Results of a phase 1b clinical trial published in Nature reveal scientists may be one step closer to finding a treatment that safely impedes the biological progression of Alzheimer’s disease.
The CDC estimates 5 million Americans have Alzheimer’s. Without the development of effective treatments, the number of people with the disease may rise to 13.8 million by 2050, according to a 2013 Neurology study.
The hallmarks of Alzheimer’s disease neuropathology, which are visible under the microscope and through use of PET imaging, include amyloid plaques and neurofibrillary tau tangles.
While palliative therapies, such as donepezil and rivastigmine, may be prescribed to delay symptom onset, no treatments that slow the progression of Alzheimer’s disease pathology currently exist.
Building on Decades of Research
During the past 20 to 25 years, researchers have sought preventive or curative therapies for Alzheimer’s. The first drugs developed target amyloid plaques and essentially test what is known as the amyloid hypothesis.
“Many, but not all, researchers believe that accumulation of a particular form of beta-amyloid protein plays a role in an initiating event that ultimately leads to the microscopic brain abnormalities and memory and thinking problems we see in individuals with Alzheimer’s disease,” says Eric M. Reiman, MD, Executive Director of the Banner Alzheimer’s Institute in Phoenix. “The thinking is that through one mechanism or another, there is an increase in individual beta-amyloid peptides, or proteins, and that, in the case of Alzheimer’s disease, the form of this protein and its 42 amino acids aggregates with other amyloid-beta 42 proteins in what we refer to as soluble oligomers and insoluble fibrils, or plaques.”
These oligomers and fibrils are suspected of interfering with cell-to-cell communication within the brain and eventually cause cell death, according to the Alzheimer’s Association.
Using transgenic animal models of Alzheimer’s disease created in the 1990s, researchers began exploring the 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 designed to destroy amyloid plaques within the brain.
Exploring the Methodology and Results
The PRIME study was a small trial designed to test the safety and tolerability of aducanumab, as well as the drug’s effect 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 five 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, respectively, for 54 weeks. Results revealed significant, dose-dependent reductions in beta-amyloid levels among the participants who received aducanumab.
“What they found was that their antibody was very effective at reducing brain amyloid burden as measured by PET scanning,” says David Knopman, MD, Chair of the Alzheimer’s Association Medical and Scientific Advisory Council and Consultant in Neurology at the Mayo Clinic. “That’s created the excitement around this drug.”
The most frequently reported adverse effect was amyloid-related imaging abnormalities. Of the 165 original participants, 20 dropped out of the study due to side effects.
Although the study was neither designed nor sufficiently large to assess aducanumab’s effect on cognitive functioning, 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-Mental State Examination, which were administered at weeks 26 and 54.
“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
In a press release from Biogen, the company that developed aducanumab and funded the PRIME study, Alfred Sandrock, MD, PhD, Biogen Executive Vice President and Chief Medical Officer, expressed positivity about the results, saying, “These early studies of aducanumab show its effectiveness in removing amyloid plaque from the brain, as well as its potential effect on the slowing of cognitive decline in patients suffering from Alzheimer’s disease.”
Researchers are further investigating aducanumab’s safety and efficacy 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 cognitive decline.
“If that exploratory finding, which one needs to take with a grain of salt right now, is confirmed in the larger, more definitive phase III trials, it would be a game-changer for the field because it would provide conclusive support for the amyloid hypothesis, and it would demonstrate a relationship between the treatment, the anti-amyloid effects and the clinical benefits, 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 field.”