Gantenerumab was developed originally by Chugai Pharmaceuticals, which is now part of Hoffmann-La Roche. The treatment, administered as an injection under the skin, now is a collaboration between Hoffmann-La Roche and MorphoSys.
How gantenerumab works
Alzheimer’s disease is a progressive neurodegenerative condition that is associated with the formation of abnormal protein structures called beta-amyloid plaques and tau tangles in the brain. Scientists believe these structures lead to nerve cell death and decreased 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, the protein that builds up in the brain of Alzheimer’s disease patients and forms plaques. It has a higher affinity for beta-amyloid clumps, over 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 an immune cell takes a certain molecule inside itself and digests it.
Researchers hope that a reduction of beta-amyloid will have clinical benefits for patients, potentially slowing progression of the 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. However, 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 it would discontinue the Phase 3 Scarlet RoAD clinical trial (NCT01224106), after recommendations from an independent data monitoring committee and interim results that suggested that the trial was unlikely to meet its primary goal.
The multi-center, randomized, double-blind, placebo-controlled trial aimed to assess different doses of gantenerumab in 799 patients with prodromal Alzheimer’s. Patients initially were due to receive gantenerumab every four weeks for a two-year period, with an optional open-label extension, taking place at 156 sites worldwide. Following termination of dosing in 2014, patients continued to be monitored for at least two years.
Results from the Scarlet RoAD trial were presented at the 68th American Academy of Neurology Annual Meeting, in April 2016. After two years of monitoring patients, no significant difference in disease progression was seen between any gantenerumab dose and the placebo. However, researchers reported there was a dosage-dependent reduction in beta-amyloid in the brain, assessed by PET imaging, and that this 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 mild Alzheimer’s disease patients, began in May 2014. The trial recruited 1,000 patients at 157 sites worldwide and is ongoing. Patients receive gantenerumab or a placebo once every four weeks for 100 weeks. On completion of this trial, patients have the option to continue receiving gantenerumab for up to an extra 100 weeks as part of an open-label extension study.
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 across the U.S, Australia, Canada, France, Italy, Puerto Rico, Spain, and the U.K. It is expected to be completed in December 2023.
The company also has completed several studies investigating gantenerumab in healthy volunteers. These Phase 1 trials (NCT03236844, NCT02711423, and NCT02882009) have been carried out at sites across the U.S.
In March 2017, Hoffmann La-Roche and MorphoSys announced they intended to restart the development of gantenerumab, by investigating the safety and effectiveness of higher doses in two Phase 3 trials.
The two trials, NCT03443973 and NCT03444870, both aim to recruit up to 750 patients with early-stage Alzheimer’s to receive either gantenerumab or a placebo for two years, followed by an optional 50-week open-label extension study. The primary outcome will be the change from baseline in clinical dementia rating−sum of boxes (CDR-SOB), which estimates the severity of the disease. Secondary measures will include investigating the change in beta-amyloid plaques and tau tangles in the brain, through PET scans. The trials are expected to begin enrolling patients at sites across the world by July 31, 2018.
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