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Clavis, Clovis Shares Plunge on CO-101 Pancreatic Cancer Miss

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By Cormac Sheridan
Staff Writer

Shares in Clavis Pharma ASA (OSLO:CLAVIS) plummeted by more than 87 percent Monday following the failure of CO-101 (CP-4126) to demonstrate any impact on survival in a pivotal Phase II trial in metastatic pancreatic cancer.

Its development partner, Clovis Oncology Inc., saw its shares (NASDAQ:CLVS) drop by 41.8 percent, $8.99, Monday to close at $12.50 in trading volume that was 42 times the average. Clovis is terminating all CO-101 development activity.

CO-101 is a modified version of the nucleoside analogue gemcitabine, the standard treatment for pancreatic cancer. The addition of an elaidic acid lipid tail enables it to enter cells via passive diffusion instead of a transporter protein, called human equilibrative nucleoside transporter-1 (hENT1), which normally is required for gemcitabine transport and which is expressed at low levels in many pancreatic cancer patients.

The rationale underpinning the therapy was that the improved uptake and retention characteristics of CO-101 would translate into a survival benefit. However, there was no difference in survival between patients who received CO-101 and those who received gemcitabine. Each had a median survival of six months, regardless of their hENT1 status.

"Six months is kind of what you would expect with gemcitabine. We obviously expected CP-4126 to do better. We also expected gemcitabine to do worse in the low hENT1 population," Olav Hellebo, CEO of Oslo, Norway-based Clavis Pharma said at a press conference in Oslo.

"To our astonishment, this was even more unambiguous than we could have imagined. The two drugs behave exactly the same," Clovis CEO and President John Mahaffy, said on a Clovis conference call.

The negative hENT1 finding contradicted several retrospective studies, which had found a correlation between hENT1 status and response to gemcitabine. Mahaffy said the company was "completely perplexed" at the finding. "The hENT1 hypothesis appears irrelevant to outcome. We have nothing to hang our hat on."

"We thought the outcome could go either way heading into the data – 55 percent probability in our model – as this Phase II trial was essentially a proof-of-concept experiment wrapped inside of a pivotal study, and unfortunately the concept didn't pan out," JP Morgan analyst Cory Kasimov wrote in a research note.

All development of the drug has now been terminated, including an early stage program in lung cancer. The two companies will perform additional data analyses on the present study, and they will publish their findings.

Clovis, of Boulder, Colo., originally licensed U.S. and European rights to CO-101 from Clavis in a deal worth up to $380 million, plus royalties. The alliance was later expanded to include Asia, with another $205 million on the table. Both deals were strongly back-end loaded, however, with most of the available milestones tied to sales. Clavis received $25 million in two up-front payments from Clovis. (See BioWorld International, Nov. 25, 2009, and Nov. 17, 2010.)

In contrast, Summit, N.J.-based Celegene Corp. said Friday that a combination of Abraxane (paclitaxel protein-bound particles for injectable suspension) and gemcitabine met the primary overall survival endpoint of a Phase III trial in treatment-naive patients with advanced pancreatic cancer. Full data will be disclosed in January, but the company now plans to file for approval in both the U.S. and Europe. (See article, p. 1.)

Threshold Pharmaceuticals Inc., of South San Francisco, and Darmstadt, Germany-based Merck KGaA plan to move TH-302 into a Phase III trial in pancreatic cancer, after seeing an overall survival benefit of two months in a recent Phase IIb trial, in which a combination of TH-302 and gemcitabine was compared with gemcitabine alone. (See BioWorld Insight, Oct. 8, 2012.)

Clavis is now focusing on another modified nucleoside drug, elacytarabine, which is undergoing a Phase III trial in study in patients with acute myeloid leukemia (AML) who have failed prior therapy. "We're getting very close to the end of enrollment," Hellebo said. "We expect to have the result late in the first quarter of 2013."

Elacytarabine, like CP-4126, also contains a hydrophobic elaidic acid moiety and is designed to bypass resistance mechanism associated with low hENT1 expression. It has already demonstrated some degree of efficacy. In a Phase II trial in 61 patients with advanced acute myeloid leukemia, those on elacytarabine had an 18 percent remission rate, vs. 4 percent for matched historical controls, and those on the drug had a median overall survival of 5.3 months vs. 1.5 months for matched historical controls. A combination study with idarubicin also demonstrated promising interim data in early stage patients who had failed first-line therapy.

"We still believe in elacytarabine," Hellebo said. "I can see from the marketplace that there is not that much belief out there."

By mid-afternoon, shares in Clavis (OSLO:CLAVIS) were changing hands at NOK9.20 ($1.60), down 86 percent from Friday's close of NOK66. At that price, the company is valued at NOK305.15, barely above the NOK260.4 million in cash it reported at Sept. 30.

Clavis closed Monday at NOK8 (US$1.10), down from Friday's close of NOK66. The company said it had NOK260.4 million in cash on Sept. 30.