Ariad Pharmaceuticals Inc. changed the planned primary endpoint for an upcoming Phase III trial of its mTOR inhibitor in metastatic sarcomas.

The move came after discussions with the FDA, and could push back initiation of the study of AP32573 from this quarter to the third quarter. The company in February filed for a special protocol assessment for the study, and disclosed trial plans that would have evaluated progression-free survival as the primary endpoint.

But after the meeting with the FDA, the trial's primary endpoint was established as overall survival. Progression-free survival, which Ariad demonstrated in a 212-patient Phase II trial last year, will be a secondary endpoint.

Harvey Berger, chairman and CEO of Ariad, told BioWorld Today the endpoint change will cause a slight delay due to logistical matters, such as redoing various documentation. He said Ariad also is waiting to finalize plans with the European Medicines Agency, so all input from the EMEA and FDA can be incorporated into the study protocol.

"Given those facts, we can't be sure we'll begin enrollment in the second quarter," Berger said.

He said endpoint change is "very consistent with the guidance the FDA has given many companies for many classes of products." An example of that, he said, is the Phase III trial of Nexavar from Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp.

Onyx and Bayer reported in February that their 500-patient study in advanced liver cancer showed a statistically significant overall survival benefit.

Ariad's study also is expected to include 500 patients. The trial will include metastatic soft-tissue and bone sarcoma patients who have favorably responded to first- or second-line chemotherapy. AP32573 or placebo would be administered following the favorable responses, a period when the standard of care is no treatment. That is why placebo ethically can be given in that setting, Berger said.

Ariad said in February the study would be conducted by the Sarcoma Alliance for Research through Collaboration in cooperation with the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer. It previously said enrollment was expected to take two years.

Proving survival benefit would be expected to take longer than providing endpoints related to disease progression. Berger said, however, there is a correlation between the two, that improved progression-free survival is indicative of extended survival.

Berger said Ariad is talking to potential partners and expects to complete a deal this quarter. "The partnership will be largely an ex-U.S. partnership, with Ariad maintaining a major role in commercialization in the U.S," he said.

AP23573 is a small-molecule inhibitor of the protein mTOR, which Ariad called a "master switch" in cancer cells. Blocking mTOR, it said, creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism and angiogenesis. The compound is in earlier-stage trials in patients with solid tumors and hematologic cancers. The FDA has granted AP23573 both fast-track and orphan status, while the EMEA also designated it an orphan product. Berger said Ariad plans to present data at upcoming oncology meetings that will provide "greater insight into the drug in various indications, both alone and in combination" therapies.

Separately, Ariad expects to move its second product, AP24534, into the clinic in the second half of this year, Berger said. AP24534 is a Bcr-Abl kinase inhibitor that has shown broad activity against the common mutant forms of Bcr-Abl, including the T315I mutant, as well as the unmutated form of that oncogenic enzyme, Ariad said. Initial studies are planned in drug-resistant chronic myeloid leukemia.

Ariad on Dec. 31 reported a cash position of $39.8 million, with a net loss of about $62 million in 2006. Since then, Ariad entered an equity financing commitment with Azimuth Opportunity Ltd., under which Azimuth is obligated to purchase up to $50 million of registered Ariad stock over 18 months. The deal calls for Azimuth to pay a discount of 3.5 percent to 5.5 percent to a recent average price at the time of the drawdown.

Ariad drew down about $12.5 million from that line in March, selling Azimuth 3.07 million shares (a per-share price of about $4.07). Ariad, which controls the timing and amount of any drawdown, also would be expected to bring in funding through the anticipated AP23573 collaboration.

Ariad had about 68.6 million shares outstanding following the Azimuth investment. Its stock (NASDAQ:ACAD) gained 39 cents Thursday, or 8.6 percent, to close at $4.94. The markets were closed Friday.