October 13, 2011 — Treatment with gantenerumab, an anti–amyloid-β monoclonal antibody, resulted in a dose-dependent reduction in brain amyloid in patients with mild to moderate Alzheimer's disease (AD), a small trial shows.
However, "no consistent treatment effects on cognitive measures were noted in this small group of patients treated for a short period of time," wrote lead author Susanne Ostrowitzki, MD, who works in the Department of Neuroscience at F. Hoffmann-La Roche Ltd. — the drug’s manufacturer — in Basel, Switzerland.
"It is still unclear whether any reduction in brain amyloid level will translate into clinical efficacy."
Findings from the study, funded by the company, were reported online October 10 in the Archives of Neurology.
"This kind of antibody treatment is considered passive immunotherapy and is in contrast to active immunotherapy or vaccination where the body’s immune system is activated in response to the vaccine to produce antibodies," explained senior author Luca Santarelli, MD, also with the company, in an email to Medscape Medical News.
"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, they noted.
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)," they wrote.
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."
"As with any drug, it is critically important to identify a dose or doses, with the best risk benefit ratio," Dr. Santarelli told Medscape Medical News. "The imaging data suggest that such a dose that results in brain amyloid reduction, yet is well tolerated and does not lead to changes on MR scans, may be identified."
Combined with the ex vivo results showing gantenerumab-induced phagocytosis of amyloid in a dose-dependent fashion, the study’s findings support the hypothesis that the mechanism by which gantenerumab clears amyloid plaques is "via Fc receptor/microglia-mediated phagocytosis," the authors suggested.
"A phase 2 clinical trial is underway to investigate whether a clinical benefit can be achieved with gantenerumab-treated patients," they conclude.
Other Antibody Strategies
Asked for comment on these findings, Rachelle S. Doody, MD, PhD, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine in Houston, Texas, pointed out that "there are at least seven other antibody-related infusion treatments under development and in human stages of testing, and none of them have so far been proven to benefit patients clinically."
"We must await data from larger studies designed and powered to look at efficacy," she told Medscape Medical News.
Although amyloid reduction was "notable and statistically significant" among participants receiving the higher dose of gantenerumab, there was only a marginal effect in those receiving the lower dose, she noted.
However, in this latter group, amyloid "did not increase as much as it did for placebo treated patients, and this difference was also statistically significant."
Changes such as edema or microhemorrhage in the brain are always concerning, she added.
"In other antibody studies we have seen that such changes can often be asymptomatic, or can be associated with stroke-like symptoms. So there may be a need to monitor patients with MRI scans if these therapies are proven to be effective. The hope is that these side effects of therapy will be manageable by altering or delaying the dose of antibodies."
The study was funded by F. Hoffmann-La Roche Ltd. Eight of the 12 study authors, including Dr. Ostrowitzki and Dr. Santarelli, are full-time employees of Roche/F. Hoffmann-La Roche Ltd, and they may additionally hold Roche stock/stock options. Dr. Thurfjell is a full-time employee of GE Healthcare, and Dr. Brooks holds a part-time position as a senior neurologist with GE Healthcare, which holds a license agreement with the University of Pittsburgh based on the [11C]PiB PET technology described in this study. During the past 12 months, Dr. Brooks has also received consultancy fees from Synosia, Schering Plough, Amsterdam Molecular Therapeutics, Biogen Idec, NeuroNova, Shire, Genentech, and Janssen and honoraria from Teva, UCB, GlaxoSmithKline, and Orion Pharma. Dr. Barkhof is receiving consultancy fees from pharmaceutical companies, including F. Hoffmann-La Roche Ltd. Dr. Klunk is the co-inventor of this technology and, as such, has a financial interest in this license agreement. GE Healthcare has provided grant support and consultant fees to Dr. Klunk for studies unrelated to this work, and Dr. Klunk has received consultant fees/honoraria related to this study from Roche. Dr. Doody disclosed that her group is involved in the development of proteomic biological markers through the state-funded Texas Alzheimer's Disease Research and Care Consortium; her institution receives support from the National Institutes of Health for the Alzheimer's Disease Neuroimaging Initiative, for which she serves as the local principal investigator and on the national steering committee; and she has provided ad hoc consultation to six of the seven companies involved in the development of passive immunization therapies, including F. Hoffmann-La Roche Ltd.
Arch Neurol. Published online October 10, 2011. Full Text
Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to firstname.lastname@example.org.
Cite this: Gantenerumab Reduces Brain Amyloid in Alzheimer's - Medscape - Oct 13, 2011.