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Gantenerumab in Early Alzheimer’s Disease

Compared with placebo in the phase 3 GRADUATE I and II trials, amyloid plaque was reduced in people with early symptomatic Alzheimer’s disease who received the anti-Aβ IgG1 monoclonal antibody gantenerumab, but cognitive decline was not significantly different. “Taken together with results of trials of other anti-Aβ monoclonal antibodies, [these results] suggest the hypothesis that rapid plaque reduction, probably to a level below the threshold of detection, may be necessary to show clinical efficacy within the time frame of 18 to 27 months,” the authors conclude.

The participants were 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer’s disease. They had evidence of amyloid plaques on positron-emission tomography or cerebrospinal fluid testing at the time of assignment to gantenerumab or placebo every 2 weeks. Results were assessed based on the primary outcome of the change from baseline in the score on the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116.

“A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively,” the authors write. “The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, –0.31; 95% confidence interval [CI], –0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, –0.19; 95% CI, –0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was –66.44 and –56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%.”

Editorial: “The completion of preclinical prevention trials of lecanemab and donanemab (ClinicalTrials.gov numbers, NCT04468659 and NCT05026866, respectively), in which participants without cognitive impairment who have positive biomarkers of Alzheimer’s disease are receiving treatment for several years, is planned for 2027,” writes an editorialist. “Recently, a preclinical prevention trial of solanezumab, a monoclonal antibody that has high affinity for soluble monomers and no affinity for plaques, failed to show clinical efficacy among participants treated for more than 4 years. There was, at best, a slight attenuation of the increase in plaques but no other effect on biomarkers. An earlier, randomized trial of solanezumab was conducted in which 2,129 participants with mild Alzheimer’s disease were treated for 1.5 years. Although solanezumab was not associated with a reduction in plaque levels or a significant difference with respect to the primary cognitive outcome of the trial, it had an effect on the CDR-SB score change (−0.34; 95% CI, −0.57 to −0.11) and other effects that were in line with those of plaque-reducing antibodies. There is much we do not know about targeting amyloids in patients with Alzheimer’s disease, and perhaps we will learn more from ongoing prevention or registry trials of antiamyloid antibodies in clinical practice.”

Source: New England Journal of Medicine