By Brady Huggett

Pharmacyclics Inc. missed the co-primary endpoints in its Xcytrin Phase III trial for the treatment of brain metastases, but said digging deeper through the data could allow the company to file a new drug application.

¿We still have a substantial amount of work to do, but we wanted to communicate the top-line results as soon as possible,¿ Richard Miller, CEO and president of Pharmacyclics, said in a conference call. ¿Although the study did not meet statistical significance on the primary endpoints across all strata, it did appear to demonstrate that Xcytrin is clinically active, particularly in lung cancer patients, which represent over 60 percent of the brain metastases population. In our study, 62 percent of the patients had lung cancer.¿

Wall Street was less optimistic. Pharmacyclics¿ stock (NASDAQ:PCYC) lost $12.31 Friday, or about 56.7 percent, closing at $9.39.

The study had co-primary efficacy endpoints of survival and time to neurologic progression. The data showed median survival to be 5.2 months for all patients treated with Xcytrin plus radiation therapy, compared to 4.9 months for control patients receiving just radiation. Median time to neurologic progression for all patients treated with Xcytrin plus radiation therapy was 9.5 months, compared to 8.3 months for those patients receiving radiation alone.

While neither endpoint generated statistically significant figures, Miller and Pharmacyclics found pockets of positive data that leave the company hopeful.

The protocol for the trial analyses included examining patient subgroups based on cancer types and the extent of the disease. In lung cancer patients ¿ the largest subgroup, with 251 individuals ¿ neurologic progression was significantly improved in patients receiving Xcytrin. The median time to neurologic progression for this subgroup was 7.4 months for the control group and had not yet been reached for the group receiving Xcytrin (unadjusted p=0.048).

In the RPA Class II lung cancer patients, a subgroup of 214 patients, the median time to neurologic progression was 6.3 months for the control patients and had not yet been reached for the Xcytrin-treated patients (unadjusted p=0.013).

¿Patients with lung cancer and brain [metastases] have very few options available to them and we are impressed there is a marked difference in this patient population,¿ Miller said. ¿The effect on neurologic progression observed in this largest prespecified subgroup of patients supports the activity of the drug and indicates that Xcytrin may increase the local control of radiation therapy.¿

Patients with brain metastases often have a poor prognosis. Those enrolled in trials often die before the study ends. That unfortunate effect happened in this study as well, Miller said, stating the trial had ¿a loss of statistical power because so many patients [were] lost to analysis early.¿

¿Despite losing statistical power from the substantial number of early deaths,¿ Miller said, ¿[the data] show that for those that survived beyond the first few months, there is clinical benefit conferred by Xcytrin in terms of neurologic progression.¿

It¿s still early in the analysis stage, but Pharmacyclics said it plans on pressing ahead, completing the number crunching and potentially considering filing.

¿We are now in the process of analyzing the secondary endpoint data from this Phase III trial including neurocognitive function, quality of life and radiologic response rate that could further confirm these findings of improved local control and could be used in support of a possible NDA filing,¿ Miller said.

What those secondary endpoint data show remains to be seen. In a research note from Thomas Dietz, of San Francisco-based Pacific Growth Equities, he lowered his rating on the company to ¿neutral.¿

¿We believe that until clarity can be provided to us whether an NDA will be filed, the stock will significantly under-perform the market,¿ Dietz said. ¿If analyses of radiologic response data show that Xcytrin-treated patient¿s tumors shrink more and grow back slower, the FDA may have a basis to support an NDA filing. Such an observation of radiologic response would support the argument that Xcytrin facilitates local control of tumors and would back up the observation of increased time to neurological progression. We believe, however, that the more likely scenario is that the FDA will require another pivotal Phase III study that addresses the lung cancer subgroup.¿

While the analysis continues, Miller said the company ¿remains committed to Xcytrin¿s development and will continue to study this novel agent in other potential indications, including primary brain tumors and non-small-cell lung cancers.¿

Xcytrin selectively accumulates in cancer cells and disrupts cellular metabolism. It is designed to prevent cancer cells from repairing themselves in response to the effects of radiation and chemotherapy without increasing damage to normal tissue. Pharmacyclics has the product in a Phase II glioblastoma multiforme trial. It has several other trials for various cancers in planning and will initiate a Phase I trial to investigate Xcytrin in combination with doxorubicin in the first quarter.

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