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 has been studied as a potential combination therapy with the Roche BACE inhibitor RG7129 in mouse models of Aβ amyloidosis (see 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 (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.
In 2010, 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 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 extensio. 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. 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 is 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 (see Dec 2014 conference news).
On December 19, 2014, Roche discontinued dosing in SCarlet RoAD based on an interim futulity analysis (see 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 posthoc analysis (see Aug 2015 conference news). Subsequent reports noted biomarker and efficacy signals on the high dose among fast progressors (24 Nov 2015 conference news). This trial will continue to follow participants through 2019.
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 a clinical diagnosis of mild AD. This trial uses 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 has stopped enrolling at 389 participants but is actively continuing.
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). For all gantenerumab trials, see clinicaltrials.gov.
In 2016, Roche started two new phase 1 trials in a total of 98 healthy participants; both investigating subcutaneous administration of higher doses of gantenerumab. On March 6, 2017, MorphoSys, which partners in the development of gantenerumab, announced Roche will start two new Phase 3 trials of the immunotherapy for prodromal AD in 2017.
Clinical Trial Timeline
- Phase 2/3
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- Immunotherapy I: Baby Steps, but No Breakthroughs
- End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile
- Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well
- Gantenerumab, Aducanumab: Bobbing Up and Down While Navigating Currents of Trial Design
- 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. 2012 Feb;69(2):198-207. Epub 2011 Oct 10 PubMed.
- Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H. Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β. J Alzheimers Dis. 2012;28(1):49-69. PubMed.