June 15, 2007 (Vol. 27, No. 12)
Actinomycetes and Fungi Are Collected from Plants, Sediment, and Silt
April was a very good month for Nereus Pharmaceuticals (www.nereuspharm.com). In collaboration with the Multiple Myeloma Research Consortium, the company enrolled the first patient in a multicenter Phase I trial of NPI-0052, its drug candidate for multiple myeloma. Also, at the AACR meeting, Nereus scientists and collaborators presented six posters and participated in two mini-symposia about the firm’s oncology drugs. “This shows our drugs are progressing and we are moving into new areas of potential use,” says Kobi M. Sethna, president and CEO.
Nereus mines microorganisms collected from the ocean to find new small molecule drug candidates, much like older pharmaceutical companies discovered new drugs by screening soil. Sethna and Stan Fleming of Forward Ventures co-founded the company in 1998, along with William Fenical, Ph.D., a pioneer of marine microbiology at the Scripps Institute of Oceanography, and Michael Palladino, Ph.D., now senior vp and CTO.
Today, Nereus has two anticancer candidates derived from marine microbes in three Phase I studies. NPI-2358 is a potent and selective vascular disrupting agent that is being evaluated on solid tumors and lymphomas. NPI-0052 is a highly potent proteasome inhibitor that is targeted against solid tumors, lymphomas, and multiple myeloma. Both are “potential best-in-class drugs if they prove themselves clinically,” says Sethna.
Nereus licensed methods from the University of California, San Diego to harvest and grow microbes collected from ocean plants, sediment, and silt. Marine microbes require different conditions and nutrients than their land-loving relatives.
“We took the academic discoveries and industrialized them to pharmaceutical standards to find new drug entities on a consistent level,” says Sethna. The company concentrated on actinomycetes and fungi, known for providing a rich supply of drugs from terrestrial sources. Nereus screens these two classes of microbes for anticancer and anti-infective activity, two therapeutic classes that predominate in products from natural sources.
Nereus scientists discovered on average two novel chemical structures with biological activity each month. “The diversity we see in marine microbes is even better than what was discovered in terrestrial microbes by pharma for over 40 years,” Sethna reports. In 2004, Nereus stopped collecting new samples and screening them and switched its focus to drug development and clinical trials. “In a small biotech company, the key to success is focus,” Sethna notes.
Marine-based Oncology Drugs
NPI-2358 is one of 200 synthetic analogues made from the parent compound halimide isolated from a marine fungus (Aspergillus) that grows on sea grass. A Phase I trial of patients with advanced solid tumors started in June 2006, and the drug is advancing through dose-escalation protocols. In preclinical models of breast, sarcoma, colon, and prostate cancer, NPI-2358 disrupts tumor blood vessels by interacting with microtubules, resulting in their rapid collapse in the center of tumors and tumor cell death. This mechanism of action targets only the vasculature of tumor cells but not healthy cells, thereby potentially reducing side effects of cardiotoxicity and neurotoxicity.
NPI-2358 also acts synergistically with other chemotherapeutic agents in animal models. In one study, the company reports that lung tumor growth was reduced 74% when treated with NPI-2358 in combination with taxotere, compared to 26% when taxotere was used alone.
Similar reductions in tumor growth are observed in animal models for colon cancer when NPI-2358 is added to irinotecan, for breast tumors in a paclitaxel combination, and for sarcomas when combined with radiation. Moreover, compared to other vascular disrupting drugs, NPI-2358 has a longer duration of action and inhibits multidrug-resistant tumor cells, according to the company.
For the proteasome inhibitor NPI-0052, Nereus uses the natural compound in the clinic. NPI-0052 comes from Salinispora tropica, a new marine actinomycete identified in sediment from the ocean floor. Nereus produces a supply of NPI-0052 through an industrial, scalable saline fermentation process.
Since Millennium Pharmaceutical’s (www.mlnm.com) Velcade® was approved to treat multiple myeloma and mantle cell lymphoma, pharmaceutical companies have intensified their search for other proteasome inhibitors. Nereus is conducting two Phase I trials of NPI-0052, one on patients with solid tumors and lymphomas and the other on patients with relapsed/refractory multiple myeloma. If the drug proves effective in treating diverse types of cancer, it will have broad commercial appeal.
“We see advantages of NPI-0052 over Velcade in preclinical studies,” comments Sethna, “that we hope will be realized in humans. For example, NPI-0052 is active against multiple myeloma cells taken from patients who have become resistant to Velcade, steroid therapy, thalidomide, and lenalidomide.”
The company reports that in preclinical settings, NPI-0052 inhibits three key protease functions, is less cytotoxic to normal cells, shows a faster onset of action, and is six times more potent than Velcade. In addition, the compound can be given once weekly and is active orally or intravenously.
Collaborators Add Value
Nereus has always been a small biotechnology firm with 30 to 40 scientists. “We chose from the beginning to keep the company small,” says Sethna. Much of the preclinical work on NPI-0052 and NPI-2358 was performed by collaborators at institutions. “The preclinical work is exquisite because it was conducted at international centers of excellence,” Sethna notes.
Consequently, more than 50 papers have been published in scientific journals about Nereus’ two lead compounds. “This gives us a tremendous springboard at meetings like the AACR,” says Sethna, as well as inroads into clinical trials. For instance, preclinical work being done on NPI-0052 at the Dana-Farber Cancer Institute caught the attention of the Multiple Myeloma Research Consortium, which coordinates trials at 13 member institutions to speed the development of drugs to treat multiple myeloma.
With two oncology drugs aimed at high-profile targets, “we have two shots on goal,” claims Sethna.