20,000 leagues for biotech to explore
A look at the marine bioprospecting pipeline.
The sea covers around 70% of the earth, and contains around 97% of the world's water. It's also home to almost 240,000 species (that have been identified so far), from mammals and fish, down to bacteria and viruses. However, as a resource, it is still untapped.
Bioprospecting is the discovery and development of new products based on resources from the natural world. Hundreds of plant-based gargles, pills, infusions and ointments date back to Ancient Egypt. Between 1981 and 2014, around two-thirds of the small molecule drugs approved by the Food and Drug Administration were derived from or inspired by natural sources, according to the Journal of Natural Products.
As William Fenical of the Scripps Institute of Oceanography said in an Interview in Nature, "We are not marine organisms, so until about 1970, no one even thought of the ocean. It was left as a deep secret. It seemed ridiculous to me that the ocean — with such a vast habitat — had escaped anyone's notice. But there are good reasons. People fear the ocean; it has been considered a very hostile, inhospitable place."
For these very reasons, the history of drugs from the sea isn't particularly long. Red algae have traditionally been used to make a treatment for colds, sore throats, chest infections including tuberculosis, kidney trouble, burns, cancer and indigestion.
Moving to modern medicine, in the 1950s, the cancer drug cytarabine (ara-C) was isolated from a Caribbean sponge, and launched by Upjohn (now Pfizer) in 1969. Vidarabine (ara-C) is an antiviral from the same sponge, launched as Vira-A in 1976. Cephalosporin C, isolated from fungi in Mediterranean Sea water, led to the widely used cephalosporin antibiotics.
The most recent marine-sourced drug to reach the market is Spanish company PharmaMar's Yondelis (trabectedin), launched in 2015. This cancer drug comes from an extract from a sea squirt, first found to have anticancer activity in the late 1960s.
There are plenty of high-profile drugs that have gotten their origins from the sea. Drugs launched between 2004 and 2011 include Seattle Genetics' Adcetris (brentuximab vedotin), a cancer drug from a mollusk; Eisai's Halaven (eribulin mesylate), a cancer drug from a sea sponge; GlaxoSmithKline's Lovaza, omega-3 fatty acids from fish; and Jazz Pharmaceuticals' Prialt (ziconotide), a pain drug derived from cone snail venom.
There are more than 25 marine-derived molecules in clinical trials, with over a thousand in pre-clinical development, explained Jeanette Hammer Andersen, professor in marine bioprospecting at UiT-The Arctic University of Norway, at at BIOPROSP_17, the 8th International Conference of Marine Biotechnology, held in Tromsø, Norway, in March 2017.
"There are still many societal challenges that the marine environment could help us to meet, such as antibiotic resistance," said Hammer Andersen. "It is a source of chemical diversity, with novel targets and novel modes of action."
A snapshot of late stage development:
PharmaMar is a Madrid, Spain-based company with a focus on anticancer drugs from marine sources. Its first drug onto the market was Yondelis. Plitidepsin and lurbinectedin, both derived from sea squirts, are partnered with Chugai.
The plitidepsin Phase 3 trial in combination with dexamethasone in multiple myeloma will read out in the second half of 2017, and Phase 2 trials are under way in T-cell lymphoma as a monotherapy and in multiple myeloma as part of a triple therapy. Lurbinectedin is being assessed as a single agent in platinum-resistant ovarian cancer, with a readout in the second half of 2017, and other clinical trials are under way in small cell lung cancer, breast cancer and solid tumors.
BeyondSpring is headquartered in the U.S., but carries out clinical trials in China, with the recruitment designed to support approval in both markets. Its lead molecule, linabulin, is based on a marine fungus, and is in a Phase 3 trial in non-small cell lung cancer in combination with docetaxel.
Interim results are expected in the first quarter of 2018. Linabulin is also in clinical development for the prevention of neutropenia in chemotherapy, and in non-small cell lung cancer in combination with Bristol-Myers Squibb's Opdivo (nivolumab). The company believes that the drug has potential in combination with checkpoint inhibitors, and in CNS cancers including metastatic brain tumors.
Squalamine, an agent found in dogfish shark tissues, has potential in a wide variety of indications, including as an antimicrobial against bacteria, fungi, protozoa and viruses, as well as in cancer, macular degeneration, diabetic retinopathy and fibrodysplasia ossificans progressive (also known as stone man syndrome).
Ohr Pharmaceutical has been developing squalamine in Phase 3 for the treatment of wet age-related macular degeneration, but has paused enrollment to evaluate efficacy. The company has said that it expects prospective efficacy data before the end of 2017.
The puffer fish is a bizarre creature, puffing itself out into a spiny globe when it feels threatened. It colonized by bacteria that produce the neurotoxin tetrodotoxin, making it the second most poisonous vertebrate in the world. Wex Pharmaceuticals is developing Halneuron (tetrodotoxin) as a non-addictive and rapid-acting pain killer without opioid-like side effects based on the puffer fish toxin. It is in Phase 3 for cancer-related pain and in Phase 2 for chemotherapy-induced neuropathic pain.
Follow Suzanne Elvidge on Twitter