The pivotal phase 3 GRADUATE 1 and 2 trials will evaluate the effect of gantenerumab on amyloid load and downstream biomarkers of disease progression in patients with early Alzheimer disease.
The FDA has awarded Genentech/Roche’s investigational antiamyloid-ß (Aß) antibody agent, gantenerumab, breakthrough therapy designation for the treatment of individuals with Alzheimer disease (AD). It would be the first subcutaneous medicine for the treatment of patients with this disease, a landmark achievement for the field.1
Findings from the ongoing SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) open-label extension trials, which showed that the therapy significantly reduced brain amyloid plaques, were the basis for the decision. Investigators then used those findings to optimize the design of 2 ongoing parallel, placebo-controlled, randomized phase 3 studies, dubbed GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973).
"For more than a decade, we’ve been committed to advancing the science of Alzheimer’s as well as our investigational medicine gantenerumab, and we look forward to delivering a comprehensive and robust data set that furthers our collective understanding of this devastating disease," Levi Garraway, MD, PhD, chief medical officer, and head, Global Product Development, Roche, said in a statement.1 "This breakthrough therapy designation reinforces our confidence in gantenerumab, which would be the first subcutaneous medicine for the treatment of Alzheimer’s disease with the potential for at-home administration."
The trials, which include more than 2000 participants, evaluate the safety and efficacy of gantenerumab in people with early AD. Investigators use a monthly target dose of 1020 mg with an optimized titration, aimed at maximizing exposure and minimizing dose interruption throughout the study period for better detection of a potential clinical benefit. The company will release data from both studies in the second half of 2022.
Genentech also used findings from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU-001) study (NCT01760005) to build GRADUATE 1 and 2. This phase 2/3 double-blind, placebo-controlled randomized study began as a 2-year biomarker target engagement study and evolved into a registration study that measured cognitive outcomes of gantenerumab and solanezumab, Eli Lilly’s investigational agent, over a maximum 7-year follow-up period. Using the unique DIAN Multivariate Cognitive Endpoint to measure cognitive performance, both agents failed to reach the primary end point in patients with early-onset inherited form of AD.2
There is currently an exploratory open-label extension of DIAN-TU-001, aiming to build on learnings from the original trial, as well as further understand the relationship between biomarker changes with cognitive and clinical findings.
In 2014, Roche stopped dosing in SCarlet RoAD based on interim futility analysis, after it started the phase 3 trial of Marguerite earlier that year.3 In 2016, an update to the clinicaltrials.gov page showed that enrollment had stopped at 389 participants, well short of the anticipated 1000. Like SCarlet RoAD, Marguerite RoAD had failed an interim futility analysis. The trials were then switched to open-label extension studies, where participants with clinical diagnoses of mild AD were titrated up to 1200-mg gantenerumab.
At the 2018 Alzheimer’s Association International Conference (AAIC), data from those trials showed that treatment with the high-dose agent lowered brain amyloid by an average of 59 centiloids on florbetapir PET. At years 1 and 2, 37% and 51% of patients, respectively, had Aß plaque levels below the Aß positivity threshold. Amyloid-related imaging abnormalities, which were a concern in the phase 1 trials, were found in about one-third of participants in the extension studies, most of which were asymptomatic.4
Investigators then released additional data in the months following AAIC 2018. Over a 36-month stretch, gantenerumab showed continued reduction of Aß plaque, with mean centiloid values of –4.3 (standard error [SE], 7.5), 0.8 (SE, 6.7), and 4.7 (SE, 8.0) in the SCarlet RoAD, Marguerite RoAD double-blind placebo, and Marguerite RoAD double-blind active groups, respectively. This represented a change of –57 (SE, 10.3), –90.3 (SE, 9.0), and –74.9 (SE, 10.5) centiloids, respectively.5
There are currently several other studies that evaluate gantenerumab in AD, including Open RoAD and GRADUATION. Open RoAD is a rollover open-label study of the open-label extensions of SCarlet RoAD and Marguerite RoAD, whereas GRADUATION is an open-label study looking at the pharmacodynamic effects of once weekly administration of gantenerumab in participants with early AD.1