 2007, trabectedin received European approval to treat patients with soft tissue sarcoma, and finally in 2009 it was approved for treatment of ovarian carcinoma. The largely unexplored marine world harbors a great biodiversity and provides a unique and rich source of natural products with interesting pharmaceutical activities and potential therapeutic applications. In this context, this chapter focuses on the marine invertebrates and reviews marine natural products that are currently being assessed in clinical trials and provides a glimpse of these compounds' potential to expand the pharmacopeia in the treatment of diverse human diseases.

Keywords: Aquatic ecosystem, Bioactive activities, Bioactive compounds, Clinical trials, Human therapeutics, Invertebrates, Marine environment, Marine natural products, Pharmaceutical applications, Pharmaceutical drugs.

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* Address correspondence to Ana R. Gomes: Department of Chemistry, CESAM, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal; Tel: [phone]; Fax: [phone]; Email: [e-mail]

INTRODUCTION

Nature is a powerful olden pharmacy that harbors a vast source of biodiversity and provides a wide abundance of organisms from which to discover structurally unique bioactive compounds (BC) [1]. Although the oceans and seas harbor an abundant biodiversity of organisms, efforts to explore marine life diversity through the isolation of novel molecules has just begun (Fig. 1) [1-3]. The largely unexplored marine environment offers a variety of organisms with unique metabolic characteristics due to an incredible variety of hostile environments, such as sunlight presence/absence, nutrient availability, salinity, pressure and oxygen levels, resulting in the production of an assortment of secondary metabolites with particular and interesting properties [4].

Fig. (1))

Percentage (%) of new marine natural products discovered from marine invertebrates sources. A) Porifera (48.3%); B) Annelida (0.3%); C) Bryozoa (1.2%); D) Chordata (6,6%), E) Cnidaria (29.3%); F) Echinodermata (7.9%); G) Hemichordata (0.1%) and H) Mollusca (6.4%). Arthropoda, Nematoda and Platyhelminthes (0.0%) [1].

Covering most of the earth's surface, seas and oceans offer unexploited sources of promising agents with interesting activities for health improvement. With the constant survey of the marine habitat, marine invertebrates, which include around 60% of all marine animals, were put on the spotlight as resources for new drugs since they were reported as the source of more than 11,000 new natural compounds over the last decade [3, 4].

Although aquatic ecosystems cover most of the earth’s surface, their modern exploration only began with the appearance of modern snorkeling, scuba and the use of remotely operated vehicles (ROVs). Study of marine organisms began with the isolation of the most reachable and big animals, such as sponges, soft corals and red algae, which revealed a wide variety of molecules with peculiar chemical structures [4]. Enhancements in exploration technology, mainly scuba diving and remotely operated vehicles, allowing the collection of a greater diversity of source organisms, allied with improvements in analytical technology, spectroscopy and high-throughput screening, allowed the isolation of novel bioactive marine natural products with unique chemical structures [4-6]. The increasing effort in uncovering the chemistry and pharmacology of new natural molecules over the years has fueled marine-based drug discovery [1, 6].

Marine natural products (MNP) have long been used in medicines, with more than 5 new molecules discovered and approved for clinical use and at least 22 additional compounds derived from marine invertebrates that are in clinical trials, 17 of which are antibody-drug conjugate (ADC) [7, 8]. ADCs are composed by an antibody connected to a drug via a labile linker. After binding of the antibody to the targeted cell antigen, the ADC is taken up by the cell and the cytotoxic agent is released in its active form, thus killing the target cell. ADC has the ability to discriminate between healthy and diseased tissue, attacking only the cancer cells. The idea behind ADC is not new, and their use in vivo was already described in the literature in 1970, as well as clinical trials conducted in 1980, however with restricted success [9]. Nonetheless, a significant increase of these biopharmaceutical agents has been observed over the last 5 years, most likely due to a better understanding of the mechanism of action, a better target selection and more appropriate dosing procedures. These natural bioactive compounds show curious properties and exceptionally interesting pharmaceutical and therapeutic applications, due to their large spectrum of bioactivities, such as anti-tumor, anti-proliferative, anti-microtubule, antibiotic and anti-infective [4].

The diversity of marine life uncovered until now indicates a high potential for new pharmaceutical developments, and there is still much to be discovered in the unexplored ocean depths [3, 10]. This chapter summarizes the current status of bioactive compounds isolated from marine invertebrates that are presently in clinical trials and gives the prospect that marine natural products with a broad spectrum of biological activity represent an added value in the treatment of diverse human diseases.

