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MADRID -- When it comes to therapy for Alzheimer's disease, if a phase II trial isn't all that's expected, try a phase III. So a drug company is moving ahead with studies of the GnRH analog leuprolide.
MADRID, July 20 -- When it comes to therapy for Alzheimer's disease, if a phase II trial isn't all that's expected, try a phase III.
That seems to be the philosophy of Voyager Pharmaceutical of Raleigh, N.C., which reported at the International Conference on Alzheimer's Disease and Related Disorders here that it is moving ahead with phase III trials of a proprietary formulation of leuprolide, the GnRH analog, despite mixed findings in a phase II clinical trial for Alzheimer's.
Clinicians found that patients appeared significantly better after taking leuprolide, usually used for prostate cancer, for 48 weeks. But they did not fare significantly better than patients not receiving the drug in critical tests of cognition - a key assessment in defining control of disease in the Alzheimer's patients.
In the pooled analysis of two studies, Christopher Gregory, Ph.D., of Voyager, noted that the primary end point of significant improvement in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) was not achieved.
Although the patients on leuprolide showed a 1.87-point less decline in the scale, that difference did not reach statistical significance (P=.18). From baseline, the ADAS-cog fell 1.94 points with leuprolide; 3.81 points with placebo. Falling scores on the ADAS-cog indicate reduced cognition.
"However, we did reach our co-primary endpoint, statistical significance on the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, with 50.9% of patients unchanged or improved at 48 weeks on leuprolide compared with 34.5% of patients who were not taking leuprolide," Dr. Gregory said. "That reached statistical significance at the P=.048 level."
Dr. Gregory described the pooled results of two, placebo-controlled studies that involved 108 women and 119 men ages 65 or older with mild-to-moderate Alzheimer's. All participants in the study were already taking acetylcholinesterase inhibitors, and were stabilized on those drugs for at least three months.
About half the patients were given leuprolide on top of their medications, and the others were given placebo.
While only achieving half a loaf, the company is rapidly moving forward with twin 555-patients studies - one in North America for which enrollment is nearly complete and a second in the "rest of the world" which had just begun accruing patients. In the 56-week study, patients will receive a series of eight-week leuprolide implants that will slowly dispense medication.
"The only major change in the phase II and phase III studies," Dr. Gregory said, "was that we will not be supplementing testosterone in the men in the new studies. Instead we will measure testosterone levels at baseline and maintain those levels through the study if necessary."
Leuprolide is aimed at reducing leutinizing hormones that appear to be excessive in the brain and are believed to drive the Alzheimer's disease process. However, attacking the hormone may cause sexual side effects, he said, so testosterone replacement is being offered.
He said the connection between leuprolide and Alzheimer's occurred by accident when the wife of a metastatic prostate cancer patient who was taking leuprolide, told doctors that the drug seemed to work well "and his Alzheimer's went away too."
"The phase II data that was presented is very promising," said Howard Fillit, M.D., a geriatrician and neuroscientist and founding director of the Institute for the Study of Aging, in New York. He was not involved in the study.
"The clinicians' finding that the patients looked better is impressive," Dr. Fillit said. "This drug works by a different method of action - hormonal rather than as a cholinesterase inhibitor. We are anxiously waiting to see what the Phase III data looks like."