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 at a psychopharmacology conference sponsored by the University of Arizona.
Dr. Geoffrey L. Ahern
"A lot of hope and money and work time has been put into Alzheimer’s disease, and it doesn’t 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, 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, a protease that cleaves amyloid precursor protein to produce the amyloid-beta peptide that constitutes amyloid plaques, a defining feature of Alzheimer’s disease. The phase III trial for tarenflurbil was negative. Similarly, phase II/III clinical trials of hydroxylvaleryl monobenzocaprolactam, 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 nutraceutical 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. Proof of principle has been provided by evidence of efficacy for 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 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 IIa 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, Guillain-Barré 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, which could be advantageous. Eli Lilly, Novartis, and Eisai are also developing monoclonal antibodies against amyloid-beta protein.
Dr. Ahern declared that he has no financial interests relevant to his presentation.