STOCKHOLM – The vexed problem of conclusively proving – or disproving – the amyloid hypothesis as the key driver of the pathology of Alzheimer’s disease has been exhaustively rehearsed in multiple settings over the last decade.

A string of clinical trial failures, most notably those of bapineuzumab and solanezumab, has underlined the multiple difficulties attached to diagnosing patients, designing clinical trials and recruiting appropriate subjects to enable a drug’s efficacy signal to be assessed accurately.

The prospect of meaningful progress remains difficult without a clearcut identification of the specific molecular culprit that initiates and drives the disease cascade – and without unambiguous methods for early diagnosis. Several trials are ongoing, however, including the first preventive study, in a cohort with a genetic risk of developing an early onset form of the disease. (See BioWorld Today, May 17, 2012.)

Bioarctic Neuroscience AB, a Swedish biotechnology firm that flies a little below the radar, is betting that a combination of Bayesian statistical methods and an anti-amyloid antibody with distinctive binding properties will succeed where so many others have failed. Although it may have a relatively low international profile, Bioarctic isn’t hiding anything. The company’s name is writ large on the front of its sparkling new premises on the island of Kungsholmen in Stockholm, in a district that has historic associations with Sweden’s pharmaceutical industry.

But given that it has had a partner – Tokyo-based Eisai Co. Ltd. – for its Alzheimer’s drug discovery program from the outset, it has had little need to make much noise. “We have been working with Eisai from day one. When we first met them, we didn’t even have an antibody,” company co-founder Pär Gellerfors told BioWorld Today. The antibody that eventually emerged from its research, BAN2401, is now undergoing a phase IIb trial in 800 early stage patients.

The study got under way in early 2013 and is scheduled to run until 2016. Because of its adaptive design, it could provide some hints of efficacy before then, however. “It’s the best effort, I would say, to maybe see some efficacy,” Gellerfors said.

The trial is testing multiple doses and dosing schedules, and frequent interim analyses will influence the randomization of new recruits. It is recruiting patients with Alzheimer’s-associated mild cognitive impairment or with dementia due to mild Alzheimer’s. Patients’ cognitive function will be assessed using a new questionnaire, which the FDA has approved for the study. It is derived from several earlier instruments but is weighted toward the most discriminating measures.

Eisai is a long-term backer of the research of Bioarctic’s chairman and co-founder Lars Lannfelt, who is based at Uppsala University. Lannfelt has made fundamental contributions to the understanding of Alzheimer’s through his identification of two disease-causing mutations in Swedish families, the Swedish mutation and the Arctic mutation. The latter comprises a glycine-to-glutamic-acid substitution at codon 693 within the Abeta region of the amyloid precursor protein (APP).

It has provided the inspiration for BAN2401 an antibody that selectively binds amyloid-β protofibrils, a soluble, intermediate oligomer species that occurs during the formation of amyloid fibrils. They are elevated in individuals carrying the Arctic mutation, who develop an early onset and aggressive form of Alzheimer’s. Studies from Lannfelt’s labs and others have demonstrated that protofibrils are toxic – and open up the possibility that amyloid plaque deposits may not actually be the disease driver.

“There has always been a lack of correlation between the amount of deposition of plaque and the severity of disease,” Gellerfors said. It may not take too long to ascertain whether Bioarctic’s alternative theory holds up in the clinic.