Gantenerumab was originally developed by Chugai Pharmaceuticals, which is now part of Hoffmann-La Roche. The treatment, administered as an injection under the skin, is now being developed with Hoffmann-La Roche in collaboration with MorphoSys.
How gantenerumab works
Alzheimer’s disease, a progressive neurodegenerative condition, is associated with the formation of abnormal protein structures called beta-amyloid plaques and tau tangles in the brain. Scientists think that these structures lead to nerve cell death and diminishing brain function.
Gantenerumab is a fully human antibody, a protein that is designed to interact with a specific target, produced from MorphoSys’ HuCAL antibody technology. It binds to beta-amyloid, with a higher affinity for beta-amyloid clumps compared to free beta-amyloid that is circulating in the blood.
Once gantenerumab binds to beta-amyloid, it is thought to disassemble the plaques that have formed and remove beta-amyloid by stimulating phagocytosis, a process where a cell takes a certain molecule inside itself and digests it.
Researchers hope that reducing beta-amyloid will benefits patients, potentially slowing the progression of Alzheimer’s disease.
Gantenerumab in clinical trials
The safety profile of gantenerumab in mild-to-moderate Alzheimer’s patients was assessed in an ascending dose Phase 1 trial (NCT00531804) at sites in Denmark, Israel, Netherlands, Sweden, and the U.K. In total, 16 participants were enrolled to receive either gantenerumab (60 or 200 mg) or a placebo every four weeks. The results, published in the Archives of Neurology, confirmed that gantenerumab could reduce beta-amyloid levels in the brain. The treatment appeared to be well-tolerated, but two patients receiving the higher dose experienced inflammation (swelling) or vasogenic edema (disruption to the blood-brain barrier).
Hoffmann La-Roche announced in December 2014 that it was stopping the Phase 3 Scarlet RoAD clinical trial (NCT01224106), after an independent data monitoring committee and interim results suggested that the trial was unlikely to meet its primary goal of improving cognition at doses being used.
The multi-center and placebo-controlled trial aimed to assess different doses of gantenerumab in 799 patients with prodromal (very early) Alzheimer’s disease. Patients at 156 sites worldwide were to be given gantenerumab (105 mg or 225 mg) or placebo every four weeks for two years, with the possibility of continuing in an open-label extension. After the interim futility analysis ended dosing in 2014, patients continued to be monitored for at least two years.
Two-year results from the Scarlet RoAD trial were presented at the 68th American Academy of Neurology Annual Meeting, in April 2016.They showed no significant difference in disease progression between patients given any gantenerumab dose and those given placebo. However, researchers reported a dosage-dependent reduction in beta-amyloid in the brain as assessed by PET imaging that may lead to a clinical benefit in patients. These results are published in the scientific journal Alzheimer’s Research & Therapy.
A Phase 3 trial (NCT02051608) called Marguerite RoAD, testing gantenerumab in people with mild Alzheimer’s disease, began in May 2014. The trial recruited about 390 patients at 157 sites worldwide, and is ongoing. Patients were given gantenerumab or a placebo as an under-the-skin injection once every four weeks for 100 weeks. All also had the option of continuing, or starting, to receive gantenerumab for up to 100 weeks as part of an open-label extension study.
Results from the open-label extension of both studies were presented at the 14th International Conference on Alzheimer’s and Parkinson’s Disease in 2019, and also presented at the 2019 American Academy of Neurology (AAN) annual meeting. They showed a reduction in amyloid plaques in gantenerumab-treated patients compared to those given placebo. These findings were consistent in patients with and without amyloid-related imaging abnormalities-edema (ARIA-E) seen through PET imaging.
Hoffmann La-Roche is collaborating with Eli Lilly in a Phase 2/3 clinical trial (NCT01760005) run by Washington University School of Medicine. The randomized trial, called DIAN-TU-001, aims to assess gantenerumab and Lilly’s solanezumab in patients with dominantly inherited Alzheimer’s disease (a rare, early-onset type of Alzheimer’s). The trial is fully enrolled with 438 patients at 26 sites, and expected to finish in December 2023.
The safety and effectiveness of higher doses of gantenerumab are now being investigated in two Phase 3 trials, called GRADUATE 1 (NCT03444870), and GRADUATE 2 (NCT03443973). Roche and MorphoSys announced last year. Both trials are now enrolling up to 760 patients each with early-stage (prodromal to mild) Alzheimer’s disease, who will be randomized to receive either gantenerumab or a placebo as a subcutaneous injection — titrated up to 1,020 mg — for two years, followed by an optional 50-week open-label extension study.
These trials’ primary outcome will be the change from the study’s start (baseline) in Clinical Dementia Rating−Sum of Boxes (CDR-SOB) scale, which estimates disease severity. Secondary measures will include changes in beta-amyloid plaques and tau tangles in the brain, as determined through PET scans.
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