Novel Anti-Amyloid MAb to Be Studied in Familial Alzheimer's

A remarkable, unprecedented development. Roche's anti-amyloid MAb, crenezumab (for which there are no entries at PubMed—!), will be given in an attempt to stave off familial Alzheimer disease. According to Reuters and the NYT, the experimental drug will be studied in members of an extended Colombian family who harbor mutations in a deterministic gene (presenilin 1*) for AD. The US DHHS and Banner Health are providing $16 million and $15 million, respectively, to fund the study. The US government's support is part of the new National Alzheimer's Project (announced yesterday), which has an advertised goal of finding an effective treatment for AD by 2025.

Also according to news coverage, crenezumab was chosen as a potential preemptive treatment for AD among "25 rivals," primarily because it does not cause vasogenic edema—for instance, like Pfizer/Janssen's bapineuzumab. This information is sourced in news write-ups to a Colombian neurologist. Although I have to say Roche's MAb has really come out of left field. As someone who has followed the investigational development of anti-amyloid drugs fairly closely, this molecule has flown way under my radar—partly because it has been registered heretofore under the unfriendly research name of MABT5102A. (Nevertheless, the oversight says something about my limitations.)

According to the NIH database, crenezumab/MABT5102A is currently being investigated in two phase 2 studies in the United States, Canada, and/or the United Kingdom (see here and here). Respective study completion dates are currently designated as June and August of 2014. Presumably the data regarding vasogenic edema (or lack thereof) were determined during phase 1 study and/or confirmed during the ongoing phase 2 trials.

Roche also has the investigational anti-amyloid MAb gantenerumab, which is also in phase 2 development.

As previously written, phase 3 data for the anti-amyloid MAbs bapineuzumab and solanezumab (in existing AD) are expected sometime this summer—which is drawing nigh.

DHHS = Department of Health and Human Services; MAb = monoclonal antibody.
* Presenilin 1 is a component of a metabolic enzyme that cleaves amyloid precursor protein to ultimately create beta amyloid--the stuff the aggregates and forms plaques in the brains of patients with AD.

Update: AC Immune, from which crenezumab was licensed by Roche/Genentech, reported last year that the "drug showed no signs of cerebral vasogenic edema in any of the [phase 1 trial] patients at any dose."

Another update: You have to wonder, though. If crenezumab doesn't cause (or isn't associated with) vascular edema, how effective is it at removing amyloid? If the cause of vasogenic edema with these anti-amyloid compounds is due to the immune-mediated vascular removal of amyloid and/or a direct attack on vascular amyloid (see, for instance, Figure 5 in Sperling et al. Lancet Neurol. 2012:11:241-249), then you would expect some kind of class effect given the putative mechanism of action. Consequently I wonder at the efficacy of an anti-amyloid MAb that doesn't cause some vasogenic edema in a percentage of patients. Certainly amyloid PET imaging in this Colombian study will allow researchers to visualize the removal or prevention of amyloid buildup with crenezumab. So...wait to see. Of course, the bigger question is whether the targeting of amyloid is associated with clinical improvement or, as in this study, the prevention of AD dementia.