Editor

Though more than 10 years old, the concept of "disruptive technology" holds strong appeal, and in biotech vascular disrupting agents (VDAs) occupy a rising-star approach first discovered even longer ago.

Last month's licensing deal, which gives Antisoma plc $75 million up front from Novartis AG for rights to AS1404 and $25 million more when Phase II lung-cancer trials with the compound start early next year, brought fresh attention to the VDA space - and a renewed licking of chops by investors.

Antisoma's backers might have felt disillusioned less than a year ago, when longtime partner F. Hoffmann-LaRoche Inc. bowed out of its plan to usher AS1404 into Phase III trial, blaming "commercial reasons" for the move. (The composition-of-matter patent for AS1404 expires in 2011.) But Antisoma promised a juicy deal on the way, and Novartis stepped up.

The deal could provide as much as $890 million in milestone payments to Antisoma plus royalties, and Novartis will fund all future development as well as Phase II trials now under way.

Included in the milestone payments are approvals in four oncology indications. Novartis has shown its marketing muscle through Gleevec (imatinib), its compound for chronic myeloid leukemia. Also in the milestones package is an undisclosed non-oncology condition, most likely in ophthalmology, as Novartis outside the U.S. markets Lucentis (ranibizumab), Genentech Inc.'s therapy for age-related macular degeneration, and VDAs are being actively explored in that disease. Antisoma is retaining rights to co-commercialize the flavonoid AS1404.

Plans for the compound entail the Phase III study in front-line, squamous non-small cell lung cancer and supporting studies in lung and other cancers. The NSCLC bid goes after the sector of the market not covered by the label for the VEGF inhibitor Avastin (bevacizumab), from Genentech Inc., cleared for NSCLC in the fall of last year. If AS1404's Phase II data merit, the compound will move into Phase III trials in prostate and ovarian tumors as well.

VDAs might be regarded as the (so far) quieter counterpart to headline-making anti-angiogenesis drugs. Whereas the latter block formation of tumor blood vessels, VDAs target vessels already established, collapsing the endothelial cells in place.

Kobi Sethna, president and CEO of the much earlier-stage VDA player Nereus Pharmaceuticals Inc. likened the scans of VDA-attacked tumors to "donut holes," and told BioWorld Financial Watch that cardiotoxicity hampered the first generation VDAs' ability to chew tumors from within. AstraZeneca plc, for example, discontinued work on its VDA known as ZD6126.

The picture has changed in recent years. AS1404's profile looks clean, as does the profile for NPI-2358, one of about 200 synthetic analogues made by Nereus from a marine fungal extract. A Phase I trial against solid tumors launched last summer.

Antisoma is doing well. Behind AS1404 is a novel aptamer dubbed AS1411, seized in the early 2005 buyout of Aptamera Inc. in an all-share deal that valued the privately held firm at £11.5 million (then US$21.5 million). Early data suggest activity in renal cancer and acute myeloid leukemia. Phase II trials are expected to start late this year and early next. UK-based Antisoma ended the second half of this year with about £33.6 million (US$67 million) in cash and equivalents, not counting the upfront payment from Novartis, with a loss for the period of £6.4 million.

Others with VDAs include Myriad Genetics Inc., which started the first Phase II trial with its compound called Azixa for brain cancer in March. Like Nereus' drug, Azixa seems to work as a cytotoxin as well. The first stage of the Azixa study will include about 16 patients.

MediciNova Inc. has the VDA known as MN-029 ready to start Phase II/III studies in ovarian and NSCLC by the end of this year. The compound came from Angiogene Pharmaceuticals Ltd., which holds a worldwide license. Abbott also has a VDA, the sulfonamide ABT-751, in Phase II trials for lung, colon, breast and kidney cancers, and Bionomics Ltd. is doing preclinical work with the VDA tagged BNC105.

A higher-profile VDA force to reckon with is Oxigene Inc., which has CA4P (combretastatin A4 phosphate). The drug proved its mettle last year in Phase II trials against thyroid cancer, with chemotherapy and without. In February, CA4P yielded positive top-line Phase II data against myopic AMD, too. Full results were due for unveiling at the Association for Research In Vision and Ophthalmology meeting, which started over the weekend.

Oxigene is finalizing a Phase III study with CA4P in anaplastic thyroid cancer (ATC), with first dosing expected in the second quarter of this year. The firm is expected to test CA4P when combined with chemo agents, as compared to chemo alone, in 100 to 200 patients. After Avastin's clearance in NSCLC, Oxigene backed away from that indication as the first Phase III trial, and went with ATC instead.

Amgen Inc. is working in thyroid cancer, too - and during the conference call on first quarter earnings last month, officials said they had decided not to file for approval of AMG-706 for thyroid cancer after Phase II trial with the compound in about 180 patients with locally advanced or metastatic disease who are not candidates for radioactive iodine or local therapies.

ATC patients were left out of the Amgen study (expected to report data at the American Society of Clinical Oncology meeting in June) but some Oxigene/CA4P watchers might have taken pause when Amgen decided to wait on a filing for its drug, until the FDA offers more guidance about the regulatory path. Amgen's trial, though, was an open-label, single-arm study; Oxigene already is talking with the FDA about a randomized, controlled study.

Data from a Phase Ib trial with CA4P plus Avastin should become public in the third quarter of this year, though, and positive results would spur a Phase II study testing a quadruplet combination regimen against non-squamous NSCLC in the second half. CA4P's Phase II ovarian cancer trial is still enrolling patients. Sanofi-Aventis Group also has a combretastatin derivative, AVE8062, but it's lagging behind the Oxigene compound in Phase I trials.

While Novartis' interest in AS1404 could bring pharma sniffing around CA4P (which works by a different mechanism of action), Antisoma boasts the benefit of efficacy data from several randomized, controlled Phase II trials. Oxigene lacks randomized results with its compound, and likely will need more results before signing a partner. Either way, the Antisoma deal has drawn eyes to the space, which is likely to mature even more in the months ahead.

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