The first clinical trial to directly compare Adventrx Pharmaceuticals Inc.'s CoFactor (ANX-510) to leucovorin missed its primary endpoint of reducing serious hematological or gastrointestinal adverse events associated with the chemotherapy drug 5-fluorouracil (5-FU).

"We are, to say the least, disappointed," Adventrx CEO Evan Levine said during a conference call. Wall Street shared that disappointment, pushing the San Diego-based company's shares (AMEX:ANX) to a new 52-week low of 52 cents before closing Monday at 55 cents, down 79 percent, or $2.02.

The open-label Phase IIb clinical trial randomized 300 patients with metastatic colorectal cancer to receive first-line treatment with either CoFactor and 5-FU or leucovorin and 5-FU. Preliminary data showed that 23 of 147 patients on CoFactor/5-FU experienced a grade three or greater hematological or gastrointestinal adverse event, compared to 10 of 148 patients on leucovorin/5-FU (p<0.05).

Although the data seemed to indicate that CoFactor fared worse than its comparator, Adventrx's President and Chief Medical Officer James Merritt said the finding is "very unlikely" to be clinically significant and that, overall, the CoFactor arm showed comparable safety to the leucovorin arm.

Yet Adventrx had hoped for better. CoFactor is the active metabolite of leucovorin and is designed to enhance the efficacy and decrease the toxicity of 5-FU by allowing more stable binding to the drug's target enzyme. In a previous Phase II trial, metastatic colorectal cancer patients receiving CoFactor/5-FU experienced no grade 3 or 4 drug-related gastrointestinal or hematological toxicities.

Merritt pointed out that while the previous Phase II trial used bolus administration, the Phase IIb trial used intravenous administration, a difference he projected "will play a role in explaining the results." He also noted that the leucovorin arm of the trial showed lower-than-expected adverse events, which he said could be due to patient selection, patient management or underreporting of side effects.

Levine also looked on the bright side, pointing to "a few encouraging trends" in efficacy, namely a 6.3-month average progression-free survival and 14.7-month preliminary median survival in the CoFactor arm, compared to 6.1 months and 14.3 months, respectively, in the leucovorin arm.

Analysts were less optimistic. Jason Kantor, an analyst with RBC Capital Markets, said the Phase IIb trial "disproves the hypothesis of improved safety." Brian Lian, an analyst with CIBC World Markets Corp., agreed, adding that the trial "appears to show CoFactor is very similar if not slightly worse" than leucovorin.

As of now, Adventrx is moving forward with two ongoing CoFactor trials: a Phase II trial with 5-FU in breast cancer and a Phase III trial with 5-FU and Avastin (bevacizumab, Genentech Inc.) in metastatic colorectal cancer. Both trials use bolus administration. Merritt said the breast cancer trial will complete enrollment this year and produce data in the second half of 2008, while Levine said Adventrx needs to talk to its data safety monitoring board and potential partners about the next steps for the Phase III trial.

Neither Kantor nor Lian held out much hope for the Phase III trial.

"One of the problems with this clinical development program is you have four different studies, none using the same regimen in the same tumor type, so you could argue that none are predictive" of the others, Kantor said. Even so, there are "not a lot of good reasons" to assume the Phase III trial will be successful, he said.

Lian said his team conducted an exhaustive study of the historical data available for leucovorin, and while the Phase II CoFactor data trended toward the high end of leucovorin's data, it would be "very difficult to say the data for CoFactor are meaningfully better." He added that "given the difficulty in really seeing CoFactor's advantages, and today's data, it's tough to rationalize why you'd continue the Phase III."

Beyond CoFactor, Levine said Adventrx will focus on its pipeline of cancer and infectious disease drugs, particularly ANX-530 and ANX-514.

ANX-530 is an emulsion of the chemotherapy drug Navelbine (vinorelbine, GlaxoSmithKline plc) and is undergoing a clinical trial designed to support approval under the 505(b)(2) pathway. Data are expected next month, and a new drug application filing could follow in 2008.

ANX-514 is an emulsion of the chemotherapy drug Taxotere (docetaxel, Sanofi-Aventis Group) and is slated to begin a bioequivalence study designed to support approval under the 505(b)(2) pathway later this year.

Both Kantor and Lian remained cautious about the prospects of ANX-530 and ANX-514, noting that vinorelbine is not a large market and that investors remain cautious about reformulated taxanes due to recent setbacks such as Sonus Pharmaceuticals Inc.'s Phase III failure with Tocosol Paclitaxel. (See BioWorld Today, Sept. 25, 2007.)