Synonyms: MABT5102A , RG7412
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: APP and 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. Phase 2 trials in people with mild to moderate AD are proceeding at up to 15 mg/kg per month. 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, five-year study, crenezumab is the first immunotherapy to be put into trial as part of the Alzheimer Prevention Initiative. Starting in 2013, crenezumab will be compared to placebo for its ability to reduce amyloid-related biomarkers and prevent subsequent functional decline in presymptomatic carriers of autosomal-dominant presenilin mutations. Most trial participants live in and near Medellin, Colombia; some U.S. participants with similarly predisposing gene mutations will also be recruited.