Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease

Abstract

Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease.

Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was 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.

Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. 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%.

Conclusions: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Figure 1.. Screening, Randomization, Treatment, and Follow-up.

Overall, 6 participants (1 in the GRADUATE I trial and 5 in the GRADUATE II trial) were randomly assigned to receive placebo but did not receive at least one dose.

Figure 2 (facing page).. Clinical Outcomes.

Shown is the adjusted mean 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) (Panel A), in the score on the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog₁₃; range, 0 to 85, with higher scores indicating greater cognitive impairment) (Panel B), and in the total score on the Alzh eimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL; range, 0 to 78, with lower scores indicating greater functional impairment) (Panel C) through week 116. I bars indicate 95% confidence intervals. The analyses were performed with conditional mean imputation followed by analysis of covariance. The primary outcome was the change from baseline in the CDR-SB score at week 116; secondary outcomes included the change from baseline in the ADAS-Cog₁₃ and ADCS-ADL scores at week 116. Data are shown for participants who had available baseline values for a given outcome.

Figure 3.. Biomarker Outcomes.

Shown is the adjusted mean change from baseline in the amyloid level (Panel A) and the tau level (Panel B) on positron-emission tomography (PET) through week 116. I bars indicate 95% confidence intervals. In the amyloid PET substudy, the main outcome was the change from baseline to week 116 in the amyloid level. The amyloid level was assessed on florbetaben or flutemetamol PET and was measured as a standardized uptake value ratio (SUVR), which is the ratio of the standardized uptake value in the composite region of interest to the value in the inferior cerebellar cortex; the SUVR results were converted to centiloids. In the tau PET substudy, the main outcome was the change from baseline to week 116 in the tau level. The tau level was assessed in medial temporal, lateral temporal, frontal, and parietal composite regions on PET with ¹⁸F-GTP1 (Genentech tau probe 1, an investigational radioligand for in vivo imaging of tau protein aggregates) and was measured as an SUVR.