View Product Demo  To learn how CoFactor works to improve the performance of the drug 5-FU in the treatment of cancer patients, view the product demo. – View product demo [685 Kb, Flash file]

ANX-510 (COFACTOR)

Background and Opportunity
CoFactor is a folate-based biomodulator designed to replace leucovorin as the preferred method to enhance the activity and reduce associated toxicity of the widely used cancer chemotherapeutic agent 5-FU. Compared to leucovorin, CoFactor creates more stable binding between the active form of 5-FU and the target enzyme, thymidylate synthase, or TS. CoFactor bypasses the metabolic pathway required by leucovorin to deliver the active form of folate, potentially allowing 5-FU to work more effectively.

Inhibiting TS is a well-established and effective method of killing rapidly dividing cells, such as tumor cells. Inhibition of TS is most frequently accomplished through use of 5-FU, the metabolite of which binds to TS and disrupts cell replication. Binding between TS and the metabolite of 5-FU requires the action of a specific folate: 5,10-methylenetetrahydrofolate, or MTHF.

Currently, the source of MTHF in the clinical setting is leucovorin. Leucovorin effectiveness, however, may be limited because it undergoes as many as four metabolic conversions to become the active folate MTHF; that is, leucovorin is an indirect source of MTHF and often insufficient to achieve desired levels of TS inhibition in tumor cells. Even in high doses, leucovorin may not reach the desired concentration in the tumor tissue to be effective in helping 5-FU achieve its anti-tumor potential. We are developing CoFactor as a direct source of MTHF.

We believe that 5-FU/leucovorin will continue to form the backbone of chemotherapy in metastatic colorectal cancer. Although there are a number of drugs under development to treat colorectal cancer, most are additions to 5-FU/leucovorin-containing regimens. In 2005, global sales of leucovorin, including the single-isomer formulation of leucovorin, exceeded $500 million.

Clinical Development History
Based on encouraging data from a phase 1/2 clinical trial completed in 1997 and our own preclinical work:

• In July 2004, we initiated a 50-patient phase 2 clinical trial of CoFactor in first-line metastatic colorectal cancer, in which 5-FU was administered as a bolus;
• In May 2005, we initiated a 300-patient phase 2b clinical trial of CoFactor in first-line metastatic colorectal cancer, in which 5-FU was administered as an infusion;
• In June 2006, we initiated a 1,200-patient phase 3 clinical trial of CoFactor in first-line metastatic colorectal cancer, in which 5-FU was administered as a bolus; and
• In December 2006, we initiated a 31-patient phase 2 clinical trial of CoFactor in advanced breast cancer, in which 5-FU is administered as a bolus.

Throughout 2005, we announced the results of the 50-patient phase 2 clinical trial. Blinded third-party radiologists determined that 35% of patients receiving 5-FU/CoFactor achieved an objective response, the primary endpoint for the clinical trial, defined as a complete (100% regression of tumors) or partial (at least 50% regression of tumors) response lasting at least four weeks. Based on historical comparator data, objective response for patients with first-line metastatic colorectal cancer receiving 5-FU/leucovorin was 21%. In addition, in June 2006, we announced that longer-term follow-up evaluations suggested that patients who initiated treatment with 5-FU/CoFactor had similar long-term survival to patients who initiated treatment with oxaliplatin- or irinotecan-containing regimens and that 5-FU/CoFactor was a viable first-line treatment in a sequential treatment strategy.

Recent Developments and Future Plans
In October 2007, we announced results from our phase 2b clinical trial of CoFactor for the first-line treatment of metastatic colorectal cancer, in which 5-FU was administered as an infusion. The 5-FU/CoFactor arm did not demonstrate statistically significant improved safety in the trial's primary endpoint, a reduction in the proportion of patients reporting at least one hematological or gastrointestinal adverse event of grade 3 or greater. Additionally, no statistically significant differences between the arms were observed across overall safety and efficacy variables.

In November 2007, we announced that we discontinued enrolling patients in our phase 3 clinical trial of CoFactor for the first-line treatment of metastatic colorectal cancer. This decision followed advice we received from our data safety monitoring board, or DSMB, and analysis of the phase 2b clinical trial results. While the DSMB did not identify safety concerns with CoFactor, it recommended closure of the phase 3 clinical trial, citing a slow accrual rate due, in part, to current and projected treatment preferences for colorectal cancer. In addition, further analysis of the phase 2b clinical trial, in which 5-FU was administered by infusion, uncovered no significant differences between the study arms with regard to either efficacy or safety. At the time we discontinued the phase 3 clinical trial, 89 patients had been enrolled.

We anticipate announcing three sets of CoFactor clinical data in mid-2008:

• Results relating to the primary endpoint in our phase 2 clinical trial of CoFactor in advanced breast cancer, in which 5-FU was administered as a bolus;
• Results relating to overall survival in our phase 2b clinical trial of CoFactor in first-line metastatic colorectal cancer, in which 5-FU was administered by infusion; and
• Available data from our discontinued phase 3 clinical trial of CoFactor in first-line metastatic colorectal cancer, in which 5-FU was administered as a bolus.

Following analysis of the three sets of CoFactor data we expect in mid-2008, we expect to have greater insight into the value of developing CoFactor independently in particular indications and cancer stages. We will assess development plans for our CoFactor program following this analysis. We continue to believe that CoFactor may improve 5-FU-based chemotherapy in which 5-FU is administered as a bolus and, using the right administration methods, that CoFactor remains a viable product candidate.

• Click here for more information on our clinical and regulatory strategy for ANX-530
• Click here for more information on our commercialization strategy for ANX-530