Despite a prior refusal, Pharmacyclics Inc. is filing a new drug application for Xcytrin (motexafin gadolinium) in combination with standard radiation therapy for non-small-cell lung cancer patients with brain metastases.
The company, of Sunnyvale, Calif., believes trial data underlying the submission warrant approval, despite prior FDA communication to the contrary. The agency's Division of Drug Oncology Products in February refused to accept the Xcytrin NDA because the drug failed to show statistically significant differences between treatment arms in the pivotal study's primary endpoint. (See BioWorld Today, Feb. 22, 2007.)
Nevertheless, Pharmacyclics has "filed over protest," President and CEO Richard Miller said, noting that the "unusual procedure" requires the FDA to review the submission and therefore comb through the totality of the data. The agency is scheduled to complete its evaluation by Dec. 31.
Given data that demonstrated Xcytrin's positive impact, the severity of the disease and lack of options for those patients, as well as the company's use of a novel endpoint, Miller told BioWorld Today that "the data merited a complete and thorough review" by the FDA. "We're hoping that we can work with the FDA now, interactively, and make sure that the NDA gets the complete review that it deserves."
The original submission was based on the results of two randomized trials and an integrated analysis of the two. Both studies made use of a new neurologic progression endpoint designed with the FDA to assess Xcytrin's clinical benefit when added to radiation by measuring factors such as mental status, balance, speech, visual problems, paralysis and memory at baseline and again at various subsequent time points. (See BioWorld Today, Dec. 26, 2006.)
The first of those trials, which included 251 lung cancer patients and 150 others with brain metastases from other solid tumors, did not show a statistically significant benefit overall. Median survival was 5.2 months for all Xcytrin-treated patients compared to 4.9 months for those who received just radiation. But it did show a clinically and statistically significant improvement in time to neurologic progression in the lung cancer group, per a pre-specified subset analysis, leading to the next trial. The follow-up study, a 554-patient pivotal trial designated the SMART trial, showed a 5.4-month improvement in the pre-specified primary endpoint, with a median time to neurologic progression of 15.4 months for Xcytrin compared to 10 months for radiation alone (p=0.122). (See BioWorld Today, Dec. 17, 2001, and Dec. 20, 2005.)
Though not statistically significant, Miller said the data signaled a strong and promising treatment effect in a disease for which nothing has worked beyond radiation therapy. "When one looks at the data in detail," he added, "you start to realize that we're measuring really robust, very strict and stringent clinical measurements. People get really sick before they're scored, and because of that, you lose a little bit of sensitivity."
An integrated analysis of the 805 lung cancer patients in the two Phase III studies demonstrated a statistically significant, 6.4-month improvement in time to neurologic progression for patients receiving Xcytrin plus radiation compared to control. The median duration was 15.4 months in the Xcytrin arm compared to nine months for control (p=0.016). Two secondary endpoints also favored the Xcytrin group compared to those receiving radiation alone: time to neurologic progression as determined by investigators (p=0.015) and time to neurocognitive progression (p=0.02). In addition, the Xcytrin-radiation combination was generally well tolerated in all the studies.
"Maybe we ought to put the data in the context of the clinical need," Miller said, "and the clinical requirements that the disease placed on us in order to do the testing we did."
Lung cancer is the most common cause of brain metastases, which are estimated to occur in up to half of the 200,000 lung cancer patients diagnosed each year in the U.S. The metastases impact motor functions and one's abilities to think and memorize. "It's your identity, your personality and your ability to function," he added. "It's devastating."
Miller, who said the company would welcome an advisory panel meeting to go over the data, noted the precedent for FDA review of NDAs based on missed Phase III endpoints. Should the agency not approve Xcytrin in the indication, he said, Pharmacyclics "at this point in time" has no plans for additional work in brain metastases.
The company owns worldwide rights to the redox-active drug, which is designed to concentrate in tumors and induce apoptosis by blocking an enzyme called thioredoxin reductase that's responsible for maintaining cells' oxidation levels. Other studies are testing its use lung cancer, glioblastoma and lymphomas, all of which are in Phase II.
On Monday, Pharmacyclics' stock (NASDAQ:PCYC) lost 7 cents to close at $3.28.