To give you a sense of the dire unmet medical need in pancreatic cancer, consider that Tarceva (used in combination with gemcitabine) received approval based on a median overall survival of only 12 days longer than gemcitabine alone. Even with Tarceva's approval, gemcitabine remains the backbone of pancreatic cancer treatment.
In November 2009, Clovis licensed rights to CO-101 (formerly known as CP-4126), a novel, lipid-conjugated form of gemcitabine, from Norway-based
(extra credit to anyone in the U.S. who had heard of Clavis before this deal; I hadn't).
In order to be effective, gemcitabine must first get into the cancer cell. To do so, gemcitabine relies on a protein known (mind-numbingly) as human Equilibrative Nucleoside Transporter 1, or hENT1. Unfortunately, research indicates that more than half of all pancreatic cancer patients have low levels of hENT1, which means gemcitabine provides little or no benefit.
Clovis says CO-101 is designed to enter pancreatic cancer cells independently of a patient's hENT1 status. Once inside the cell, CO-101 is converted to the active form of gemcitabine.
Results from Clovis' pivotal "LEAP" study in metastatic pancreatic cancer should be available by year-end. After a biopsy to establish hENT1 status (
has developed a companion diagnostic), 360 chemo-naive patients were randomized to receive either CO-101 or gemcitabine. If CO-101 demonstrates a survival benefit over gemcitabine in low hENT1 patients (the primary endpoint), Clovis executives believes the study will support regulatory filings in the U.S. and Europe.
I believe the hENT1 hypothesis. Clovis has a lot of supportive data -- at least five published studies -- that suggest gemcitabine-treated patients with low levels of hENT1 have shorter survival than those with normal or high hENT1 expression. I am also unconcerned by the decision to use metastatic biopsy sites, rather tissue from the more difficult-to-access pancreas, to assess hENT1 status. Previously collected data, admittedly from only a small group of patients, show perfect hENT1 correlation between primary and metastatic tumor tissue.
Finally, Clovis is employing a smart trial design with reasonable assumptions that will give a clear-cut answer to whether CO-101 works or not. The company has assumed CO-101 will nearly double survival compared to gemcitabine in hENT1 low patients, from 4 months to 7.7 months. These estimates are based on calculations made from survival data in the Gemzar/gemcitabine label, assuming half of all patients have low hENT1 (I checked the math; it works out). Obviously, this would be a highly meaningful benefit.