Xenova Group plc immediately expects to commence the first of two planned Phase III trials for TransMID, a candidate for brain cancer.
The Slough, UK-based firm Tuesday said it reached an agreement with the FDA under the special protocol assessment program to run two Phase III trials rather than one large Phase III as agreed upon by KS Biomedix Holdings plc (KSB), the previous owner of the candidate. Xenova gained control of TransMID via its $13.5 million all-share takeover of KSB last August. (See BioWorld Today, Aug. 20, 2003.)
Xenova's stock (NASDAQ:XNVA) Tuesday rose 17 cents to close at $1.83.
By running two smaller trials, the firm said it will increase its chances of eventually winning U.S. regulatory clearance, David Oxlade, CEO of Xenova, told BioWorld Today. Indeed, single large trials are more costly and require success in achieving an extremely aggressive statistical endpoint, he said.
"By splitting it in two, we achieve a number of things. Firstly, it is the kind of structure the FDA prefers, and secondly, the p' value [will be] 0.05, which is obviously preferable," Oxlade said. In a larger study, the p' value would be 0.01.
Beyond that, from a risk-management standpoint, the two-trial approach provides shareholders with a more sensible risk-reward profile, he said.
TransMID, a modified diphtheria toxin conjugated to transferrin, was granted FDA fast-track status in August 2001 and orphan drug status in December 2001. In addition, the European Commission granted TransMID orphan designation in March 2002.
TransMID is designed to shrink tumors and in some cases eliminate them from the brain, Oxlade said.
On receiving the go-ahead from the FDA, Xenova began shipping product for the first trial. The timeline for the second trial is dependent on the success and progress of the first.
Indeed, if recruitment goes according to plan, the decision on the second study would occur in the third or fourth quarter of 2004.
"If the first Phase III goes really well - either the data are extremely impressive, in which case discussion with the regulators will take place about perhaps accelerated approval, or if it is just proceeding as expected - then the second trial could be initiated as planned," Oxlade said.
The firm anticipates filing for U.S. approval in 2007.
Each of the trials is designed to enroll 323 patients with non-resectable, progressive or recurrent glioblastoma multiforme who have failed conventional therapy. The studies will be randomized, open-labeled, multicentered trials and will compare TransMID to a number of presently used chemotherapeutic agents regarded as "best standard of care" (BSC). The patients will be randomized in a 2:1 ratio of TransMID:BSC across about 50 sites in the European Union, Israel and North America.
The primary endpoint is overall survival time with a planned interim analysis to be conducted after 50 percent of the required events have been observed.
In an earlier open-label Phase II study, patients receiving TransMID achieved a significant increase in overall survival, compared with historical survival figures. Indeed, median survival for patients receiving TransMID was about 37 weeks. That compares to the average life expectancy for those patients, which is about 26 weeks, the company said.
"TransMID is a potentially quite important drug because brain cancer patients have had very little in the way of therapeutic options other than surgery or radiotherapy," Oxlade said. "In many patients surgery is not possible, so from the standpoint of brain cancer, this is obviously a potentially very important development and contribution. We are realistic, but optimistic about its potential."
When TransMID binds to transferrin receptors on the surface of the cell, the diphtheria toxin gains entry to the cell. Once inside, the diphtheria toxin interferes with protein synthesis and ultimately kills the cell. Transferrin receptors particularly are prevalent on rapidly dividing cells, and the high level of transferrin receptor expression on glioma cells relative to normal brain tissue makes transferrin an appropriate targeting mechanism for the diseased cells, the company said.
TransMID is licensed to Nycomed Denmark A/S, of Roskilde, Denmark, in Europe; Sosei Co Ltd., of Tokyo, in Japan; Medison Pharma Ltd., of Petach-Tikva, Israel, in Israel; and Ranbaxy Laboratories Ltd. in India. Xenova has retained North American rights.
Oxlade believes the regulatory approval application in Europe also will be filed in 2007. The firm has not determined whether it will seek a marketing and commercialization partner in the U.S.