Confirming in part what many in the Alzheimer’s field have expected, Pfizer Inc.said July 23 that the intravenous Alzheimer’s disease treatment bapineuzumab has failed to hit co-primary efficacy endpoints in a Phase III trial of patients with mild-to-moderate disease who carry the risk-prone ApoE4 gene.

The top-line results from Study 302 are the first to be reported of four large studies carried out by Pfizer and Janssen Alzheimer Immunotherapy R&D LLC. While disappointing, they are not unexpected, based on Phase II results, and those expectations have driven both scientific and business decisions in the field for some time.

“Investors have expected that bapineuzumab and related monoclonal antibodies for Alzheimer’s, like Eli Lilly’s solanezumab, are highly likely to fail and so far this assumption has been correct,” wrote Sanford C. Bernstein & Co. analyst Tim Anderson in a July 23 research note.

Bapineuzumab is a monoclonal antibody designed to clear plaques, or accumulations of a specific beta-amyloid fragment, Aβ-42, from the brain in patients with mild-to-moderate forms of in Alzheimer’s disease Also see "J&J And Elan Strike A Deal On Key Alzheimer's Disease Assets" - Pink Sheet, 6 July, 2009.. Researchers have surmised that the plaques are early events that trigger degradation and that drugs aimed at this target could tackle disease progression, rather than just symptoms.

Though the beta amyloid target has been popular with pharma, the development space has been fraught with disappointments. The new data are also sure to add fuel to the debate whether researchers should target amyloid plaques, and, if so, when. The field has already begun to test anti-beta amyloid interventions in patients who have yet to show cognitive decline, with the goal of stopping accumulation of the protein fragments before they begin. Recently published research, in which people with a rare genetic mutation that reduces production of beta amyloid also protects them from Alzheimer’s disease, seems to bolster the Aβ hypothesis. Still, others in the field believe Aβ is more effect than cause and are exploring other targets. ([A#2012900118])

Those who have the apolipoprotein E epsilon 4 mutation are at higher risk for Alzheimer’s and more vulnerable to swift disease progression. The just-released Phase III data showed bapineuzumab was ineffective in these patients, confirming results of a Phase II trial that concluded in 2008. The Phase III arm in ApoE4 non-carriers will continue, with results set to be presented at the European Federation of Neurological Sciences meeting in September. Janssen is leading that study, and Pfizer is responsible for two ex-North American Phase III studies, also investigating bapi’s effects on carriers and non-carriers.

The North American Study 302 evaluated the drug’s performance in about 1,100 ApoE4 carriers against placebo. The drug failed to improve cognitive function, as measured by change in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ACAS-Cog), and function, measured by the Disability Assessment for Dementia, Pfizer announced. Patients with the ApoE4 genotype who were enrolled in a follow-on extension study will not receive any more doses of the drug, but they will have a follow-up evaluation, the company said.

An interim analysis of a second Phase III study testing the drug in ApoE4 carriers outside North America will now be expedited in light of the failure of Study 302.

Based on the 2008 bapineuzumab Phase II data, the odds of success in non-carriers might be higher, wrote ISI Group analyst Mark Schoenebaum in a research note.

But in large part, attention has already turned toward treating patients who show little or no symptomatic effect of the disease. The concern is that amyloid plaque clearance is like cleaning up the debris after a bomb has gone off: too late for therapeutic effect. A consortium that includes Roche’s Genentech Inc. recently announced it would test an anti- Aβ monoclonal antibody in a prevention trial in a population of people with genetic mutations that doom them to an early-onset version of Alzheimer’s.

Most are in Colombia and share a common ancestry. Led by the Banner Alzheimer’s Institute in Tucson, Ariz., the trial will use the antibody crenezumab, discovered by AC Immune SA and co-developed by Genentech, in large part because of its safety profile in early human studies. The aim is to avoid the vasogenic edema – which again was a problem in the newly released top-line bapi data, just as it was in the Phase II bapi program – that forced lower dosing of bapineuzumab. Other companies are testing anti- Aβ therapies in presymptomatic patients, as well.

However, except in the early-onset genetic-based forms of the disease, biomarkers for confidently identifying people likely to develop Alzheimer’s are still under development. There is nothing akin to the markers for cardiovascular risk that make statins such an easy call for doctors and their patients.

Bapineuzumab Failure Raises More Doubts About Beta Amyloid Approach In Alzheimer’s

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