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Investigational gantenerumab was not associated with slower clinical decline in people with early Alzheimer's disease, the and trials found.

Change from baseline scores on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) -- a 0-18 scale with higher values indicating more cognitive impairment -- was 3.35 with gantenerumab and 3.65 for placebo in GRADUATE I (difference -0.31, 95% CI -0.66-0.05, P=0.10).

CDR-SB baseline change was 2.82 with gantenerumab and 3.01 with placebo in GRADUATE II (difference -0.19, 95% CI -0.55-0.17, P=0.30), Randall Bateman, MD, of Washington University School of Medicine in St. Louis, and co-authors reported in the .

"When the analysis of the primary outcome was based on pooled data from both trials, the results were generally consistent with the results from the primary analysis in each trial," the researchers noted.

At week 116, 28% of participants in GRADUATE I who received gantenerumab and 26.8% in GRADUATE II achieved amyloid-negative status, defined as an amyloid level of ≤24 centiloids.

"Gantenerumab didn't fully remove amyloid plaques in most patients and didn't substantially improve cognitive or clinical decline at the doses used," Bateman said in an email to 番茄社区.

"The drugs that remove amyloid plaques to normal levels (as measured by PET scans) in most patients have consistent clinical benefit," he added. "However, anti-amyloid antibodies that don't fully remove plaques haven't shown substantial benefit."

Two other anti-amyloid monoclonal antibodies, aducanumab (Aduhelm) and lecanemab (Leqembi), are available for the treatment of early Alzheimer's disease, and a third, donanemab, likely will be approved soon, observed Lon Schneider, MD, of the University of Southern California in Los Angeles, in an . (Aducanumab was granted accelerated approval by FDA, and lecanemab has full approval.)

"Depending on one's perspective, the results of the antibody trials to date either reinforce confidence in this therapeutic approach and its clinical meaningfulness or support a view that the effects are small, unreliable, and barely distinguishable from no effect," Schneider wrote.

Given gantenerumab's similarities to the approved drugs, he continued, "it is surprising that two phase III trials of gantenerumab ... did not show significant benefits."

In the gantenerumab trials, secondary cognitive and functional outcomes showed small mean effects similar to those seen with the approved drugs, Schneider noted.

"For half these outcomes, the between-group differences would have been significant if the primary analysis had not failed and had not been part of a hierarchical statistical analysis plan," he pointed out. "In a planned analysis combining data from the two trials as though they were one trial with 1,965 participants, the between-group difference for the primary outcome might have been considered significant, favoring gantenerumab."

GRADUATE I and II enrolled participants ages 50 to 90 years with mild cognitive impairment or mild dementia from Alzheimer's disease who had evidence of amyloid plaques on PET or cerebrospinal fluid (CSF) testing. Participants (985 in GRADUATE I and 980 in GRADUATE II) were randomized to receive gantenerumab or placebo subcutaneously every 2 weeks, for 116 weeks. Gantenerumab doses were increased over 36 weeks to 510 mg.

Participants had a mean age of about 71 and approximately 58% were women. Around two-thirds in each trial had one or two APOE ε4 alleles; within that group, most had one APOE ε4 allele.

Pooled data showed that 90.1% of those receiving gantenerumab and 87.1% of those receiving placebo had at least one adverse event. Injection-site reactions occurred in 16.8% of the gantenerumab group and 7.7% of the placebo group and were typically mild. There were 10 deaths in the gantenerumab group which were considered to be unrelated to the drug, and 14 deaths in the placebo group.

Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) occurred in 24.9% of the gantenerumab group and 2.7% of the placebo group. "The incidence approximately doubled with each APOE ε4 allele present," the authors noted. New ARIA with hemosiderosis (ARIA-H) occurred in 22.9% of participants with gantenerumab and 12.3% with placebo.

Schneider noted a potential for unblinding in the trial, especially with high incidences of injection-site reactions, vasogenic edema, and hemorrhage which can become apparent to researchers and participants.

The researchers also acknowledged the lack of racial diversity in the U.S. trial population as a limitation. Differences in protocols between the GRADUATE studies and earlier trials of anti-amyloid drugs make it difficult to compare trials, they added.

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