A preliminary analysis of atrasentan Phase III data from Study M00-211 in end-stage prostate cancer patients, reviewed by an Independent Data Monitoring Committee, demonstrated improvements in development of bone pain as an adverse event, prostate-specific antigen (PSA) levels, and biochemical markers of skeletal progression in patients taking atrasentan versus placebo. However, the study did not meet its primary endpoint of time-to-disease progression, and therefore will be stopped. Additional Phase III studies in prostate cancer and Phase II studies in other tumour types will continue. Atrasentan, formerly known as ABT-627, is an investigational selective endothelin-A receptor antagonist (SERA).

Study M00-211, an 810-patient, multi-national, double blind placebo-controlled clinical study, examined the effect of atrasentan in men with advanced metastatic hormone-refractory prostate cancer. The time-to-disease progression endpoint was defined as a composite of several different clinical events, including the need for pain medication, chemotherapy or radiation and progression of cancer in bone. If a patient experienced disease progression by any of these criteria, he was considered to have completed the trial. The majority of patients who completed the trial did so within three months of starting treatment. These results in both the placebo and atrasentan arms are consistent with the rapid progression of bone disease in this end-stage patient population.

Patients who have completed the trial may continue treatment with atrasentan through an extension study if it is determined that they are receiving clinical benefit from the drug.

"We entered these trials knowing there is no effective therapy for these very sick end-stage prostate cancer patients. And although we're disappointed that Study M00-211 didn't meet its very stringent primary endpoint, we're still very encouraged that we continue to see activity in this patient population," said Perry Nisen, M.D., Ph.D., divisional vice president, Global Oncology Development at Abbott Laboratories. "We learned a great deal from this study. The effects on PSA levels and bone markers strengthen our belief about atrasentan's potential benefit in prostate cancer and other tumour types, which are the focus of our other ongoing and future studies."

In Study M00-211, atrasentan demonstrated statistically significant improvements in mean change of PSA levels versus placebo: (atrasentan: 175 nanograms/mL vs. placebo: 257 nanograms/mL, p = 0.045); development of bone pain as an adverse event (24 per cent vs. 34 per cent; p = 0.003); and improvements in mean change of biochemical markers of skeletal progression (total alkaline phosphatase 27 IU/L vs. 94 IU/L, p < 0.001; bone alkaline phosphatase 9 IU/mL vs. 34 IU/mL, p < 0.001).

Atrasentan was well tolerated in this study. The patient dropout rate in M00-211 was lower than seen in the Phase II atrasentan trial and was comparable in patients receiving atrasentan versus placebo (10.8 per cent vs. 9.5 per cent). The most common adverse events seen more frequently in patients receiving atrasentan versus placebo were also consistent with Phase II findings and were: headache (14 per cent vs. 9 per cent), peripheral edema (swelling) (21 per cent vs. 7 per cent), and rhinitis (19 per cent vs. 7 per cent).

Abbott will continue its second Phase III pivotal trial (M00-244) involving men with less advanced prostate cancer that has not spread (non-metastatic), and Study M01-366, a 200-patient Phase II study in men with rising PSA following prostate cancer surgery. Additionally, Abbott continues to explore atrasentan in earlier stages of prostate cancer and other cancers, including renal cell carcinoma, ovarian, breast, brain, colorectal, and non-small cell lung cancers.

Abbott is contacting atrasentan investigators and regulatory authorities to inform them of these events. Patients will be contacted directly by study investigators.

These events will have no impact on Abbott's earnings in 2003 or in 2004.

More than one million men have been diagnosed with prostate cancer, which is the second-leading cause of cancer death in men. Approximately 30 percent of men with prostate cancer develop incurable metastatic disease.

Atrasentan belongs to a class of oral drugs that block the activity of endothelin, a protein normally produced in the body that can stimulate the growth and spread of cancer cells. Both endothelin and its receptor are found in various cancers including prostate, non-small cell lung, colorectal, breast and renal. There are two endothelin receptors, ET-A and ET-B. The ET-A receptor appears to be important in prostate cancer progression and atrasentan selectively targets this receptor.

Atrasentan was granted fast-track review status by the FDA. Abbott's ongoing clinical development program for atrasentan includes a Phase III study in men without metastatic disease, Phase II studies in earlier stages of prostate cancer and the drug's use in combination with other agents. In addition to prostate cancer, Phase II trials of atrasentan are underway in other cancers where both endothelin and the endothelin-A receptor are found, and where preclinical data suggests a potential role for therapy.