Pharmacyclics undergoes 'file over protest' for Xcytrin NDA

Pharmacyclics, Inc. has announced its request to the U.S. Food and Drug Administration (FDA) that its New Drug Application (NDA) for Xcytrin (motexafin gadolinium) Injection be filed over protest.

The NDA seeks approval to market the drug for the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (i.e., cancer that has spread to the brain from another part of the body).

In December 2006, the Company submitted an NDA to the FDA's Division of Drug Oncology Products requesting marketing clearance for Xcytrin in combination with radiation therapy for the treatment of brain metastases from NSCLC. In February 2007, it received a refuse to file letter from the FDA citing failure to demonstrate statistically significant differences between treatment arms in the primary endpoint of the pivotal study to support approval.

File over protest is a procedure permitted by regulation, which allows sponsors to have their NDA filed and reviewed when there is disagreement over the acceptability of the NDA.

Pharmacyclics is taking this action to ensure that its NDA receives a complete review. According to the regulations, the filing date will be on or about April 30, 2007, which is 60 days after the company requested a meeting to discuss the refuse to file letter. FDA has either four or eight months to review the NDA depending on whether it designates the filing for Priority or Standard review. There can be no assurance that the NDA will be approved or that there will be an advisory panel meeting to review the data.

"We strongly believe that the clinical data justify a complete and thorough review and that a panel of experts be given an opportunity to examine and evaluate the data," said Richard A. Miller, M.D., president and CEO of Pharmacyclics. "We owe it to patients suffering from brain metastases from non-small cell lung cancer, a devastating and debilitating disease for which there are limited treatment options, to proceed with every reasonable effort to make this drug available. We are eager to work with the FDA to complete the review of our NDA."

According to the National Cancer Institute, over 200,000 patients will be diagnosed with lung cancer this year in the U.S. Lung cancer is the most common cause of brain metastases, which are estimated to occur in up to 50% of lung cancer patients. Spread of lung cancer to the brain may occur early in the course of disease or may be a late complication of this illness. This is a disease that causes devastating and deadly neurologic problems and is increasing in incidence.

No drug or treatment has ever been shown to provide neurologic benefit to these patients.

Brain metastases occur when cancer cells spread to the brain and grow, causing major neurologic complications. Patients with brain metastases usually suffer serious deterioration of neurologic and neurocognitive function such as paralysis, loss of vision, disturbances of gait and speech, decrease in mental status, loss of short-term memory, compromised verbal skills and reduction in cognitive ability. Standard therapy for patients with brain metastases from lung cancer involves the prompt use of cranial radiation, which is used to prevent neurological deterioration and improve neurologic outcomes.

"After consultation with investigators, experts and patient groups, we decided to have our NDA filed over protest because there are other examples of NDAs for oncology drugs that have been accepted for filing without meeting the primary endpoint with statistical significance. In some cases this has led to product approvals, particularly in cases where the unmet need is great, the drug is well tolerated and there are few if any other treatment options available," added Dr. Miller. "We collectively believe that it is in the best interests of patients to do everything we can to make this drug available for treatment of this horrible condition."

The NDA submission was based on the results of two randomized trials and an integrated analysis of both trials. These trials utilized an innovative neurologic progression endpoint designed with FDA to assess the clinical benefit of treatment. The first of these trials, which included 251 NSCLC patients and 150 patients with brain metastases from other solid tumors, showed a clinically and statistically significant improvement in time to neurologic progression in patients with NSCLC.

The follow up pivotal 554-patient SMART trial showed a 5.4 month improvement in time to neurologic progression, the primary pre-specified endpoint, with a median time to neurologic progression of 15.4 months for Xcytrin compared to 10.0 months for the control (with a p-value equal to 0.12). While not statistically significant, this represented a very strong and promising treatment effect in a disease for which nothing has worked beyond radiation therapy.

An integrated analysis of the 805 lung cancer patients in these two large Phase 3 studies demonstrated a statistically significant 6.4 month improvement in time to neurologic progression for patients receiving Xcytrin plus whole brain radiation therapy compared to those receiving radiation alone. The median time to neurologic progression was 15.4 months compared to 9.0 months, respectively, with a p-value equal to 0.016. Secondary endpoints also showed a significant benefit for Xcytrin plus whole brain radiation compared to radiation alone: time to neurologic progression as determined by investigators, P = 0.015 and time to neurocognitive progression, P = 0.02. In addition to this consistent treatment effect, Xcytrin plus radiation therapy was generally well tolerated across all studies.

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