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Affiris: Alzheimer's 'breakthrough' needs confirmation

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By Cormac Sheridan
Staff Writer

Affiris AG claims to have achieved the first evidence of disease modification in Alzheimer's, although the result will, for now at least, lead to widespread head-scratching rather than celebration.

In a phase II trial of its peptide-based therapeutic vaccine AD02, the Vienna, Austria-based company found that the substance it used as placebo, now dubbed AD04, appeared to halt disease progression through a poorly understood effect that was unconnected with AD02's presumed mechanism of action.

The study recruited 332 patients with early stage disease, who were randomized on a 1-to-1 basis to receive either AD02 or AD04 over a one-year treatment period. The primary endpoint combined cognitive (modified ADAS-cog) and functional (modified ADCS-ADL) scores at 18 months. Secondary endpoints included volumetric MRI measures of patients' brains. The principal investigator on the study was Bruno Dubois, of Salpêtrière University Hospital in Paris, a prominent Alzheimer's scientist and clinician.

Forty-seven percent of those who received AD04 exhibited what the company called "effects consistent with disease modification" for at least 18 months. Moreover, the cessation of disease progression was correlated with a stabilization of hippocampus volumes.

"You can't achieve that by a placebo effect. This is something that is real and that is defined by the EMA and the FDA as a prerequisite for disease modification," Affiris CEO and co-founder Walter Schmidt told BioWorld Today.

For now, the company is keeping details of AD04 under wraps. "We want to leave this question unanswered," Schmidt said. "I think we have to do our commercial homework first." That means filing for patent protection on the substance, as it was never intended to be used as a drug in the first place.

It is quite distinct from AD02, a peptide-based therapeutic vaccine designed to induce a B-cell response against amyloid beta, the extracellular deposition of which is one of the pathological hallmarks of Alzheimer's. Although the company does not have a whole lot of supporting evidence as yet, AD04 may trigger an innate immune response that leads to phagocytic clearance of amyloid beta.

"This is our hypothesis. There are definitely no antibodies generated against amyoloid beta as there is no peptide antigen injected," Schmidt said. "It's not a vaccine; it's not working via B cells and antibodies."

As the present study was not a prospective trial of AD04, the company will need to repeat the exercise in a controlled study. "We have seen unexpected disease modification in a group for which we [didn't] have a placebo group," Schmidt said. The firm has not yet decided when the study will start. "We are now at the stage of evaluating our options. After that we will decide how to move it forward," he said.

AD02 previously was licensed to London-based Glaxosmithkline plc as part of an alliance worth up to €430 million (US$586 million), but GSK terminated its involvement last fall, leaving Affiris with full freedom to operate. (See BioWorld Today, Oct. 27, 2008.)

Medical history is amply supplied with major breakthroughs that arise from apparent anomalies. It will take additional confirmatory work to establish whether AD04 is one of them – or whether it is more akin to Dimebon (latrepirdine), an antihistamine with a long history of use in Russia, for which New York-based Pfizer Inc. paid $225 million up front to San Francisco-based Medivation Inc. for rights in Alzheimer's and other neurodegenerative conditions. That drug failed to demonstrate efficacy in phase III trials. (See BioWorld Today, Jan. 18, 2012.)

Although a slew of antibodies and therapeutic vaccines targeting amyloid beta has fallen by the wayside over the past decade, the so-called amyloid hypothesis is by no means unproven. The lack of an early, clear-cut diagnostic for the condition, which is further exacerbated by the absence of reliable biomarkers, means that clinical investigators are still largely flying blind in their efforts to tackle the disease.

Several programs are ongoing, however, some of them based on genetic insights into the condition. Crenezumab, AC Immune SA's anti-Abeta antibody partnered with the Genentech division of Roche AG, is undergoing a phase II prevention trial in a Colombian cohort with a genetic predisposition to develop early onset Alzheimer's. Lausanne, Switzerland-based AC Immune also is developing a therapeutic vaccine, ACI-24, which raises an antibody response directed at the beta-sheet conformation of amyloid protein. A phase I/IIa trial is ongoing.

Earlier this year, Cambridge, Mass.-based Biogen Idec Inc. entered a multiproduct alliance with Eisai Co. Ltd. that includes BAN2401, an antibody targeting amyloid beta protofibrils, which was originally discovered by Bioarctic Neuroscience AB, of Stockholm. A phase IIb trial is under way in 800 patients. (See BioWorld Today, March 4, 2014, and March 6, 2014.)