By Brady Huggett

Protein Design Labs Inc. missed the primary endpoint in its Zamyl Phase III trial but said it should have the right data for a new drug application filing regardless.

The initial review of the data from the Zamyl (formerly Smart M195) Phase III trial in patients with acute myeloid leukemia showed, in all evaluable patients on an intent-to-treat basis, Zamyl and chemotherapy generated an overall response rate of 43 percent in patients, compared to a 26 percent response rate in patients receiving chemotherapy alone (p=0.015).

¿We believe the data show that when you combine Zamyl with the standard chemotherapy regimen and compare that to the standard regimen alone, you see a significant improvement in response rate,¿ said Robert Kirkman, PDL¿s vice president, business development and corporate communications.

The defined primary endpoint for the trial, however, required a complete response to occur in patients within 70 days of the initiation of therapy. Analysis under this definition did not demonstrate a statistically significant difference between the Zamyl and chemotherapy arm and the chemotherapy alone arm. But by relaxing the strict definition of complete response, Kirkman said, the data improve step by step.

¿The original protocol defined complete response as occurring by day 70, meaning they only looked at 70 days,¿ he told BioWorld Today. ¿That was an arbitrary decision and we have now looked at the data without that limitation and that showed a 30 percent response rate and a 21 percent response rate in the control group.¿

Those results, which required a bone marrow biopsy that demonstrated 5 percent or fewer blast cells, a normal platelet and absolute neutrophil count and transfusion independence in order to be included, were not statistically significant (p=0.182). But, when including patients who had less than a normal platelet count, Kirkman said, the statistically significant 46 percent response rate was seen.

Thus, by using the overall response rate definition, Zamyl could be ready for filing, Kirkman said.

¿You have to understand that the overall response rate was not an endpoint that was used in leukemia trials when we wrote the protocol,¿ Kirkman said, and pointed to the acute myeloid leukemia product, Mylotarg, as a precedent for this overall response rate definition.

American Home Products Corp., of Madison, N.J., has a nonexclusive license under PDL¿s antibody humanization patents to market Mylotarg, for which PDL earns royalties. The drug was approved in May 2000 for the treatment of patients 60 years or older in first relapse with CD33-positive acute myeloid leukemia who are not considered candidates for cytotoxic chemotherapy. Kirkman said AHP used the overall response rate definition to get that drug approved, citing reasons other than leukemia as explanation for the lower platelet counts.

¿AHP, for Mylotarg, used this endpoint in their trials and we became aware of it,¿ he said. ¿We think it is a valid endpoint and it indicates that there is a significant improvement with [Zamyl and chemotherapy] over what you see just with chemotherapy alone. Our plan is to file for approval based on this trial.¿

Protein Design Labs, of Fremont, Calif., will complete its analysis of the data, including secondary endpoints such as overall survival, over the next few months. Once that analysis is finished, PDL will approach both the FDA and European regulatory authorities concerning filing. And while the company will continue with further Zamyl trials, the intent of the studies will be to expand the drug¿s use, not to gather additional data for a filing package.

If approved, Kirkman said PDL would like to market the product in the U.S. and Canada, although it ¿is open¿ to the possibility of co-promotion deals in those areas. For Europe, it prefers a co-promotion deal, and a complete marketer in Asia.

Zamyl is a humanized antibody that binds to the CD33 antigen on myeloid leukemia cells. It¿s the humanized version of the murine M195 monoclonal antibody that was licensed in from Memorial Sloan-Kettering Cancer Center, of New York.

PDL¿s pipeline also includes Remitogen, in Phase II trials for non-Hodgkin¿s B-cell lymphoma; Humanized Anti-IL-4, in Phase II asthma trials; and Nuvion, in Phase I/II psoriasis trials and Phase I trials for both graft-vs.-host disease and inflammatory bowel disease. It does have daclizumab on the market for kidney transplant rejection. However, the product was developed and is handled by F. Hoffmann-La Roche Ltd., of Basel, Switzerland.

¿If [Zamyl] is approved, it will become our first directly marketed product,¿ Kirkman said. ¿It has clearly been our corporate vision to become a fully integrated pharmaceuticals company ¿ that is, to create, develop, manufacture and market drugs. We already do three of those things and this takes us one step closer to that goal.¿

PDL¿s stock (NASDAQ:PDLI) fell $2.62 Friday to close at $37.95.

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