Negative results of bapineuzumab clinical trials may question the basis of Alzheimer’s disease

After several years of clinical testing, Pzifer and Johnson&Johnson recently announced that one of their most promising drugs to treat Alzheimer’s, bapineuzumab, has failed to meet primary endpoints in a phase III trial. As a consequence, not only 130 positions have been eliminated, but also the molecular basis of this neurodegenerative disease itself has been questioned.

The drug consists of a monoclonal-humanised antibody against beta-amyloid, a toxic protein for the brain whose accumulation is believed by many scientists to be responsible for the degenerative changes associated with this illness. The immunotherapy seemed the perfect solution in order to clear the build-up of amyloid plaques or prevent its formation, as the binding of the antibodies to the plaques should be able to remove them from the brain, thus improving the cognition or daily functioning of the patients.

The intravenous formulation of bapineuzumab was tested on 1,100 people with mild-to-moderate disease. Moreover, all of them carried the ApoE4 genotype (about half of the Alzheimer’s population shares this genotype), which raises the risk of suffering from Alzheimer’s and may also worsen its symptoms. Although in early phase II trials performed on 2008 the drug did not show significant effects, they decided to keep on testing due to the promising theoretical benefits of this kind of treatment. However, in phase III trials patients who took the drug did not significantly outperform the placebo.

The negative results of the trial could suggest that beta-amyloid might not be the culprit in Alzheimer’s disease. Alternatively, some experts think there could be another reason behind this failure: the drug may have been administrated to people at a late stage of the disease. Yet, this statement doesn’t make any sense; if amyloid is in fact the toxic component, an effective anti-amyloid immunotherapy should succeed in slowing disease progression. Besides, there is a phase I case report published in The Lancet (Amyloid-β vaccination for Alzheimer's dementia, 2008) of an anti-amyloid vaccine in which the authors did not observe prevention of progressive degeneration despite of the clearance of amyloid plaques.

All in all, the publication of this negative result is expected to be a turning point with regard to the molecular basis of the disease; the amyloid hypothesis is probably dead for the moment.

References:
1.- Ed Silverman (October 2012) J&J Cuts 130 Jobs After Alzheimer Drug Fails. Pharmalot.
2.- Michelle Castillo (July 2012) Anticipated Alzheimer's drug bapineuzumab shows no patient benefits in trial. CBSNews.
3.- Nathan Sadeghi-Nejad (July 2012) The Lessons Of Failure: What We Can Learn From Bapineuzumab's Blowup. Forbes.
4.- doi:10.1016/S0140-6736(08)61580-9
5.- doi: 10.1212/WNL.0b013e3181c67808

Written by Julio Rios for The All Results Journals.