Synonyms: RO4909832, RG1450
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Chugai Pharmaceutical Co., Ltd., Hoffmann-La Roche
Gantenerumab is a fully human IgG1 antibody designed to bind with subnanomolar affinity to a conformational epitope on Aβ fibrils. It encompasses both N-terminal and central amino acids of Aβ. The therapeutic rationale for this antibody is that it acts centrally to disassemble and degrade amyloid plaques by recruiting microglia and activating phagocytosis. Gantenerumab preferentially interacts with aggregated brain Aβ, both parenchymal and vascular. The antibody elicits phagocytosis of human Aβ deposits in AD brain slices co-cultured with human macrophages. It also neutralizes oligomeric Aβ42-mediated inhibitory effects on long-term potentiation in rat brains. In APP/PS-1 transgenic mice, gantenerumab binds to cerebral Aβ, reduces small plaques by recruiting microglia, and prevents new plaque formation. Gantenerumab does not alter plasma Aβ (Bohrmann et al., 2012). It has been studied as a potential combination therapy with the Roche BACE inhibitor RG7129 in mouse models of Aβ amyloidosis (Apr 2013 news).
Four Phase 1 trials conducted internationally in a total of 308 patients have tested the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of infused and subcutaneous gantenerumab in healthy controls and people with Alzheimer's disease, respectively. Gantenerumab was generally safe and well-tolerated, but amyloid-related imaging abnormalities (ARIA) are a concern. For example, in one published study, two of six patients in the highest-dose group had focal areas of inflammation or vasogenic edema on MRI scans in brain areas with the most amyloid reduction (Ostrowitzki et al., 2012). The imaging finding was transient, but ARIA are being monitored closely with MRI in subsequent trials. One dosing study with 16 participants indicated an 11 percent difference in the amount of amyloid change between placebo and the higher dose at six months.
In 2010, Roche started a Phase 2 trial of 105 or 225 mg gantenerumab injected subcutaneously once a month into 360 participants, and in 2012 expanded the study to a Phase 2/3 registration trial of 799 people. Called SCarlet RoAD, this multinational, 159-center study of gantenerumab's effect on cognition and function in prodromal Alzheimer's disease delivered treatment for two years with the option of a two-year extension. Co-primary endpoints were the Clinical Dementia Rating Sum of Boxes (CDR-SOB) and change in brain amyloid levels as measured by PET. The trial included a PET sub-study of 90 participants. SCarlet RoAD enrolled people aged 50 and older whose memory function tested below normal on the Free and Cued Selective Reminding Test (FCSRT-IR), whose MMSE was 24 or above, whose CDR was 0.5, and who were positive on amyloid PET. This was one of first times the new diagnostic criteria by the International Working Group were applied in a large clinical trial. At the November 2014 CTAD conference, data were reported to suggest that this screening process worked to enroll a homogenous population of early symptomatic patients whose memory deficit was likely due to underlying Alzheimer's pathology (Dec 2014 conference news).
On December 19, 2014, Roche stopped dosing in SCarlet RoAD based on an interim futility analysis (Dec 2014 news). In July 2015, Roche reported no efficacy on primary or secondary endpoints in this trial, but a trend toward a benefit in the fastest progressors based on post hoc analysis (Aug 2015 conference news). Subsequent reports noted biomarker and efficacy signals on the high dose among fast progressors, and the data was formally published (Nov 2015 conference news; Ostrowitzki et al., 2017). SCarlet RoAD participants who entered the open-label extension study were titrated up to 1,200 mg subcutaneous gantenerumab. The slower this titration, the less ARIA-E they experienced (Dec 2017 conference news). The open-label extension will run until July 2020.
In March 2014, Roche started a Phase 3 trial of monthly subcutaneous injections of gantenerumab in what was anticipated to be 1,000 patients with clinical diagnoses of mild AD. This trial, called Marguerite RoAD, used the ADAS-cog and ADCD-ADL as co-primary and various biomarkers and clinical/neuropsychiatric measures as secondary outcomes. On October 10, 2016, the clinicaltrials.gov entry for this study was updated to reflect that this trial had stopped enrolling at 389 participants. Roche later reported that, like SCarlet RoAD, Marguerite RoAD had failed an interim futility analysis. It was switched to an open-label extension study, with participants titrated up to 1,200 mg gantenerumab.
