Washington Editor
The FDA told Pharmacyclics Inc. that Xcytrin (motexafin gadolinium) injection in combination with radiation was not approvable to treat patients with non-small-cell lung cancer (NSCLC) whose disease has spread to the brain.
News of the rejection, which came after trading ended Friday, sent shares of Pharmacyclics (NASDAQ:PCYC) tumbling 26 percent to close at $1.74 Monday. Shares fell another 14 cents Wednesday to close at $1.60.
It wasn't the first time Xcytrin met with a negative reception from the FDA. Regulators last February refused to file the Sunnyvale, Calif.-based firm's December 2006 new drug application (NDA) citing failure of Xcytrin in a Phase III study of 554 patients to demonstrate statistically significant differences between treatment arms in its primary endpoint of time to neurologic progression. (See BioWorld Today, Dec. 26, 2006, and Feb. 22, 2007.)
That trial, known as the Study of Neurologic Progression with Motexafin Gadolinium and Radiation Therapy, or SMART, showed that patients who received Xcytrin, a redox-active drug that has been shown to disrupt redox-dependent pathways in cells and inhibit oxidative stress-related proteins, in combination with whole-brain radiation therapy had a median time to neurological progression of 15.4 months compared with 10 months for patients who received radiation alone. However, the 5.4-month improvement in time to neurologic progression was not statistically significant, the FDA told Pharmacyclics.
Nonetheless, the company proceeded with its application process in April under a regulatory procedure known as file over protest that allows biologic and drugmakers to have their NDAs reviewed when there is a disagreement about the acceptability of the supporting data or other information. (See BioWorld Today, April 24, 2007.)
The NDA included an integrated analysis of SMART and an earlier study of about 250 participants with NSCLC. The combined data demonstrated that patients receiving Xcytrin had a 6.4-month improvement in time to neurologic progression, which the company argued was statistically significant.
But the FDA ultimately rejected the application, Pharmacyclics said Friday in a statement.
"We are disappointed that brain metastases patients with limited options and serious neurologic problems will not have access to Xcytrin, which we believe has shown important clinical activity in this indication," said CEO Richard A. Miller.
Brain metastases occur in about half of the 200,000 patients diagnosed each year with lung cancer.
Pharmacyclics contended that Xcytrin's mechanism of action inhibits the enzyme thioredoxin reductase, which is a tumor growth promoter.
Pharmacyclics plans to continue to develop Xcytrin as a treatment for various cancers, Miller said, adding that the firm is seeking a corporate partner for the program.
The company said it recently completed patient enrollment in three multicenter Phase II trials evaluating Xcytrin as a monotherapy, in combination with Sanofi-Aventis Group's Taxotere (docetaxel), and in combination with Eli Lilly and Co.'s Alimta (pemetrexed) in patients with advanced relapsed NSCLC.
Data from those trials are expected in the first half of 2008, the firm said.
Pharmacyclics' other drug candidates are PCI-24781 (formerly CRA-024781), a histone-deacetylase inhibitor that currently is being tested in a Phase I/II trial, and preclinical compounds PCI-27483, a Factor VIIa inhibitor, and PCI-32765, a Bruton's tyrosine kinase inhibitor.