The major phase trial NCT enrolled participants with mild

The major phase 2 trial (NCT01343966) enrolled 431 participants with mild to moderate AD who received either low-dose SC crenezumab 300 mg or placebo biweekly (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks 38, 40. No significant treatment benefits were observed for the primary (ADAS-Cog12 and CDR-SB) or secondary outcomes at either dose. However, in a post hoc subgroup analysis of the high-dose cohort, crenezumab treatment was observed to attenuate decline on the ADAS-Cog12 in the mildest subgroup (MMSE 22–26). A parallel 91-participant biomarker study reported no treatment effects on brain fibrillar Aβ by PET, but CSF Aβ rose slightly with treatment 41, 42. Adverse events were balanced between treatment groups, and only one case of ARIA-E was reported in an APOE ε4 homozygote receiving the high dose. These data were interpreted as supporting the testing of crenezumab at even higher doses in prodromal to mild AD (confirmed by positive Aβ on PET). A phase 3 study (NCT02670083) is ongoing in participants with prodromal to mild AD (MMSE 22–30) using a higher dose of crenezumab (38). Participants are randomly assigned to receive intravenous crenezumab or placebo every 4 weeks for 100 weeks, and the primary outcome measure is the CDR-SB. Crenezumab is also being evaluated in a secondary prevention paradigm as part of an Alzheimer Prevention Initiative trial of 300 cognitively normal presenilin 1 carriers from the world’s largest early-onset AD kindred in Antioquia, Colombia (NCT01998841) (10).
Ponezumab Ponezumab (PF-04360365; Pfizer Inc.), a humanized IgG2 mAb, targets the C-terminus of Aβ40 (residues 30–40) (43). Compared with IgG1, IgG2 calcitriol hormone have a lower propensity to induce immune effector function (44). A number of phase 1 trials tested safety, pharmacokinetics, and pharmacodynamics of ponezumab in mild to moderate AD 44, 45, 46. These trials pointed to a favorable safety profile without evidence of ARIA, but the antibody was poorly detectable in CSF. Two subsequent phase 2 studies revealed no clinical efficacy, and development of ponezumab for AD was discontinued (44).
BAN2401 BAN2401 (BioArctic Neuroscience AB, Stockholm, Sweden, and Eisai Co., Ltd., Tokyo, Japan), a humanized IgG1 mAb, selectively binds and clears soluble Aβ protofibrils. It was derived from the E22G Arctic mutation in the amyloid precursor protein and has been shown to reduce Aβ protofibrils in the brain and CSF of Tg-ArcSwe mice (47). In a phase 1/2a study using single and multiple ascending intravenous doses (48), BAN2401 was well tolerated with no cases of ARIA-E. A phase 2b 18-month trial testing five different intravenous doses was launched in January 2013 in prodromal or mild AD (confirmed by positive Aβ on PET) (NCT01767311) (49).
Aducanumab Aducanumab (BIIB037; Biogen, Inc., Cambridge, MA), a fully human IgG1 mAb, selectively reacts with Aβ aggregates, including soluble oligomers and insoluble fibrils (50). It binds the N-terminus (residues 3–6) and recognizes a conformational epitope present on aggregated species of Aβ but absent from monomers. Aducanumab was developed by screening libraries of memory B cells from healthy elderly individuals for reactivity against aggregated Aβ. In Tg2576 mice, an analog of aducanumab was shown to cross the blood-brain barrier, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner (50). A phase 1b clinical trial has been completed in which participants with prodromal or mild AD and Aβ-positive PET scans who received 1 year of monthly intravenous infusions of aducanumab (1, 3, 6, or 10 mg/kg) evidenced reduced brain fibrillar Aβ in a dose- and time-dependent manner (Figure 1) (50). The phase 1b study was not powered for efficacy; however, exploratory analysis of clinical assessments demonstrated dose-dependent slowing of progression at 1 year. CDR-SB scores declined less with aducanumab treatment, with the greatest slowing for the 10-mg/kg dose. MMSE scores likewise declined less with aducanumab treatment, with the greatest slowing at 3 and 10 mg/kg.