TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A monthly column dedicated to reviewing the literature and sharing clinical implications.
Monoclonal antibodies targeting different forms of the amyloid-β (Aβ) protein in individuals with Alzheimer disease (AD) have shown varying results in phase 2 and 3 clinical trials. Gantenerumab is a fully human, subcutaneously administered monoclonal antibody of the IgG1 class that specifically targets aggregated Aβ. It has been tested for the treatment of AD.
The Study
Bateman RJ, Smith J, Donohue MC, et al. Two phase 3 trials of gantenerumab in early Alzheimer’s disease. N Engl J Med. 2023;389(20):1862-1876.
Study Funding
F. Hoffmann–La Roche
Study Objectives
Two phase 3 trials, GRADUATE I and II, were conducted to assess the clinical and biological effects as well as the safety of gantenerumab in individuals with mild cognitive impairment or mild dementia due to AD.
Methodology
The GRADUATE I and II trials were phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group trials. They spanned 288 sites across 30 countries on 5 continents, with 156 sites in 15 countries for GRADUATE I and 152 sites in 18 countries for GRADUATE II.
The participants in the GRADUATE I and II trials were individuals aged 50 to 90 years with mild cognitive impairment or mild dementia due to AD. The eligibility criteria included: Clinical Dementia Rating (CDR)-Global score of 0.5 to 1, indicative of very mild to mild dementia, respectively; a Mini-Mental State Examination score of 22 or higher; a Free and Cued Selective Reminding Test cueing index score of 0.67 or lower; and free recall score of 27 or lower.
Additionally, participants needed to have evidence of amyloid plaque on PET scan or a ratio of phosphorylated tau 181 to AB42 of more than 0.024 on cerebrospinal fluid. Certain exclusions applied, including taking anticoagulants or GV-971, and patients with significant findings on MRI at screening that could cause cognitive impairment.
In this clinical trial, participants were randomly assigned in a 1:1 ratio to receive gantenerumab or a placebo, either at clinical site or at home by nurse. Randomization occurred according to participants’ clinical stage, apolipoprotein (APOE)-ε4 genotype, use of medications for Alzheimer disease, and geographic region of participants. During the clinical trial, the dosage of gantenerumab was increased to 510 mg over 36 weeks.
Once the target dose was achieved, participants received gantenerumab every 2 weeks. Originally planned for 104 weeks, the double-blind treatment period was extended to 116 weeks due to the COVID-19 pandemic.
The primary outcome of this study was the change in cognitive impairment as measured by the CDR–Sum of Boxes (CDR-SB) score. The CDR-SB score ranges from 0 to 18, with higher scores indicating greater cognitive impairment.
Study Results
A total of 985 and 980 participants were enrolled in the GRADUATE I and GRADUATE II trials, respectively. Of the participants in the GRADUATE I trial, 499 were randomly assigned to receive gantenerumab and 480 were assigned to receive placebo. In the GRADUATE II trial, 498 and 477 participants were randomly assigned to gantenerumab and placebo, respectively.
The study authors obtained baseline characteristics on age, gender, clinical stage of dementia, cognitive scale scores, apolipoprotein (APOE)-ε4 genotype, and amyloid burden on PET scan. The characteristics of the participants were found to be similar between treatment groups.
The baseline CDR-SB score was found to be 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. In the GRADUATE I trial, the mean change from baseline was 3.35 in the gantenerumab group and 3.65 in the placebo group (difference, –0.31; 95% CI, –0.66 to 0.05; P = .10). In the GRADUATE II trial, mean change was 2.82 in the gantenerumab group and 3.01 in the placebo group (difference, –0.19; 95% CI, –0.55 to 0.17; P = .30).
A prespecified analysis of pooled data from both trials showed a difference in clinical decline that favored gantenerumab over placebo (difference, –0.26; 95% CI, –.0.51 to –0.01).
The amyloid level on PET scan among participants receiving gantenerumab was lower than the level among those receiving placebo. The difference in mean amyloid level between the gantenerumab group and placebo was –66.44 centiloids in the GRADUATE I trial and –56.46 centiloids in the GRADUATE II trial.
