CAPE-127 has its clinical target validated by multiple marketed drugs. 5FdUMP and FUTP are active metabolites of other FDA-approved, fluoropyrimidine anti-neoplastic drugs, 5-fluorouracil (5-FU) and the orally administered capecitabine (Xeloda®, Genentech), and three other anticancer prodrugs marketed internationally, doxifluridine, floxuridine, and Tegafur. 5-FU was discovered in 1955 for its anticancer activity based on higher extraction of radioactive uracil by liver tumor cells and is still used today as a popular chemo IV drug for many types of solid tumors including in local therapies for liver cancer. However, none of the prodrugs are approved for liver cancer as a systemic agent in US or effective to treat liver cancer due to lack of sufficient liver exposure and liver selectivity.

Scientific Rationale and Competitive Advantage

CAPE-127 is the first-in-class oral agent with novel prodrug technology to deliver 5FdUMP to the liver in high efficiency and selectivity, which has not been achieved with other prodrug technologies. The liver-targeting capability of CAPE-127 is based on a chemical modification of 5FdUMP into an inactive orally available prodrug form that is activated enzymatically in the liver to release 5FdUMP, avoiding the formation of 5-FU and other fluoropyrimidine metabolites. By targeting the release of 5FdUMP to the liver, it is expected that CAPE-127 will reduce systemic exposure of toxic fluoropyrimidine metabolites compared to 5-FU, FUDR and capecitabine and minimize gastrointestinal (GI), bone marrow and mucosal toxicity. CAPE-127 is rapidly absorbed orally and efficiently activated to 5FdUMP upon first-pass metabolism. This leads to high 5FdUMP concentrations in the liver, and possibly primary and metastatic liver tumor cells, and low levels of fluoropyrimidine metabolites in the systemic circulation and off-target tissues and organs. The expected differential delivery of 5FdUMP, as an equivalent of non-invasive local therapy, will allow optimization of antitumor efficacy and improvement in safety, and provide a new approach to meet the unmet needs in liver cancer treatment.

Preclinical data demonstrated superior liver targeting of CAPE-127 over NUC-3373, a phosphoramidate (ProTide) prodrug of 5-FU (Nucana, Edinburgh, UK), and capecitabine. The potential therapeutic advantage of CAPE-127 includes a much greater amount of 5FdUMP in liver and higher liver targeting ratio (5FdUMPliver/FUDRblood) than NUC-3373 and capecitabine in the rat model. Furthermore, conversion of CAPE-127 to 5FdUMP occurs selectively in the liver compared to kidney and colon (see below).

The liver-targeting profile of CAPE-127 was verified in two high species, dogs and monkey and the study results are shown below. It was found that the liver selectivities of CAPE-127 in dogs and monkeys were higher than in rats.

Unique Clinical Opportunities

CAPE-127 is approved by FDA to enter phase 1 clinical trials in cancer patients after completion of all required preclinical studies. The lead indication is planned for liver metastasis in colorectal cancer followed by expansion to liver mets from other solid tumors. An estimated more than 30K patients in the US annually present with colorectal cancer (CRC) with liver metastasis (~65% of all CRC patients) and have less favorable response to many therapeutic interventions. Treatment options for liver mets specifically are severely limited. Many patients were precluded from being treated with novel therapeutics such as the immuno-oncology antibody agents due to a poor prognosis. Hepatic metastases are estimated to cause 50% of death attributed to CRC. The expected differential delivery of 5FdUMP to the liver, as an equivalent of non-invasive local therapy, presents unique opportunities to meet the unmet needs in liver cancer treatment.