MARINE BIOACTIVE COMPOUNDS

As shown in Table 1, there are currently five drugs approved by Food and Drug Administration (FDA), namely cytarabine (Cytosar-U®, Depocyt®), vidarabine (Vira-A®), ziconotide (Prialt®), eribulin mesylate (Halaven®) and brentuximab vedotin (Adcetris®). Trabectedin (Yondelis®) has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA), and is finishing relevant phase III trials for approval in the US.

Currently, there are 24 marine natural compounds in clinical trials. Those that are in phase III development include Plitidepsin (Aplidin®), in phase II trials: ABT-414, PM00104 (Zalypsis®), DMXBA, glembatumumab vedotin, PM01183, PSMA-ADC, phase I/II trials: DNIB0600A, pinatuzumab vedotin, polatuzumab vedotin, and in phase I trials, include AGS-16C3F, ASG-67E, ASG-15ME, ASG-22ME, bryostatin, DEDN6526A, DMUC5754A, DSTP3086S, HuMax®-TF-ADC, marizomib, MLN-0264, PM060184, SGN-CD19A, SGN-LIV1A.

These compounds are described in more detail (e.g., discovery, mode of action, clinical application) in the following section. The corresponding chemical structures of each compound are provided and noted with boldface numbers in parentheses following each compound name.

Marine Compounds: Approved Drugs

Cytarabine

Cytarabine (1), also known as cytosine arabinoside, arabinosylcytosine, Ara-C and Cytosar-U® is a chemotherapy agent approved in 1969 by Food and Drug Administration (FDA) [11]. Initially isolated from the Caribbean sponge Tethya crypta, this pyrimidine nucleoside obtained from spongothymidine (2), is currently synthesized and used in the treatment of acute myeloid leukemia, acute lymphocytic leukemia, and blast crisis phase of chronic myelogenous leukemia, meningeal leukemia and non-Hodgkin lymphoma [12-14].

Table 1 A current perspective of marine pharmaceuticals.

Cytarabine acts by rapidly converting into cytosine arabinoside triphosphate, which competes with DNA polymerase's natural substrate, deoxycitidine triphosphate, leading to DNA damages during the S phase cell cycle. Ara-C is also responsible for inhibiting RNA polymerase and nucleotide reductase enzymes, both needed for DNA synthesis [15, 16]. Cytarabine is currently developed by Bedford Laboratories as plain cytarabine (Cytosar-U®) and by Enzon Pharmaceuticals as liposomal formulations (Depocyt®).

Vidarabine

Vidarabine (3), also named arabinofuranosyladenine, adenine arabinoside, Ara-A and Vira-A® is an antibiotic obtained from Streptomyces antibioticus, and approved in 1976 by FDA. Developed from spongouridine (4) (initially isolated from the Caribbean sponge Tethya crypta), this synthetic nucleoside was used to treat patients with superficial keratitis caused by herpes simplex virus, recurrent epithelial keratitis caused by herpes simplex virus type 1 and 2 and acute keratoconjunctivitis [17-19]. In in vitro studies, Vira-A® shows broad spectrum action against DNA viruses and antineoplastic activity [20]. Vidarabine is rapidly phosphorylated into adenine arabinoside triphosphate, which is its active form, and inhibits replication of herpes viral DNA by both competitive inhibition of viral DNA polymerase and incorporation into the DNA strand by substitution of some adenosine bases, thus destabilizing it [20]. Vira-A® was marketed by King Pharmaceuticals.

Ziconotide

Ziconotide (5), (SNX-111 and Prialt®) is a strong analgesic agent only approved by FDA in 2004. Ziconotide is a synthetic form of ω-conotoxin MVIIA (6), obtained from the venom of the marine snail Conus magus and is currently considered for treatment of severe chronic pain in patients with cancer or AIDS [21-23].

Ziconotide is a selective N-type calcium channel blocker. The binding of this neurotoxic drug to calcium channels, located in the dorsal horn of the spinal cord, inhibits the release of pro-nociceptive neurotransmitters, resulting in pain mitigation [24-26]. Prialt® is marketed by Jazz Pharmaceuticals.

Trabectedin

Trabectedin (7), also recognized as ET-743, ecteinascidin 743 and Yondelis® is an anticancer agent approved in 2007 by European Commission to treat patients with advanced soft tissue sarcoma after anthracyclines and ifosfamide failure [27, 28]. In 2009, trabectedin associated with pegylated liposomal doxorubicin was approved for the treatment of relapsed platinum-sensitive ovarian cancer [29, 30]. Yondelis® is also being evaluated in other tumor types, such as breast and prostate cancer [30-32]. Trabectedin is a tetrahydroisoquinoline alkaloid found in the tunicate Ecteinascidia turbinata (collected in the Caribbean and Mediterranean Sea), and it is currently prepared synthetically [33, 34].

