Washington Editor

The FDA rejected Pharmacyclics Inc.'s new drug application for Xcytrin (motexafin gadolinium), essentially telling the company that the data underlying the submission were insufficient for review despite prior feedback to the contrary.

As a result, its shares (NASDAQ:PCYC) tumbled by 36.7 percent on Wednesday, falling $1.85 to $3.19 on far heavier than usual volume.

Explaining the agency's decision, Pharmacyclics President and CEO Richard Miller said on a conference call that the "refuse-to-file letter" was based on the "failure of our trials to demonstrate statistically significant differences between treatment arms in the prespecified endpoints." The Sunnyvale, Calif.-based company filed at the end of last year to market Xcytrin for brain metastases due to non-small-cell lung cancer. (See BioWorld Today, Dec. 26, 2006.)

Its NDA followed primary endpoint misses in two Phase III trials, but Miller said those data, which "produced a significant magnitude of benefit," prompted FDA staffers to give the company the green light to file, based on previous "high-level discussions" with the agency. But clearly that blessing proved untimely.

"Unfortunately at this time," Miller said, "that evidence was not persuasive enough."

In the most recent of the studies, patients treated with both Xcytrin and whole-brain radiation therapy had a median time to neurologic progression of 15.4 months compared to 10 months for those treated with whole-brain radiation therapy alone (p=0.122). In the previous trial, median survival was 5.2 months for all patients treated with Xcytrin plus radiation therapy compared to 4.9 months for those who received just radiation. Xcytrin plus radiation patients had a median time to neurologic progression of 9.5 months compared to 8.3 months for those on radiation alone. (See BioWorld Today, Dec. 17, 2001, and Dec. 20, 2005.)

Pharmacyclics developed the use of time to neurologic progression as the studies' endpoint, in consultation with the FDA, explained Leiv Lea, the company's chief financial officer. "Since patients don't live that long" with brain metastases, he told BioWorld Today, it's important "to control the tumor in their brain." This is determined clinically by assessing functional abilities, both mental and physical, such as balance, speech, visual problems, paralysis, mental status and memory.

Miller said it was too early to determine whether Pharmacyclics would conduct any further studies in brain metastases, an area of limited research activity. He also said it was premature to predict the impact of the FDA's decision on partnering plans for Xcytrin.

"We will be evaluating our options" in this indication, Miller said, to "determine the best path forward."

The company owns worldwide rights to the redox-active drug, which is designed to concentrate in tumors and induce apoptosis by inhibiting the enzyme thioredoxin reductase. Additional work has tested its use in treating brain metastases with radiosurgery and lymphoma.

Xcytrin continues to be studied in three Phase II trials for the second-line, systemic treatment of lung cancer, two in combination with chemotherapy and another as a single agent. Lea said lung cancer activity observed during the brain metastases trials led the company down that path. Data on typical tumor progression endpoints should come out at forthcoming scientific conferences throughout the year.

More than 170,000 patients will be diagnosed with lung cancer this year in the U.S., and the disease is the most common cause of brain metastases, which are estimated to occur in up to half of lung cancer patients.

Pharmacyclics had $50.3 million in cash reserves as of Dec. 31.