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Pharmacyclics` Stock Crushed After Failed Phase III Of Xcytrin

Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)


Posted on: 12/20/2005

Pharmacyclics' Stock Crushed After Failed Phase III Of Xcytrin

By Karen Pihl-Carey

Staff Writer

A missed primary endpoint in a pivotal study of its lung cancer brain metastases drug, Xcytrin, sent Pharmacyclics Inc.'s stock plunging more than 64 percent Monday.

The drug is at the top of the Sunnyvale, Calif.-based company's pipeline, and the trial represents the second Phase III in which Xcytrin (motexafin gadolinium) has failed.

The most recent study began three years ago and was designed to confirm observations from the original Phase III study, which missed the primary endpoints but showed the drug, when added to whole-brain radiation therapy (WBRT), significantly prolonged time to neurologic progression and decreased deaths due to brain tumor progression in lung cancer patients. (See BioWorld Today, Dec. 20, 2002.)

"In the last trial, we looked at any kind of tumor that spread to the head, and what we found in that study was the biggest benefit was in lung cancer," said Richard Miller, president and CEO of Pharmacyclics.

While Xcytrin injection did demonstrate a longer time to neurologic progression in the second study focused on lung cancer patients, the difference was not statistically significant when compared to the control arm.

Pharmacyclics' stock lost almost two-thirds of its value, with shares (NASDAQ:PCYC) plummeting 64.1 percent Monday, or $5.90, to close at $3.30. Greg Wade, a senior research analyst with San Francisco-based Pacific Growth Equities, downgraded the stock from "buy" to "neutral."

"Taken at face value, we believe top-line results suggest that Xcytrin has a highly uncertain regulatory future ahead of it," Wade stated in a research note.

The randomized, controlled Phase III trial, called SMART (Study of Neurologic Progression with Motexafin Gadolinium and Radiation Therapy), compared the safety and efficacy of WBRT alone to WBRT plus Xcytrin, and enrolled 554 patients from 94 centers in North America, Australia and Europe. The primary endpoint of time to neurologic progression (TNP) was determined by a blinded-events review committee.

Top-line results showed that the median TNP was 15.4 months for patients in the Xcytrin group compared to 10 months for those treated with WBRT alone (p=0.122, hazard ratio=0.78). Xcytrin also failed to show a significant difference in survival, a secondary endpoint.

"We have a p' value of 0.122," Miller told BioWorld Today. "There looks like there's clear evidence of activity here. We've got to finish analyzing our data and meet with the FDA" within the next few months to determine a path forward.

Pharmacyclics had planned to file a new drug application for Xcytrin in 2006. It expected to market it in the U.S. alone, and partner it everywhere else, but that strategy may change depending on its talks with the FDA.

Pacific Growth is anxiously awaiting further, more detailed data from the study, Wade wrote, "both for their potential to resurrect a regulatory path forward (which we put at present as unlikely) and for the potential scientific value that may provide support for the efficacy of Xcytrin that is not within the top-line results."

One area that may interest a potential partner and the FDA centers on SMART data from patients enrolled in North America. Researchers noticed significant differences between the 348 North American patients enrolled and those from other regions: More were female; there was a shorter time from primary cancer diagnosis to the development of brain metastases, and there was less use of post-randomization chemotherapy. When breaking out that North American group, which represented 63 percent of all patients, researchers found a median TNP of 24.2 months for the Xcytrin-treated group, compared to 8.8 months for the WBRT alone group (p=0.004, hazard ratio=0.53).

"Overall, there's evidence of a strong trend, but particularly in the patients from North America - almost two-thirds of those enrolled - there was a very strong effect," Miller said.

The study also showed positive trends in favor of the Xcytrin arm in relation to reduced steroid use and a reduced need for salvage radiation therapy to the brain. Xcytrin was well tolerated, and its most common grade 3 and 4 adverse events, all of which were reversible, included hypertension, elevated liver enzymes and fatigue.

A drug shown to disrupt redox-dependent pathways in cells and inhibit oxidative stress-related proteins, Xcytrin is designed to selectively concentrate in tumors and induce apoptosis. Miller said there are about 150,000 patients per year in the U.S. with brain metastases from any kind of cancer. About two-thirds of those patients have lung cancer.

"There is, as we speak, no approved drug for treating brain metastases patients," he said. "[Xcytrin] would be the first drug or biologic to use in this disease."

Earlier this month, Pharmacyclics released data from earlier-stage studies of Xcytrin: Phase I results showed Xcytrin injection, when given in combination with Zevalin (ibritumomab tiuxetan), was well tolerated and had synergistic activity in patients with Rituxan (rituximab)-refractory low-grade and transformed non-Hodgkin's lymphoma; Phase II results demonstrated single-agent activity in refractory low-grade lymphoma and chronic lymphocytic leukemia; and preclinical data showed that Xcytrin's active agent, motexafin gadolinium, increased survival in animal models of amyotrophic lateral sclerosis.

In September, Pharmacyclics began enrolling patients in a Phase II trial of Xcytrin in combination with WBRT and sterotactic radiosurgery to treat brain metastases from solid tumors, and it started another Phase II study of the drug as a second-line treatment for patients with recurrent, metastatic non-small-cell lung cancer.

Miller said that despite the missed endpoint in SMART, the Phase III trial's evidence of activity will impact Xcytrin's other clinical programs by speeding up enrollment.

"The activity we see in this trial is going to make interest in the other trials escalate," he said.

Pharmacyclics has one other pipeline product: Antrin (motexafin lutetium), which is in early clinical trials for coronary artery disease. Both Xcytrin and Antrin are ring-shaped small molecules called texaphyrins.

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