Alzheimer’s research moves earlier as amyloid data approaches

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As outcomes approach from the most rigorous tests to date of the Alzheimer’s disease amyloid hypothesis – phase III results from Eli Lilly’s solanezumab and Pfizer and Elan’s bapineuzumab – US backing of a similar antibody being developed by Roche shows much hope still exists that targeting this mechanism will yield therapies for the devastating degenerative brain disease.

Announced yesterday as part of the US government’s drive to support research into Alzheimer’s, the NIH will help fund a novel study of crenezumab in patients yet to develop symptoms to see if the drug can stave off the disease. Researchers are increasingly convinced that for amyloid-targeting treatments to prove effective, they need to be started before symptoms appear. Having recruited patients with existing evidence of disease many expect the solanezumab and bapineuzumab trials to fail; the crenezumab study shows the focus of a-beta research is already shifting to even earlier stage patients.

Binding and clearing

Much research into potential Alzheimer’s therapeutics is focused on beta amyloid plaques in the brain. Beta amyloid is a fragment of the amyloid precursor protein, which in healthy brains is broken down and eliminated. In Alzheimer’s disease patients they form deposits, or plaques, that are thought to contribute to the degradation of brain cells.

Crenezumab, like solanezumab and bapineuzumab, works by binding to amyloid proteins to promote clearance from the brain.

Researchers are increasingly convinced that to have any substantial impact on Alzheimer’s disease, the plaques and protein tangles need to be prevented from forming in the first place. Amyloid accumulates in patients' brains about 15 years prior to the onset of dementia, so it seems likely that early diagnosis and treatment, before significant damage to nerve cells has occurred, is the key to helping patients.

However without reliable, early diagnosis techniques or effective drugs to treat identified at-risk patients, neither of which exist at the moment, the door to exploiting amyloid-targeting therapies remains firmly locked. The collaborators pushing forward with crenezumab hope the trial they have designed will establish a viable route to exploit these types of drugs effectively.

Slowing progression

The trial, costing around $100m, will recruit 300 patients, to be funded mainly by Roche with the NIH and Banner Alzheimer’s Institute contributing around $15m each. Patients will mostly be recruited from an extended family in Colombia who have a genetically driven predisposition to early onset Alzheimer’s; symptoms are typically triggered around the age of 45.

The trial is designed to determine whether the drug can reduce participants’ chances of developing the disease’s symptoms, preserve memory and thinking abilities, and slow the progression of Alzheimer’s biomarkers.

The collaborators say that if crenezumab is shown to sustain memory and cognition in people certain to develop Alzheimer’s, prevention trials could be designed to test it and other anti-amyloid drugs in a larger segment of the population. If the treatment’s effects on brain imaging and other biological measurements of the disease are shown to predict its clinical benefit, the study could also establish a much more rapid way to test future therapies.

That this study is being started before the results from solanezumab and bapineuzumab are known is probably a fair indicator of the low hopes of success for these trials.

Evidence on horizon

Data should emerge soon, with solanezumab expected to report first. In January Lilly said that an independent data monitoring committee recommended the two ongoing phase III pivotal trials for solanezumab continue without modifications, based on pre-planned interim safety and futility analyses. Two trials called Expedition and Expedition 2 recruited 1,000 patients with mild to moderate Alzheimer’s, who received the drug, or placebo, for 80 weeks.

The primary endpoints measure changes on two scales assessing cognitive function and functional performance. Results are anticipated in the third quarter of the year but few expect a positive read out. Analysts from Morgan Stanley, for example, model a 90% chance of failure.

Bapineuzumab, which binds to different amino acids of the beta amyloid protein, is considered to have a slightly higher chance of success due to what appears to be greater potency and marginally more encouraging earlier data. The two pivotal studies, due to report later in the year, have been designed to distinguish between carriers of a gene associated with risk of developing the condition and responsiveness to therapy, but again recruited symptomatic patients.

Best hope

With little confirmative evidence of cognitive improvement gleaned from earlier studies of either of these antibodies, the developers’ high risk gamble to push into large and expensive pivotal studies represent as much of bet on the amyloid theory of Alzheimer’s as on the compounds themselves.

However even if the studies do flop, the reasons for their failure will provide crucial insight into many aspects of amyloid research. Chiefly, many will be hoping to find evidence that the amyloid hypothesis is in fact correct – it remains far from proven that the plaques cause the degeneration and it is possible that other mechanisms are at work.

Other potential reasons for failure include the wrong dose of the drugs being given over too short a time period. However many suspect it will simply come down to enrolling patients too far advanced to help.

Which is what has spurred the trial with crenezumab. For while the amyloid hypothesis is unproven, it remains the best hope.

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