Aducanumab Reduces Amyloid Plaques in Early Alzheimer's: PRIME Published

Deborah Brauser

September 06, 2016

The investigational Alzheimer's disease (AD) treatment aducanumab (Biogen Inc) decreases amyloid plaques, as measured by positron emission tomography (PET), and slows cognitive decline in a dose-dependent manner up to 1 year, additional findings from the phase 1b PRIME trial show.

Results from the trial were the basis for the US Food and Drug Administration (FDA) Fast Track designation, granted September 1.

Initial results from the trial were first presented at last year's AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases, and reported by Medscape Medical News at that time, with further subgroup results presented at the American Academy of Neurology 67th Annual Meeting.

The study included 165 patients with confirmed β-amyloid (Aβ) deposition who were randomly assigned to monthly intravenous infusions of placebo or 1, 3, 6, or 10 mg/kg of aducanumab. The early findings showed significant reductions in amyloid plaque at week 54 for those receiving the 3- and 10-mg/kg doses.

More data are now published in the September 1 issue of Nature, including positive 1-year results for the 6-mg/kg cohort, whose evaluation had not been completed at the earlier presentations.

Exploratory results also show decreased cognitive impairment scores from baseline to 1 year for the 3- and 10-mg/kg dosage groups. But the investigators, led by Jeff Sevigny, Biogen, Cambridge, Massachusetts, caution that "the study was not powered to detect clinical change."

Still, recruitment has already begun for the multicountry phase 3 trials known as ENGAGE and EMERGE. Each study is expected to include 1350 patients and to be completed in February 2022.

Invited to comment on PRIME, James Hendrix, PhD, director of global science initiations for the Alzheimer's Association, told Medscape Medical News that the study "is very exciting" but should be balanced with the knowledge that it's still an early-stage trial.

"If after the phase 3 trials are completed and we see a slowing in the accumulation of amyloid in the brain, but we don't see improvement in cognition, I think that would be a severe blow to the 'amyloid hypothesis'," said Dr Hendrix.

"But at this point, I think it does support that amyloid is important for treating Alzheimer's disease. And I would say I'm cautiously optimistic" about the findings, he added.

Formerly Known as BIIB037

Aducanumab, previously known as BIIB037, is a "human recombinant monoclonal antibody derived from a de-identified library of B cells" collected from healthy or slowly declining elderly volunteers, the manufacturer noted in a statement.

The drug "is thought to target aggregated forms of beta amyloid including soluble oligomers and insoluble fibrils deposited into the amyloid plaque in the brain of AD patients," the company added, noting that it's been hypothesized that removing this plaque may reduce clinical decline in these patients. However, past studies using antibodies to clear Aβ have not been successful.

In PRIME, 165 patients (mean age, 72.6 years) with prodromal or mild AD were enrolled at 35 sites in the United States between October 2012 and January 2014. All were randomly assigned to placebo (n = 40) or aducanumab infusions in doses of 1 mg/kg (n = 31), 3 mg/kg (n = 32), 6 mg/kg (n = 30), or 10 mg/kg (n = 32).

Aβ was measured by florbetapir PET imaging, and the mean PET standard uptake value ratio (SUVR) for the entire group was 1.44 at baseline.

The 3-, 6-, and 10-mg/kg aducanumab groups showed significant decreases in the plaques between baseline and 54 weeks (all, P < .001). But the SUVR composite score was lowest in the 10-mg/kg group (1.16).

Exploratory results showed dose- and time-dependent reductions in clinical impairment, as measured by the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At 1 year, the greatest slowing on the CDR-SB was in the group taking the highest dose of the active drug, whereas the greatest slowing on the MMSE was in both the 3- and the 10-mg/kg groups.

High Rate of Adverse Events

Forty participants discontinued treatment, including 38% of the 10-mg/kg group vs 25% of the placebo group. Discontinuations also occurred in 23%, 19%, and 17% of the 1-, 3-, and 6-mg/kg groups. Half of the 40 total patients who discontinued cited treatment-related adverse events (AEs) as the reason they dropped out.

The percentage of the groups reporting any AE ranged from 84% of those receiving the 3-mg/kg dose to 98% of those receiving placebo.

The most common AEs were amyloid-related imaging abnormalities (ARIAs), headaches, and urinary tract infections. ARIA-vasogenic edema (ARIA-E) occurred in 41% and 37% of the 10- and 6-mg/kg groups, respectively, but there were no related hospitalizations. The investigators point out that ARIA-E was most common in APOEε4 carriers.

The paper also cites data from a preclinical animal study of mice, which were first presented at AD/PD in 2013. It also showed that the drug reduced β-amyloid levels in a dose-dependent manner.

Together, the findings "justify further development of aducanumab for the treatment of AD," write the researchers. "Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis."

As mentioned, the FDA granted Fast Track designation to the drug just last week.

"By collaborating with regulators through programs like Fast Track, we hope to bring effective treatments to patients and families affected by Alzheimer's disease as quickly as possible," said Alfred Sandrock, MD, PhD, executive vice president and chief medical officer at Biogen and corresponding author for PRIME, in a press release.

The new ENGAGE and EMERGE trials have been designed to evaluate safety and tolerability of aducanumab vs placebo in slowing cognitive decline in patients with early AD from multiple locales throughout the world, including the United States, Canada, Spain, Korea, Australia, Japan, Denmark, and the United Kingdom.

The primary outcome measure will be change from baseline to week 78 in CDR-SB score; with secondary outcomes including changes in MMSE, AD Assessment Scale-Cognitive Subscale, and AD Cooperative Study-Activities of Daily Living Inventory scores. The trials will each have a placebo-controlled phase, followed by an optional long-term extension phase.

"We Root for Every Candidate"

Dr Hendrix commented that one of the most exciting parts of the current study was the use of PET imaging to find participants who have high levels of amyloid deposits and are still early in the disease progression.

In addition, the PET scans showing changes in the levels after treatment "correlated well in a dose-dependent way to the cognitive decline findings," he said.

"I think it's a well-designed trial and it's the first time that amyloid PET imaging has been used in this way."

Dr Hendrix noted that the Alzheimer's Association was an early funder of this type of imaging technology. "There are now three FDA-approved amyloid PET tracers. And this has really enabled our understanding of Alzheimer's progression and made it possible for these type of drug strategies that can go for prevention — and hopefully treat the disease before it totally ravages someone's brain," he said.

He added that past studies may have suffered from not using this technology to detect amyloid levels in participants, instead basing AD diagnoses on cognition scores alone. "Some of these people might not have actually had Alzheimer's and that can screw up your trial design. That could maybe explain why some of those candidates didn't work," he said.

"There have been lots of disappointments over the years. But at the Alzheimer's Association, we remain optimistic and we root for every candidate. We want new therapies for the 5 million Americans who have Alzheimer's disease," stressed Dr Hendrix.

"If we don't do anything to change the trajectory, we're going to have 3 times that number by the middle of the century. That's why we need more shots on goal to attack this disease from multiple ways," he concluded.

The study is funded by Biogen. Dr Sandrock is an employee of Biogen. Disclosures for the coauthors are in the paper. Dr Hendrix has disclosed no relevant financial relationships.

Nature. 2016;537:50-56. Abstract

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