Promising AD Treatments Remain in Pipeline: Amyloid Fibril Antiaggregation Therapy and Neurotrophic Agents Are Still under Consideration

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EXPERT ANALYSIS FROM A PSYCHOPHARMACOLOGY CONFERENCE SPONSORED BY THE UNIVERSITY OF ARIZONA

TUCSON - More than 60 drugs remain in the developmental pipeline for Alzheimer's disease, although the past several years have seen numerous once-promising agents bite the dust.

"It's discouraging. A number of medications have gone out of research development in the last 2-3 years, and they were ones that I personally had great hope for," said Dr. Geoffrey L. Ahern.

"A lot of hope and money and work time has been put into Alzheimer's disease, and it does not always come up positive.

"It's kind of sad how many of these things go belly up after looking very promising in phase I and early phase II clinical trials.

"It always seems to be in phase III that they go boom," observed Dr. Ahern, who is professor of neurology, psychology, and psychiatry, and director of the behavioral neuroscience and Alzheimer's clinic at the University of Arizona, Tucson.

Among the notable failures was tarenflurbil. This drug is a modulator of gamma-secretase, which is a protease that cleaves amyloid precursor protein to produce the amyloid-beta peptide that consists of amyloid plaques, a defining feature of Alzheimer's disease.

The phase III trial for tarenflurbil was negative. Similarly, phase 11/III clinical trials of hydroxylvaleryl monobenzo-caprolactam, a gamma-secretase inhibitor, have been halted.

An alternative approach to the treatment of Alzheimer's disease relies upon inhibiting aggregation of amyloid fibrils with the goal of reducing levels of soluble amyloid-beta peptide.

One such agent, tramiprosate, showed evidence of disease stabilization in phase II studies, but North American phase III trials proved either negative or inconclusive, and the phase III European study has been stopped.

Tramiprosate's manufacturer, Neurochem, plans to market it as a nu-traceutical rather than pursuing further development of tramiprosate as a drug, according to Dr. Ahern.

Development of neotrofin, a drug that mimics the effects of nerve growth factor and other neurotrophins, which generate or support the growth of brain cells, has been discontinued because of disappointing phase II study results.

So what still looks promising for Alzheimer's disease?

Amyloid fibril antiaggregation therapy is not dead, despite the setback with tramiprosate.

Dr. Ahern is involved in ongoing phase II/III clinical trials of Elan's amyloid fibril antiaggregation agent known for now as D005, which is based upon a sugar found in coconut, oak bark, and dogwood flowers.

Nor is treatment with neurotrophic agents a closed avenue, despite the failure of neotrofin. …

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