Trabectedin is characterized by its peculiar chemical structure composed by three fused tetrahydroisoquinoline rings, named subunits A, B and C. Both subunits A and B allow the interaction with the minor groove of the double-stranded DNA, while subunit C overhangs from the DNA double helix, promoting interactions with neighboring nuclear proteins. The drug prompts a cascade of events that disturbs numerous transcription factors, DNA repair pathways, and DNA binding proteins. Trabectedin is also capable of modifying tumor microenvironment by altering the synthesis of cytokines, as well as chemokines by aberrant and normal cells [35]. Yondelis® is being developed and marketed by Pharmamar.

Eribulin Mesylate

Eribulin mesylate (8), (E7389, Halaven®) is an anticancer drug approved in 2010 by FDA for treatment of metastatic breast cancer patients after receiving at least two prior anthracycline- and taxane-based therapeutics [36, 37]. Halaven® is being marketed by Eisai Inc. to treat several other solid tumors, such as prostate cancer, non-small cell lung cancer, and sarcoma [38, 39]. Eribulin mesylate is a synthetic equivalent of halichondrin B (9), a natural compound, originally isolated from the marine sponge Halichondria okadai [40]. Halaven® is a microtubule inhibitor. It inhibits microtubule growth, although without affect microtubule shortening during the mitosis. This mode of action leads to G2/M phase arrest, promoting cell death as a result of prolonged mitotic blockage [36].

Brentuximab Vedotin

Brentuximab vedotin (10) also named as INN-brentuximab vedotin, SGN-35 and Adcetris® is an antibody-drug conjugate (ADC) targeting cluster of differentiation 30 (CD30) which proved effective in the treatment of anaplastic large cell lymphoma and relapsed or refractory Hodgkin lymphoma [41, 42]. Approved by FDA in 2011, this interesting ADC combines an anti-CD30 monoclonal (cAC10) to a potent microtubule disrupting agent, called monomethyl auristatin E (MMAE) via valine-citrulline peptide linker (11). MMAE is a synthetic antimitotic agent derived from dolastatin 10 (12), a natural antineoplastic drug derived from peptides initially isolated from the marine shell-less mollusk Dorabella auricularia and currently also from a marine cyanobacterium Symploca sp. [43, 44]. Adcetris® rapidly initiates internalization after binding to CD30 on cell surface. MMAE is transported to lysosomes, where is released and binds to tubulin, inhibiting microtubule polymerization, inducing G2/M-phase growth arrest and cell death by apoptosis of the CD30 expressing cells [45-47]. Brentuximab vedotin is marketed as Adcetris® by Seattle Genetics.

Marine Compounds: Phase III Trials

Plitidepsin

Plitidepsin (13) (dehydrodidemnin B and Aplidin®) is a chemical natural cyclic depsipeptide identified from Mediterranean tunicate Aplidium albicans, and presently produced by chemical synthesis. Plitidepsin induces early oxidative stress and the inhibition of protein phosphatases causing apoptosis by activating c-Jun N-terminal protein kinases (JNK) and p38 MAPK which lead to mitochondrial cytochrome C release and subsequently initiates the apoptosis cascade. Plitidepsin is also capable of inducing G1 and G2 arrest by interfering with protein synthesis [48-50]. Preclinical studies have demonstrated strong anticancer activity against several human cancer cells (MDA-MB-231, ACHN, and A-498) and in xenografts mice. Plitidepsin phase I/II clinical trials revealed encouraging results in patients as an anticancer agent [51, 52]. Currently, plitidepsin is in phase III trials for multiple myeloma, lymphoma and leukemia. Aplidin® is being developed by Pharmamar.

Marine Compounds: Phase II Trials

ABT-414

ABT-414 is an ADC containing an anti- epidermal growth factor receptor (anti-EGFR) antibody attached to the cytotoxic monomethyl auristatin F (MMAF) (14). ABT-414 was prepared to be stable in the bloodstream and release the MMFA only into targeted tumor cells. Preclinical studies demonstrated high efficiency in mice xenografts using human mutant and wild-type EGFR-positive cells [53]. ABT-414 is currently in phase II trials for the treatment of glioblastoma multiforme, as well as for the squamous cell tumors [53, 54]. ABT-414 is developed by Abbott Pharmaceutical.

DMXBA

DMXBA (15) also called 3-(2,4-dimethoxybenzylidene)-anabaseine and GTS-21, is a synthetic analogue of anabaseine, an alkaloid found in marine worms, belonging the Phylum Nemertea [55]. DMXBA is a nicotinic agonist described to selectively activate α7 nicotinic acetylcholine receptors (AChRs), which are produced on central nervous system neurons and astrocytes, as well as on peripheral macrophages [56, 57]. Preclinical in vitro studies demonstrated neuroprotective activity, thwarting the harmful effects of beta-amyloid in cerebral cortex neuron cells. In vivo studies, DMXBA displays anti-inflammatory activity, mediated through macrophage α7 receptors [57]. Currently in phase II trials, DMXBA is also in clinical studies to treat patients with cognitive disorders in schizophrenia, Parkinsonism and Alzheimer’s disease [58-61]. GTS-21 is registered by Comentis Inc., an entity conducting treatments for Alzheimer’s disease.

