West Coast Editor

Roche's loss became Novartis' gain - maybe - in the increasingly competitive cancer space occupied by vascular disrupting agents (VDAs), where Antisoma plc holds a strong position.

Less than a year after losing partner F. Hoffman-La Roche Inc. for AS1404, Antisoma is getting $75 million up front in a licensing deal with Novartis AG and $25 million more when Phase III lung cancer trials with the VDA start early next year.

Antisoma's shares (LSE:ASM) rose £4.75 (US$9.50) Thursday, or 9 percent, to close at £57.25.

Longtime partner Roche, of Basel, Switzerland, declined to take AS1404 into Phase III trials and cited "commercial reasons" - most likely referring to the 2011 expiration tag on the compound's composition-of-matter patent in the U.S. - and London-based Antisoma promised an "eye-watering" deal for the compound on the way in December, when the firm had less than six months of operating cash.

The deal has arrived. Novartis, also of Basel, could provide as much as $890 million in milestone payments, along with royalties, and will fund all future development as well as Phase II trials now under way.

Antisoma retains right to co-commercialize the flavonoid AS1404, which "has been bumped around a little bit," and could be hampered by the patent expiry, noted Kobi Sethna, president and CEO of San Diego-based Nereus Pharmaceuticals Inc., an earlier-stage VDA player.

Nereus has NPI-2358, one of about 200 synthetic analogues made after finding the activity and novel chemistry from a marine fungal extract. A Phase I trial against solid tumors launched last summer. "The patent life on our compound is just starting," Sethna said.

Plans for Antisoma's AS1404 include the Phase III study in squamous non-small-cell lung cancer, and supporting studies in lung and other cancers. If Phase II data merit, the compound will move into Phase III trials in prostate and ovarian tumors, too.

Unlike anti-angiogenesis drugs, which block formation of tumor blood vessels, VDAs target vessels already established, causing endothelial cells to collapse.

"The tumor is eaten away, from the inside out," Sethna said, adding that VDAs have been around for "quite a long time. The first generation came on the scene maybe 12 or 15 years ago, but they had some liabilities, in terms of fairly significant cardiotoxicity. For a fair amount of years, these drugs were not looked on favorably." London-based AstraZeneca plc discontinued work on its VDA known as ZD6126.

Second- and third-generation products look much better than first versions, Sethna said, and "the Antisoma compound is reasonably clean." Nereus' drug, at least in preclinical work, appears safe for the heart as well as the central nervous system, he said.

"Our compound is slightly different, inasmuch as - based on preclinical data - we see dual action," Sethna told BioWorld Today. "It not only disrupts tumor blood flow but seems to have a direct effect on tumor cells. We've seen some single-agent activity in some models, as well as very good activity in combination [with chemo and/or radiation]." NPI-2358 also appears to boast a long duration of action as it disrupts blood flow, he said.

Others with VDAs in the works include Oxigene Inc., of Waltham, Mass., with CA4P (combretastatin A4 phosphate). Paris-based Sanofi-Aventis Group has the combretastatin derivative AVE8062 in Phase I trials, but Oxigene's compound is ahead, proving effective last year in Phase II trials against thyroid cancer, with chemo and without. In February, CA4P yielded positive Phase II data against myopic macular degeneration, and Oxigene likely will unveil full ophthalmic data during a scientific meeting in May.

Meanwhile, the firm is putting the final touches on a Phase III study with CA4P in anaplastic thyroid cancer, with first dosing expected in the second quarter of this year. The trial is likely to test CA4P when combined with chemo agents, as compared to chemo alone, in 100 to 200 patients.

Data from a Phase Ib trial with CA4P plus the approved VEGF inhibitor Avastin (bevacizumab), from South San Francisco-based Genentech Inc., should become known in the third quarter of this year, and positive results would lead to a Phase II study testing a quadruplet combo regimen against NSCLC in the second half. CA4P's Phase II ovarian cancer trial still is enrolling patients.

Also in the VDA pool is Myriad Genetics Inc., of Salt Lake City, which started the first Phase II trial with Azixa for brain cancer in March. Azixa, like Nereus' drug, is believed to work as a cytotoxin and VDA. The first stage of the Azixa study will include about 16 patients.

MediciNova Inc., of San Diego, has MN-029 ready to start Phase II/III studies in ovarian and NSCLC and are expected to start by the end of this year. The VDA came from Oxford, UK-based Angiogene Pharmaceuticals Ltd., which holds a worldwide license.

Abbott, of Abbott Park, Ill., has the sulfonamide ABT-751 in Phase II trials for lung, colon, breast and kidney cancers. "They don't call it by [the VDA] nomenclature, but that's how it works," Sethna said.

Adelaide, Australia-based Bionomics Ltd. is doing preclinical work with the VDA known as BNC105. "It's taken a long time for these drugs to be accepted, but this whole class is going to get a lot of recognition," Sethna said.