5-fluorouracil, or 5-FU, is one of the world’s most widely-used anti-cancer 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 and reducing the debilitating side effects.
While 5-FU is a current mainstay of contemporary oncology treatment, it has some therapeutic drawbacks and limitations:
is given by vein (intravenously) and often by prolonged, multi-day infusions.
produces highly variable blood levels in patients. Low levels can reduce its effectiveness and high levels can increase its side effects.
is broken down (catabolized) to form α-fluoro-β-alanine (F-BAL). This compound appears to cause neurotoxicity and “hand-foot syndrome” which are debilitating and dose-limiting side effects of 5-FU therapy. Importantly, F‑BAL also decreases the antitumor activity of 5‑FU in lab animals.
Eniluracil: Mechanism of Action
By inactivating DPD, eniluracil prevents the breakdown of 5-FU to F-BAL. Eniluracil also greatly prolongs exposure of the tumor cells to 5‑FU.
When eniluracil is properly used in combination with 5-FU, it resolves many of the therapeutic drawbacks and limitations of 5-FU noted above.
For instance, eniluracil:
enables 5‑FU to be dosed orally
converts highly variable blood levels of 5‑FU to highly consistent and predictable levels
extends the elimination half‑life of 5‑FU from about 10 minutes to about 5 hours
prevents the formation of F-BAL, which is the apparent causative agent for hand-foot syndrome and for 5‑FU-induced neurotoxicity. F‑Bal also decreases the antitumor efficacy of 5‑FU in lab animals.
Thus, eniluracil has the potential to make 5-FU more effective and better tolerated.
Eniluracil: Clinical Development
Eniluracil plus 5‑FU was previously being developed by GlaxoSmithKline (GSK). Although the therapy was successful in Phase I and Phase II clinical trials, it tended to produce less antitumor activity than the control therapy in two Phase III trials. Development was subsequently stopped.
Since then, Adherex has learned that with the dose and schedule used in the previous GSK Phase III trials may not have been optimal. Preclinical studies have shown that when eniluracil is present in high ratios to 5‑FU, it decreases the antitumor activity. In the Phase III trials, the ratio of eniluracil to 5‑FU was 10 to 1.
Currently, Adherex has relied on Dr. Spector's 20 years experiencee with eniluracil to create a revised protocol designed to avoid the problems of the earlier GSK Phase III trials as well as those encountered in Adherex's more recent trials. Adherex is considering disease targets and trial designs.
Eniluracil: Market Opportunity
Xeloda®, a currently available oral 5-FU prodrug, has worldwide sales of over US$1 billion each year. Eniluracil + 5-FU/leucovorin 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.