Promising AD treatments remain in pipeline: amyloid fibril antiaggregation therapy and neurotrophic agents are still under consideration.
EXPERT ANALYSIS FROM A PSYCHOPHARMACOLOGY psychopharmacology (sī'kōfär'məkŏl`əjē), in its broadest sense, the study of all pharmacological agents that affect mental and emotional functions. CONFERENCE SPONSORED BY THE UNIVERSITY OF ARIZONA (body, education) University of Arizona - The University was founded in 1885 as a Land Grant institution with a three-fold mission of teaching, research and public service.
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 Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation and neural plasticity. 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 nerve growth factor
n. Abbr. NGF
A protein that stimulates the growth of sympathetic and sensory nerve cells.
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 fibril /fi·bril/ (fi´bril) a minute fiber or filament.fibril´larfib´rillary
collagen fibrils 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 dogwood or cornel (kôr`nəl), shrub or tree of the genus Cornus, chiefly of north temperate and tropical mountain regions, characteristically having an inconspicuous flower surrounded by large, showy bracts which flowers.
Nor is treatment with neurotrophic agents a closed avenue, despite the failure of neotrofin.
Proof of principle has been provided by evidence of efficacy for intrathecal intrathecal /in·tra·the·cal/ (-the´k'l) within a sheath; through the theca of the spinal cord into the subarachnoid space.
Intrathecal infusion of nerve growth factor in patients with Alzheimer's disease, although this is a therapy that's clinically impractical as it entails accessing the basal forebrain via stereotactic stereotactic /ster·eo·tac·tic/ (-tak´tik)
1. characterized by precise positioning in space; said especially of discrete areas of the brain that control specific functions.
2. pertaining to stereotactic surgery. brain surgery. Interest is now focused on Cerebrolysin, an intramuscularly administered agent which in phase II trials led to improvements in memory and concentration in about two-thirds of treated patients.
Cerebrolysin is approved in Austria and several dozen other countries, and U.S. clinical trials are ongoing.
Immunotherapy both active and passive, continues to be a highly active area of investigation in Alzheimer's disease. Active immunization was nearly derailed for a time with the early halt of a phase Ha study of AN-1792, the highly publicized first so-called Alzheimer's vaccine, after 18 of 360 subjects developed florid encephalitis, paralysis, or death.
Intriguingly, however, 5-year follow-up of titer-positive patients showed a significant reduction in placement in long-term care facilities.
AN-1792's downfall is thought to have been that it was a synthetic form of the full 42 amino acid amyloid-beta peptide. Pfizer, Wyeth, and Novartis are now developing vaccines that use smaller amyloid fragments as immunogens.
The Pfizer vaccine, for example, uses just 6 of the 42 amino acids from amyloid-beta peptide. These new vaccines seem to have far fewer side effects.
But the first immunotherapy to gain an indication for Alzheimer's disease may well be Baxter's polyclonal intravenous immunoglobulin, Dr. Ahern predicted.
This passive immunotherapy is already familiar to neurologists, who have long used it in treating patients with multiple sclerosis, Guil-lain-Barre syndrome, and other disorders. It's well tolerated. Data from phase II studies showed evidence of benefit in patients with mild to moderate Alzheimer's disease, and phase III trials are ongoing.
Another approach to passive immunization using exogenous antibodies is bapineuzumab, a monoclonal antibody against amyloid-beta protein, being developed by Wyeth and now in phase III testing. A monoclonal antibody is a more specific form of therapy than IVIG IVIG Intravenous immunoglobulin, see there , which could be advantageous.
In addition, Eli Lilly Novartis, and Eisai are developing monoclonal antibodies against amyloid-beta protein.
Dr. Ahern declared that he has no financial interests relevant to his presentation.
Another approach to passive immunization using exogenous antibodies is bapineuzumab, a monoclonal antibody against amyloid-beta protein, which is now in phase III testing.