In an international collaboration, Genentech of S. San Francisco, California, the Banner Alzheimer’s Institute in Phoenix, Arizona, and the US National Institutes of Health are joining to spend over $96 million for the first of three clinical trials for the drug crenezumab. Created by Genentech, this experimental drug is a humanized monoclonal antibody (mAb) that binds to the amyloid beta protein (Aβ). The main experimental group will be people who are likely to develop early Alzheimer’s disease due to autosomal dominant gene mutations. Other biomarkers will be looked at as well. These three clinical trials will determine the validity of the amyloid beta theory, and the tracking of biomarkers and clinical outcomes will allow future trials.
Despite the significant amount of risks, including the fact that the drug will be tested on healthy individuals with normal cognitive function, with the support of regulators from the United States and Europe, the researchers have been successful in gaining financial support from industry partners. Other funding comes from philanthropic groups and the government.
Crenezumab was chosen because it should be more effective in early disease. Not only does it target a variety of amyloid beta forms, but its mechanism differs from that of other anti-Aβ antibodies since it counts on microglial engulfment of Aβ.
The first trial, sponsored by the Alzheimer’s Prevention Initiative (API), will start either late 2012 or early 2013. The population the drug will be tested on is an extended family in Medellin, Colombia, of 300 members. Many are carriers of the gene encoding presenilin-1 (PS1), which onsets Alzheimer’s symptoms around 50 years of age. Some noncarrier controls and participants with varied mutations in the United States will participate in this trial as well. The duration of the trial will be five years and will include an interim analysis at two years to test the effects of crenezumab on a set of Alzheimer’s biomarkers. If there is any response from the biomarkers, the trial will continue with the hopes of improved cognitive function at the end. The second trial, sponsored by Dominated Inherited Alzheimer’s Network (DIAN) is a two-staged, five year trial on carriers of autosomal dominant mutations of PS1, PS2, and amyloid precursor protein (APP). The first stage will test three drugs that target the Aβ protein and will commence late 2012 or early 2013. The third and largest trial will start mid-2013. Known as the “Anti-Amyloid Treatment in Asymptomatic AD” (A4 trial), it is sponsored by Alzheimer’s Disease Cooperative Study and will include 1,000 participants from the general population in their 70s and early 80s. However, unlike the other two trials, these participants will be chosen based on measurements (by amyloid positive emission tomography) of high Aβ burdens in their brain. The duration will be three years of double-blind treatment with two years of follow-up. The goal of the last trial, as stated by neurologist Reisa Sperling, the head of the A4 trial, is “to see a difference in the slop of decline, in the rate of decline”.
Drugs that have targeted Aβ, such as Eli Lilly’s solanezumab, have failed their clinical trials. This may be a result of the overdue treatment, as the disease would have already damaged the neurons for too long for the drugs to be effective. Despite the risk involved, the upcoming trials for crenezumab mark a new approach towards treatment for Alzheimer’s disease.
Garber, Ken. "Genentech's Alzheimer's antibody trial to study disease prevention." Nature Biotechnology. 30.8 (2012): 731-32. Print.
August 17, 2012
Michael Mullan Alzheimer's Disease