Promising Plaque-Lowering Drug Studied for Clinical Efficacy

An experimental drug for Alzheimer’s disease— Hoffmann-Laroche’s gantenerumab—can reduce amyloid plaques in individuals with the disease, according to research reported in the October Archives of Neurology.

The senior investigator for the study was Luca Santarelli, M.D., senior vice president of neuroscience at the company, which is based in Basel, Switzerland.

“It is likely that the accumulation of amyloid in brain is the primary causative factor in Alzheimer’s disease,” Paul Aisen, M.D., director of the Alzheimer Disease Cooperative Study at the University of California, San Diego, told Psychiatric News. “The leading strategy for the development of disease-modifying therapy for Alzheimer’s involves reducing brain amyloid. The demonstration by these investigators that … gantenerumab achieves target engagement with brain amyloid reduction in Alzheimer’s is thus a very positive step toward the development of an effective treatment; the results of ongoing trials with gantenerumab are eagerly awaited.”

“This type of treatment may have great value in treating people with amyloid burden while they are still cognitively normal,” Raymond Lo, M.D., a neurologist and Alzheimer’s researcher at the University of California, Berkeley, added. The caveat, however, he stressed, is “if we are able to identify these at-risk people.”

In this study, 16 subjects with probable mild or moderate Alzheimer’s disease were randomly allocated to receive two to seven infusions of either gantenerumab (60 mg or 200 mg) or a placebo every four weeks. They ended up being treated for between two and seven months. PET scans of their brains before and after treatment were compared.

Gantenerumab led to a dose-dependent reduction in amyloid in the brains of the Alzheimer’s subjects who received it. The average percent change in cortical brain amyloid level in those individuals, relative to the level in individuals who got a placebo, was minus 16 percent for the 60 mg group and minus 36 percent for the 200 mg group.

“Although we had seen promising reductions of plaques in animal models with this treatment, the results, and especially the rapidity of the effects observed, in this trial went beyond our expectations,” Santorelli told Psychiatric News.

Two subjects in the 200 mg group showed transient inflammation or edema at the brain sites with the highest level of amyloid reduction. Both patients also developed micro-hemorrhages, and one of them was mildly symptomatic with headache, dizziness, gait instability, and tremor. All other subjects were asymptomatic.

Gantenerumab consists of monoclonal antibodies against amyloid plaques. Still other research performed in conjunction with this study suggested that the drug works via the process of phagocytosis.

If gantenerumab causes plaques to be removed rapidly from patients’ brains, it might lead to a saturation in the clearance mechanisms and explain why two subjects showed transient edema or micro-hemorrhages, the scientists speculated.

Although dose-dependent reductions in amyloid plaques were observed in the subjects who received the drug, no consistent treatment effects on cognitive measures were noted during the short treatment time. Thus the next step will be to see whether gantenerumab’s ability to clear plaques from the brain translates into clinical efficacy. Hoffman-Laroche has already launched a phase 2 trial to see whether this is the case, Santarelli and his colleagues noted.

Santarelli explained to Psychiatric News that the trial is called the Scarlet ROAD study. Some 360 individuals will participate in it at about 100 study centers in 15 countries. Each participant will be involved in the study for about two years.

The individuals being recruited for this study, he said, will need to be in the prodromal stage of Alzheimer’s, “when hopefully less damage to the brain has occurred.” For example, a person may be unable to recall events from the recent past, and certain biomarkers in the brain may reveal whether he or she is prodromal.

The study, he indicated, will assess gantenerumab’s ability to keep “the clinical signs of prodromal Alzheimer’s from getting worse. We will be studying the effects of gantenerumab on participants’ ability to remember information, to solve problems, and to go about day-to-day activities.”

The study was funded by Hoffmann-Laroche.

“Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab” is posted at <http://archneur.ama-assn.org/cgi/content/full/archneurol.2011.1538>. Information on the Scarlet RoAD study is posted at <www.scarletrdstudy.com>.