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Trial Shows Antibody Slows Alzheimer’s Cognitive Decline

model of amyloid-beta peptides

Stick-ribbon model of amyloid-beta peptides (public domain/Wikimedia Commons)

1 September 2016. A clinical trial shows older individuals with early or mild cases of Alzheimer’s disease treated for a year with an engineered human antibody have less decline in mental functions associated with Alzheimer’s disease. Results of the trial and a related preclinical study with lab mice were reported yesterday in the journal Nature (paid subscription required).

Alzheimer’s disease is progressive neurodegenerative disease affecting growing numbers of older people worldwide. People with Alzheimer’s disease often have deposits of abnormal substances in spaces between brain cells, known as amyloid-beta peptides, as well as misfolded tangles of proteins inside brain cells known as tau. The Alzheimer’s Association says some 5.4 million individuals in the U.S. have the disorder, of which 5.2 million are age 65 or older. By 2050 that number is expected to increase to 13.8 million.

The Nature paper reports on work at University of Zurich in Switzerland, led by neuroscientist Roger Nitsch, director of the university’s Institute of Regenerative Medicine. Nitsch and colleagues from the biotechnology company Biogen and University of Zurich spin-off enterprise Neurimmune, tested aducanumab, an engineered antibody designed to reduce amyloid-beta peptide plaques in the brain associated with Alzheimer’s disease. Nitsch is a founder of Neurimmune and the company’s president.

Neurimmune, in Zurich, first developed aducanumab using a technology the company calls reverse translational medicine that derives antibodies from B cells, white blood cells in the immune system, donated by healthy older individuals with either no signs or very slow cognitive decline. While engineered and designed to attack specific targets, the antibodies retain many human properties, according to the company, and invoke little if any immune reactions. Biogen, in Cambridge, Massachusetts, licensed aducanumab from Neurimmune, and the two companies are collaborating on further development, including clinical trials.

The researchers reported on preclinical tests of aducanumab on genetically altered mice that developed amyloid-beta plaques, with results showing the antibody entering the brain and binding to the plaques. Most of the paper, however, describes an early-stage clinical trial with 165 individuals, age 50 and older, diagnosed in early stages or with mild cases of Alzheimer’s disease. The trial was designed to test the safety of aducanumab in various dosage levels (against a placebo), and also the antibody’s chemical activity in the body, including clearance of amyloid-beta accumulations in the brain.

The results, measured by positron emission tomography, or PET, scans of participants’ brains show after 1 year of intravenous treatments of aducanumab every 4 weeks, participants receiving the antibody cleared at least some amyloid-beta plaques compared to the placebo, with patients receiving higher doses of the antibody clearing more of the plaques than those receiving lower doses.

The team also used the opportunity to test cognitive performance of participants with two standard rating scales of mental decline, Clinical Dementia Rating and Mini-Mental State Examination. Participants were initially screened with those tests to be included in the trial. The results show participants receiving aducanumab had slower decline in cognitive function than their counterparts receiving a placebo. “While patients in the placebo group exhibited significant cognitive decline,” says Nitsch in a university statement, “cognitive ability remained distinctly more stable in patients receiving the antibody.”

The main adverse effects reported were amyloid-related imaging abnormality, or ARIA, associated with micro-hemorrhages and collection of fluid around cells in the brain that show up on MRI scans, as well as temporary mild to moderate headaches in some cases. The researchers say these adverse effects result from the clearance of amyloid-beta plaques.

Biogen is recruiting participants for 2 late-state clinical trials, code-named Emerge and Engage, each testing aducanumab against a placebo with 1,350 participants, on slowing cognitive and functional impairment.

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