Study results also revealed participants achieved amyloid-negative status on PET scan imaging as follows: 28% treatment group and 2.4% placebo in the GRADUATE I trial; 26.8% treatment group and 0% placebo in the GRADUATE II trial. In reviewing MRIs, the researchers noted participants in the gantenerumab group had a greater decrease in whole-brain volume and a greater increase in ventricular volume than those in the placebo group.
The incidence of amyloid-related imaging abnormalities with edema (ARIA-E) was 24.9% in the gantenerumab group and 2.7% in the placebo group. The incidence of ARIA-E approximately doubled with each APOE-ε4 allele present.
Study Strengths
1. The study consisted of 2 large, randomized, double-blinded, placebo-controlled clinical trials.
2. A Jadad score of 5 out of 5, indicating high-quality studies.
3. A significant effort to maximize fidelity to protocol and maintain blinding in data collection processes.
4. Reasonable inclusion/exclusion criteria leading to high generalizability.
5. Attempts to analyze and draw conclusions from the individual trials in addition to the pooled data.
Study Limitations
1. A lack of racial diversity (> 80% White) in the trial population from the United States, which may affect the generalizability of findings.
2. Multiple differences between the protocol for these trials and the protocols for earlier trials of antiamyloid monoclonal antibodies make it difficult to draw comparisons between trials.
3. A very large trial (10,000 participants screened over 288 sites and 30 countries) can lead to potential difficulties with maintaining adherence to standardized protocol.
4. There is a risk of bias and unblinding due difficulties of adequately masking parenteral medications as well as high incidences of injection-site reactions, vasogenic edema, and hemorrhage resulting in suspended infusions, more frequent imaging, dropout, etc.
Most cases of ARIA-E were asymptomatic. ARIA-E with temporally associated central nervous system symptoms occurred in 5.0% of participants in the gantenerumab group and 0.2% of participants in placebo group. Serious symptomatic ARIA-E occurred only in the gantenerumab group (1.1%). The incidence of new ARIA-E with hemosiderosis was 22.9% in the gantenerumab group and 12.3% in the placebo group.
Conclusions
The randomized controlled phase 3 trials GRADUATE I and II demonstrated no significant difference between the gantenerumab group and the placebo group in the primary clinical outcome, the change in baseline in the CDR-SB score. Furthermore, the results of 3 secondary clinical outcomes did not support a beneficial clinical effect of the drug.
Only about a quarter of the participants receiving gantenerumab attained amyloid-negative status, which is likely the necessary threshold to achieve clinical efficacy based on previous trials. In the gantenerumab group, 11 cases of serious symptomatic ARIA-E occurred, 2 cases leading to permanent discontinuation of gantenerumab and 4 cases leading to permanent discontinuation of the trial.
Practical Applications
The current trials do not support the use of gantenerumab for the slowing of cognitive decline in early symptomatic AD. If monoclonal antibody treatments become more widely available, it will be important to educate patients and families on expectations of treatment, as well as weighing the cost of treatment and potential adverse effects against the intended clinical benefits.
Bottom Line
The 2 high-quality phase 3 randomized controlled trials GRADUATE I and II looking at the use of the antiamyloid antibody gantenerumab did not lead to a slower decline in cognitive function than placebo over a period of 116 weeks among participants with early AD.
Dr Kubista is a first-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Perez Meek is a second-year psychiatry resident at Creighton University. Dr Sramek is a third-year psychiatry resident at Creighton University. Dr Mullen is a fourth-year psychiatry resident at Creighton University.
Dr Tampi is professor and chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and he is a member of the Psychiatric Times editorial board.
References
1. Bateman RJ, Smith J, Donohue MC, et al. Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease. N Engl J Med. 2023;389(20):1862-1876.
2. Schneider LS. What the gantenerumab trials teach us about Alzheimer’s treatment. N Engl J Med. 2023;389(20):1918-1920.
3. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.
