> Treatment resistance
> Debilitating side effects
Background
5-fluorouracil, or 5-FU, is one of the world’s most widely-used oncology agents. 5-FU is currently first or second line therapy for a variety of cancers, including colorectal, breast, gastric, head and neck, ovarian and basal cell cancer of the skin.
Eniluracil is an irreversible inhibitor of dihydropyrimidine dehydrogenase, or DPD, the enzyme primarily responsible for the rapid breakdown of 5-FU in the body. Eniluracil is being developed by Adherex to improve the therapeutic value of 5-FU by making it effective in cancers currently resistant to 5-FU and by reducing the debilitating side effects of 5-FU therapy.
While 5-FU is a current mainstay of contemporary oncology treatment, it has some therapeutic drawbacks and limitations:
· It has to be given by vein, or intravenously, and often by prolonged, multi-day infusions.
· Its use is typically associated with variable and unpredictable blood and tissue levels between patients. Low levels can reduce its effectiveness and high levels can increase the side effects.
· It can cause severe and often dose-limiting side effects. For example, a breakdown product of 5-FU is alpha-fluoro-beta-alanine, or F-BAL. This breakdown product is thought to be associated with neurotoxicity and “hand-foot syndrome,” which are debilitating and dose-limiting side effects of 5-FU therapy.
· Some tumors are naturally resistant to 5-FU due to intrinsically high DPD levels in the tumor cells. In other cases, the tumors can develop resistance to 5-FU as DPD levels rise following therapy.
Eniluracil: Mechanism of Action
Eniluracil irreversibly inhibits the activity of DPD, thereby substantially slowing the breakdown of 5-FU and prolonging exposure of the tumor cells to the drug.
When eniluracil is properly used in combination with 5-FU, it may resolve many of the therapeutic drawbacks and limitations of 5-FU noted above. For instance, we expect combining eniluracil and 5-FU will have the following benefits:
· 5-FU becomes orally active, eliminating the need for intravenous (IV) administration.
· The blood and tissue levels of 5-FU become more consistent, resulting in improved efficacy and reduced side effects.
· Elimination of F-BAL production may avoid the disabling side effect of “hand-foot syndrome.”
There is another important potential benefit of the combination of eniluracil and 5-FU: the combination may expand the range of cancers that currently respond to therapy with 5-FU. Some tumors are naturally resistant to 5-FU due to inherently high levels of DPD in the tumor cells. Eniluracil may eliminate these high levels of DPD activity in the tumor, thereby potentially expanding the use of 5-FU into broader cancer indications and areas of significant unmet need.
Thus, the use of eniluracil in combination with 5-FU has the potential to make 5-FU:
· more effective
· better tolerated, and
· available in an oral form, replacing the need for IV administration.
Eniluracil: Clinical Development
Eniluracil was previously under development by GlaxoSmithKline (GSK). GSK’s development program for the combination of eniluracil and 5-FU met with success in early development. However, three Phase III trials undertaken by GSK failed and development was stopped.
Since then, Adherex has generated preclinical and clinical data which provide a new understanding of the pharmacology of eniluracil – namely, that with the dose and schedule used in the previous GSK Phase III trials, eniluracil not only irreversibly inhibits the breakdown of 5-FU as expected, it also temporarily blocks the activation of 5-FU into the metabolites responsible for its anti-cancer activity. Thus, the 5-FU was not effective and the trials failed. Adherex has now identified three key factors that are necessary to optimize the combination of eniluracil and 5-FU:
1. use of an effective anti-cancer dose of 5-FU
2. use of a proper ratio of the eniluracil and 5-FU dosages
3. use of a proper schedule of administration for the two drugs.
Adherex's development plan for eniluracil is focused on two cancer opportunities where there is unmet need:
· Treatment resistance – expanding the use of 5-FU therapy to new indications
· Debilitating side effects – reducing the “hand-foot syndrome”.
Eniluracil and Liver Cancer
Eniluracil and Treatment-resistant Breast Cancer
Eniluracil: Current Clinical Trials
Adherex is currently studying the combination of eniluracil + 5-FU in a Phase I trial in patients with solid tumors to define the dose-limiting toxicities and maximum tolerated dose of weekly dosing of Adherex's proprietary combination. Following completion of this study, we plan to initiate a Phase II trial of the combination in taxane- and anthracycline-resistant breast cancer.
In September 2006, Adherex also launched a Phase I/II trial in liver cancer in Asia. Upon conclusion of the Phase I dose escalating portion of the study, we plan to immediately expand into the Phase II portion of that trial to establish both the safety of Adherex's proprietary dose and schedule for the combination in the Asian population and to provide initial efficacy information in liver cancer. At the end of 2006, we concluded a clinical proof-of-mechanism trial which confirmed that our intended schedule of administration of eniluracil in combination with 5-FU irreversibly blocked DPD as intended, but importantly, did not inhibit the activation of 5-FU into an effective anti-cancer agent, as we believe occurred in the previous GSK Phase III trials.
For additional information about Adherex's ongoing clinical trials of eniluracil, please visit www.clinicaltrials.gov.
Eniluracil: Market Opportunity
Xeloda®, or capecitabine, a currently available oral 5-FU prodrug, has worldwide sales of over US$1 billion each year. Eniluracil + 5-FU could not only compete with Xeloda® in its currently approved indications (with either a reduced toxicity profile, enhanced efficacy, or both) but also may open up new indications where 5-FU (and Xeloda®) is not currently used, expanding the reach of a drug that is already one of the world’s most widely used.
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