Synonyms: MABT5102A , RG7412
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Approved for: None
Crenezumab is a passive immunotherapy approach in which patients are treated with monoclonal antibodies that specifically recognize Aβ peptides. Crenezumab recognizes multiple forms of aggregated Aβ, including oligomeric and fibrillar species and amyloid plaques with high affinity, and monomeric Aβ with low affinity. This humanized antibody uses an IgG4 backbone. It was engineered to clear excess Aβ while exerting reduced subsequent effector function on microglia; the rationale is to stimulate amyloid phagocytosis while limiting release of inflammatory cytokines as a way to avoid side effects such as vasogenic edema (see Adolfsson et al., 2012).
Two Phase 1 safety trials in healthy volunteers and people with Alzheimer's disease produced no evidence of vasogenic edema or cerebral microhemorrhage, allowing Phase 2 to use higher doses and achieve higher brain exposure than was possible with previous immunotherapy approaches. ABBY is a Phase 2 trial evaluating up to 15 mg/kg per month of crenezumab, conducted at more than 90 sites in North America and Europe in 450 people with mild to moderate AD. ABBY, as well as a 91-patient biomarker substudy, were completed in spring 2014 and continued into an open-label extension trial of 361 patients that will run until May 2016.
In addition to ongoing trials in people with mild to moderate Alzheimer's disease, crenezumab is also being tested in a prevention paradigm. In a landmark, adaptive, five-year study, crenezumab is the first immunotherapy to be evaluated as part of the Alzheimer Prevention Initiative (see May 2012 story). Starting in 2013, bimonthly, subcutaneous injection of crenezumab is being compared to placebo for its ability to stave off cognitive decline and affect Alzheimer's biomarkers in presymptomatic carriers of autosomal-dominant presenilin mutations, such as PSEN1 E280A. Most trial participants live in and near Medellin, Colombia; some U.S. participants with similarly predisposing gene mutations will also be recruited. The participants in this trial did not meet criteria for mild cognitive impairment at the time of enrollment. The trial uses a composite consisting of five separate cognitive tests as its primary outcome (see Feb 2013 Webinar). It also uses an extensive list of secondary outcomes, including safety, time to progression to MCI, as well as clinical outcomes and fluid and imaging biomarkers. This Phase 2 trial expects to recruit 300 participants and is set to run until 2020.
This antibody is listed in clinicaltrials.gov under both crenezumab and MABT510A. For all trials, see clinicaltrials.gov.