An experimental drug being developed by Roche Holding AG removed amyloid plaques from the brains of Alzheimer’s disease patients in a small early-stage study, according to data published in the Archives of Neurology, Oct 10.
Many researchers suspect the build-up of such plaques may be a cause of the memory robbing disease, although that theory has yet to be definitively proved.
The next step will be to investigate whether removal of brain amyloid translates into clinical benefit for patients at doses of the experimental drug, gantenerumab, that are well tolerated and safe.
Gantenerumab, a biotech drug designed to bind to amyloid plaques in the brain and remove them, is being targeted at the early stages of Alzheimer’s with the hope it can slow progression of the disease while patients are still able to function.
Administering gantenerumab circumvents stimulation of the adaptive immune system and ensures adequate antibody exposure in the Alzheimer’s patient.
The study included data from 16 AD patients, aged 50 to 90 years, who were included in a positron emission tomographic (PET) substudy of a larger multiple ascending dose trial.
For inclusion in the study the patients must have probable AD according to the National Institute of Neurological Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association criteria, a Mini-Mental State Examination Score between 16 and 26 (inclusive), a magnetic resonance imaging (MRI) scan consistent with AD, and a modified Hachinski ischemia score of 4 or less.
APOE genotyping was performed for all patients.
The patients were assigned to receive intravenous infusions of gantenerumab (60 mg, n = 6; 200 mg, n = 6) or placebo (n = 4) once every 4 weeks to a total of 7 infusions, but because of early termination of dosing in the 200-mg gantenerumab group, not all participants received 7 infusions.
In the 60-mg group, all patients received 7 infusions, while in the 200-mg group 1 patient received 5 infusions, 2 patients received 4 infusions, 2 patients received 3 infusions, and 1 patient received 2 infusions. In the placebo group, 2 patients received all 7 infusions, 1 patient received 5 infusions, and 1 patient received 2 infusions.
Baseline images were compared with images obtained at the end of treatment to determine the change in brain amyloid, as measured by carbon 11-labeled Pittsburgh compound B PET.
Additionally, to evaluate gantenerumab’s ability to clear amyloid plaques via phagocytosis, primary microglial cells obtained from healthy human brain tissue during tumor surgery were incubated in different concentrations of the drug.
The study found a mean percentage reduction from baseline in cortical brain amyloid relative to placebo of 15.6% in the 60-mg group and 35.7% in the 200-mg group.
Findings in the placebo group support previous reports that “amyloid load continues to increase in many patients with mild-to-moderate AD,” the authors added.
Two patients treated with gantenerumab, both of them APOE ε4 homozygous, showed abnormalities on MRI fluid-attenuated inversion recovery (FLAIR) imaging that were “consistent with inflammation or vasogenic edema” after 2 and 4 of the 200-mg doses.
Both patients also developed microhemorrhages, and 1 was “mildly symptomatic” with headaches, dizziness, gait instability, and tremor, the investigators reported.
These adverse effects resolved spontaneously after discontinuation of dosing, similar to what has been reported after treatment with bapineuzumab.
The FLAIR abnormalities were most conspicuous in areas of more prominent amyloid reduction and “may be seen as instances of excessive pharmacological activity due to a high dose or more susceptible individuals (e.g., carriers of the APOE ε4 genotype).
However, according to the researchers, a smaller reduction in amyloid was seen with no FLAIR abnormalities at a lower dose of gantenerumab.
This suggests that gantenerumab-induced amyloid lowering can be achieved without significantly perturbing vascular permeability through inflammation or blockage of Aβ clearance pathways when appropriate dosing is selected.
Much larger trials and further study will be needed to fully understand just how gantenerumab works and whether it can stave off Alzheimer’s disease.
Early, or prodromal, Alzheimer’s disease is a condition in which a person’s memory loss is worse than can be expected by the normal aging process, while their ability to engage in daily activities is not affected to the extent that dementia would be diagnosed. Alzheimer’s disease is estimated to affect 25 million people around the world, with the number of diagnosed cases expected to rise dramatically with the aging of the enormous baby boom generation.
It is expected that the illness, which robs memory and ability to function, will affect about 63 million people by 2030, and 114 million by 2050 worldwide, according to forecasts cited by Roche.
Ostrowitzki, S., Deptula, D., Thurfjell, L., Barkhof, F., Bohrmann, B., Brooks, D., Klunk, W., Ashford, E., Yoo, K., Xu, Z., Loetscher, H., & Santarelli, L. (2011). Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab Archives of Neurology, 69 (2), 198-207 DOI: 10.1001/archneurol.2011.1538