At the 2018 AAIC conference, Roche reported that two years of high-dose gantenerumab in the SCarlet and Marguerite RoAD extension studies lowered brain amyloid by an average of 59 centiloid on florbetapir PET, with half of the 28 participants who reached this timepoint falling below the threshold for amyloid positivity, and the rest on trajectory to do so. About one-third of participants in the extension studies developed ARIA-E; the majority were asymptomatic (Aug 2018 conference news; Klein et al., 2019). In a subsequent paper, the company reported continued amyloid reductions in the third year of the extension. Of 30 participants with three-year PET scans, 80 percent reduced their amyloid load below the positivity threshold (Klein et al., 2021).
Gantenerumab, together with Eli Lilly's solanezumab, is being evaluated by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) in a Phase 2/3 trial aimed at preventing dementia in 210 people who are on the path to Alzheimer’s disease due to an inherited autosomal-dominant mutation in APP, presenilin-1, or presenilin-2. This trial began as a two-year, Phase 2 biomarker study (Oct 2012 news). This trial has boosted gantenerumab and solanezumab dosing. It later converted into a Phase 3 registration trial with a cognitive endpoint measured after four years of treatment. Gantenerumab dosing was increased fivefold midway through the trial. This trial missed its primary endpoint. Gantenerumab produced no significant treatment-related change on the DIAN Multivariate Cognitive Endpoint, a composite developed for this trial (Feb 2020 news).
Additional data were presented at the 2020 AAT-AD/PD Focus Meeting. Of 194 participants, 52 received gantenerumab and 39 completed the trial. Gantenerumab treatment led to a large reduction in amyloid plaque as per PiB PET scans, and it normalized CSF Aβ42. Gantenerumab reduced toward normal elevated levels of CSF total tau and p-tau181, and slowed the rise of CSF neurofilament light (Apr 2020 conference news; Apr 2020 conference news). Analysis of the cognitive data revealed that people who were symptomatic at baseline declined over the course of the study, while those who were asymptomatic remained stable. This dichotomy lessened the power of the study to detect treatment effects. Based on this biomarker data, DIAN-TU and Roche invited participants from all arms of this trial to an open-label extension with high-dose gantenerumab (1,020 mg monthly) for up to three years; this study started in the fall of 2020.
In 2016, Roche started two new Phase 1 trials, both investigating subcutaneous administration of higher doses of gantenerumab, in a total of 98 healthy participants. According to published results, the procedure was safe and injection pain tolerable, opening the possibility of at-home administration (Portron et al., 2020).
On March 6, 2017, MorphoSys, which partners in the development of gantenerumab, announced Roche will start two new Phase 3 trials for prodromal or mild, amyloid-confirmed AD. GRADUATE 1 and 2 began enrolling in June 2018, each at 216 different sites worldwide, with a goal of 760 participants each. Participants will be titrated up to 1,020 mg subcutaneous gantenerumab or placebo and treated for two years, with an option to continue on open-label. The primary outcome measure will be change on the CDR-SB. In March 2020, target enrollment for each trial was increased to 1,016. The trials are slated to run till 2023.
At the 2019 AD/PD conference in Lisbon, Portugal, Roche showed further analyses of the two-year data. It indicated that ARIA tends to occurs in hotspots of rapid amyloid removal, but is not required for amyloid clearance across the brain. Roche also showed how comparing titration schemes in the combined SCarlet and Marguerite RoAD open-label study informed the GRADUATE trial design of a single uptitration scheme independent of participants' ApoE genotype (May 2019 news).
In May 2020, the company began a second open-label continuation for participants in the Scarlet and Marguerite RoAD studies. The 173 participants receive antibody every four weeks, at the dose they were on previously. At the same time, Roche registered a rollover study for people who completed either the double-blind or open-label phases of Graduate 1 and 2. In this open-label continuation, an expected 2,032 participants will receive 510 mg of gantenerumab every two weeks. The trial will start enrolling in February 2021 and will run though 2024.
In December 2020, Roche began a Phase 2 trial testing once-weekly subcutaneous gantenerumab injections in 150 people with prodromal to mild AD. Starting with monthly shots of 120 mg, participants in this two-year study will ramp up to a target dose of 255 mg weekly. The primary endpoint is change in amyloid deposition from baseline; secondary outcomes include safety, pharmacokinetics, and participant experience with injection at home.
Roche is developing a new formulation of gantenerumab that uses “brain shuttle” technology to increase the antibody’s ability to enter the brain (RO7126209).
For all gantenerumab trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2/3
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Washington University School of Medicine||NCT01760005||
Last Updated: 25 Jan 2021
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