BioWorld International Correspondent

Sirenade Pharmaceuticals AG redirected its business strategy to concentrate on a particular aspect of Alzheimer's disease after showing proof of concept in a preclinical study.

The privately held company achieved positive results in slowing the development of tau-related tangles, one of two pathologies most closely associated with Alzheimer's disease. Following those results, Sirenade's management, under CEO Lynn Butler, decided to attempt to license the company's oncology programs immediately and concentrate on neurodegenerative diseases, particularly on the tau program.

"This is the first tau-directed disease-modifying agent for Alzheimer's disease," Butler told BioWorld International. The two hallmarks of the disease are tau-related tangles and beta-amyloid peptide-related plaques.

"We know that two-thirds of the people who have the plaques don't get Alzheimer's," Butler said. "Then there is some signal that stimulated formulation of these tangles, and it's the tangles that are the actual neurodegeneration.

"There are various kinases that in the past were thought to be involved in the formation of the tangles," she said. "Selective kinase inhibitors were developed and tested in various models, but none of them worked. The first in vivo animal model of neurofibulary tangles was published in 2000. We tested our compound in this model earlier this year and saw delay in progression of disease in the model. We don't know of any other company or academic study that has slowed development."

As the disease progresses, the animals develop motor deficiencies in grip, balance and other characteristics. "It's easy to measure progression of disease," Butler said, "and the dosed animals had repressed development of these symptoms."

Sirenade, of Martinsried, Germany, found the results so conclusive that it is moving away from plaque-related research entirely. The company also has decided to focus at the preclinical level on neurodegeneration. Its oncology programs in colorectal cancer, metastatic tumors and solid tumors, which the company had expected to reach clinical testing in 2007, are up for immediate out-licensing.

Butler said the company expected to file an investigational new drug application for its lead compound in Alzheimer's in the third quarter of 2006. She added that the study had produced five additional compounds showing activity at the cellular level against that particular pathology.

"We hope to use this chemistry as a tool to understand the signaling pathways in which these kinases act," she said. "It's interesting that, although two-thirds of people develop plaques, not everyone develops tangles. We would like to clarify in at least some part the relationship involved."

The company also will conduct preclinical testing to discover whether prophylactic doses of the compound inhibit development of the tangles.

Butler said the results from the orally administered compound were positive in terms of toxicity and in crossing the blood-brain barrier. The company expects clinical testing to begin in the second half of 2005.

The company is taking its new strategy into a B round of financing, which Butler hopes to close in the first quarter of 2005. To date, the company has raised €13.6 million in financing. As part of its pipeline of compounds to treat neurodegenerative diseases, it has a dopamine agonist that is in Phase I testing. Sirenade was formed in January by the merger of Nadag AG and Sireen AG. (See BioWorld International, Jan. 28, 2004.)

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