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" In all likelihood, Alzheimer's disease is going to require multiple therapies like most other diseases do. ... As the field expands, other approaches will come online as well. We certainly hope aducanumab is successful, but we know that we need to look at other therapeutic targets as well, such as the tau protein and other inflammatory mechanisms that lead to cell death." — DAVID KNOPMAN, MD, CHAIR OF THE ALZHEIMER'S ASSOCIATION MEDICAL AND SCIENTIFIC ADVISORY COUNCIL AND CONSULTANT IN NEUROLOGY AT THE MAYO CLINIC therapeutic use of antibodies that target the beta-amyloid protein. There have since been several attempts to use passive immunization with an antibody to treat Alzheimer's; however, to date, none of the therapies has been successful. The Nature paper discusses results from the PRIME study, a phase 1b clinical trial exploring the use of aducanumab — a human monoclonal antibody that is the latest in a long line of antibody therapies desig ned to destroy a myloid plaques within the brain. EXPLORING THE METHODOLOGY AND RESULTS The PR IM E st udy wa s a sma l l tr ia l designed to test the safety and tolerabil- ity of aducanumab, as well as the drug's eff ect on beta-amyloid as measured by PET imaging. Researchers recruited 165 participants who each had elevated levels of amyloid deposits in the brain visible on PET scans, as well as mild cognitive impairment. Participants were split into fi ve groups. One group received a monthly infusion of a placebo drug, while participants in the other groups received infusions of 1, 3, 6 or 10 mg/kg of aducanumab, respec- tively, for 54 weeks. Results revea led signifi cant, dose-dependent reductions in beta-amyloid levels among the partici- pants who received aducanumab. " W h at t hey fou nd wa s t h at t hei r antibody was very eff ective at reducing brain amyloid burden as measured by PET scanning," says David Knopman, MD, Chair of the A lzheimer's Association Medical and Scientifi c Advisory Council and Consultant in Neurology at the Mayo Clinic. "That's created the excitement around this drug." The most frequently reported adverse ef fect wa s a myloid-related i ma g i ng abnormalities. Of the 165 original par- ticipants, 20 dropped out of the study due to side eff ects. A lt hou g h t h e s t u d y w a s n eit h er designed nor suffi ciently large to assess aducanumab's eff ect on cognitive func- tioning, exploratory analysis suggests that the reduction in amyloid plaque may slow the progression of memory and thinking decline, as evidenced by scores from the Clinical Dementia Rating-Sum of Boxes and Mini-Menta l State Examination, which were administered at weeks 26 and 54. In a press release from Biogen, the company that developed aducanumab a nd funded the PR IME study, A lfred Sandrock, MD, PhD, Biogen Executive V ic e P r e s ident a nd C h ief Me d ic a l Offi cer, expressed positivity about the results, saying, "These early studies of aducanumab show its eff ectiveness in removing amyloid plaque from the brain, as well as its potential eff ect on the slowing of cognitive decline in patients suff ering from Alzheimer's disease." Researchers are further investigating aducanumab's safety and effi cacy through two large-scale, phase 3 studies — the ENGAGE and EMERGE studies — that are currently recruiting patients. These studies, slated for completion in spring 2022, assess whether or not aducanumab is a safe, tolerable means of slowing cogni- tive decline. "If that exploratory fi nding, which one needs to take with a grain of salt right now, is confi rmed in the larger, more defi nitive phase III trials, it would be a game-changer for the fi eld because it would provide con- clusive support for the amyloid hypothesis, and it would demonstrate a relationship between the treatment, the anti-amyloid eff ects and the clinical benefi ts, which help to speed up the evaluation of treatment in people at risk for Alzheimer's disease," Dr. Reiman says. "It would be a real shot in the arm for the fi eld." n M D N E W S .C O M /// M D N E W S S A N A N T O N I O ■ 2 017 1 7

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