Lurbinectedin

Lurbinectedin (16) also known as PM01183 is a synthetic tetrahydroisoquinoline alkaloid, containing a pentacyclic skeleton made of two rings (subunits A and B) and an additional module, named ring C. In this marine-compound, the ring C binds covalently to the DNA minor groove, prompting mostly double-strand breaks (DSBs) in DNA and transcription blockage. DNA damage accumulation, leads to S/G2 phase arrest and causes cell death by apoptosis [62]. Preclinical in vitro studies showed anticancer activity against human cell lines. In vivo studies, PM01183 also revealed cytotoxicity against a wide variety of human cancer xenografts in athymic mice [63]. Lurbinectedin is developed by PharmaMar, and is currently in phase II clinical studies to treat patients with solid tumors, such as ovarian, breast and lung cancer [64, 65].

Glembatumumab Vedotin

Glembatumumab vedotin (CDX-011) is a human monoclonal ADC targeting cancer cells expressing glycoprotein nonmetastatic B (GPNMB), a protein overexpressed by several tumors, such as melanoma and breast cancer [66-68]. The complex GPNMB-targeting antibody (CR011) is attached to a cytotoxic MMAE. After the internalization into a GPNMB-expressing tumor cell, glembatumumab vedotin breaks the linkage and MMAE is released, killing cancer cells [69]. Preclinical in vitro tests showed anticancer activity, killing melanoma and breast cancer cells expressing GPNMB. In vivo studies revealed regression of tumors expressing GPNMB [70]. Currently, glembatumumab vedotin is in phase II trials to treat patients with locally advanced or metastatic breast cancer, with an initial focus in triple negative disease. This investigation is also in progress for the treatment of melanoma [71, 72]. CDX-011 is being developed by Celldex Therapeutics.

PM00104

PM00104 (17) with a trade name Zalypsis® is a synthetic tetrahydroisoquinolone alkaloid associated to jorumycin obtained from the mucus and skin of the Pacific nudibranch Joruna funebris and renieramiycins usually found in sponges and tunicates [73].

PM00104 binds to DNA, triggering transcription and cell cycle inhibition, leading to DNA double helix breaks, cell cycle stop in the S-phase and cell death by apoptosis [73, 74]. Preclinical in vivo studies revealed encouraging results in colon, renal, prostate and breast cancer [75, 76]. Currently in phase II trials, Zalypsis® is a potential chemotherapeutic drug to treat patients with hematological malignancies and solid human tumors [77, 78]. Zalypsis® is investigated by Pharmamar.

PSMA-ADC

PSMA-ADC is an ADC that consists of a human anti- prostate-specific membrane antigen (PSMA) monoclonal antibody conjugated to MMAE through a valine-citrulline linker. PSMA is overexpressed on most of the tumor cells in prostate cancer, as well as on blood vessels supplying other solid tumors [79, 80]. The monoclonal antibody conjugate of the PSMA-ADC selectively binds PSMA. PSMA-ADC is devised to be stable in the bloodstream and only release the potent cytotoxic chemical MMAE once inside targeted tumor cells, disrupting the microtubule filaments causing cell cycle arrest and apoptosis [81]. Preclinical studies demonstrated anti-cancer activity in prostate tumor cells and in xenografts models [82]. PSMA-ADC is presently in phase II trials to treat patients with prostate cancer and is investigated by Progenics Pharmaceuticals [83].

Marine Compounds: Phase I/II Trials

DNIB0600A

DNIB0600A is an ADC comprising a humanized IgG1 anti-NaPi2b monoclonal antibody linked to an anti-mitotic agent MMAE that showed anti-proliferative activity in xenograft models. Information on the linkage method is scarce, however, NaPi2b is a multi-transmembrane, sodium-dependent phosphate transporter that is expressed in human lung, ovarian, and thyroid cancers [8, 84]. DNIB0600A is currently in phase I/II clinical trials against non-small cell lung cancer and platinum resistant ovarian cancer according to the NIH database and is studied by Genentech/Roche [83].

Pinatuzumam Vedotin

Pinatuzumab vedotin (DCDT-2980S) is an ADC, composed of a monoclonal IgG1 antibody targeting CD22, a human B-lymphocyte antigen, linked to an anti-mitotic agent MMAE via a protease-cleavable