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 (see Bohrmann et al., 2012). It is being studied as a potential combination therapy with the Roche BACE inhibitor RG7129 in mouse models of Aβ amyloidosis (see Apr 2013 news story).
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 (see 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.
Roche started a Phase 2 trial of doses of 105 or 225 mg of gantenerumab injected subcutaneously once a month into 360 participants, and in 2012 expanded the study to a Phase 2/3 registration trial of 770 people. Called SCarlet RoAD, this is a multinational, 159-center study of gantenerumab's effect on cognition and function in prodromal Alzheimer's disease; it runs for two years but offers the option of an additional two years of treatment. This trial enrolls people aged 50 and older whose memory function tests below normal on the Free and Cued Selective Reminding Test (FCSRT-IR), whose MMSE is 24 or above, whose CDR is 0.5, and who are positive on amyloid PET. Co-primary endpoints are the Clinical Dementia Rating Sum of Boxes (CDR-SOB) and change in brain amyloid levels as measured by PET. The trial included a PET substudy of 90 participants. Outcome data are expected in 2015.
Gantenerumab, together with Eli Lilly's solanezumab, is also being investigated by the Dominantly Inherited Alzheimer Network (DIAN) 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. In an ongoing, two-year phase, the trial is evaluating whether gantenerumab can halt or reverse pathological changes in the preclinical biomarkers known to be present in the trial participants. The trial’s subsequent, three-year phase will assess whether such biomarker effects halt the Alzheimer’s process, preventing cognitive symptoms (see Oct 2012 news story). For all gantenerumab trials, see clinicaltrials.gov.
Clinical Trial Timeline
- DIAN Trial Picks Gantenerumab, Solanezumab, Maybe BACE Inhibitor
- First Stab at Combination Therapy Yields Additive Effect
- Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L. Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab. Arch Neurol. 2011 Oct 10; PubMed.