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  • The excellent safety profile of

    2023-09-18

    The excellent safety profile of solanezumab and encouraging trends in the exploratory analyses in mild AD led to its inclusion in two secondary prevention trials, which are continuing in the hope that earlier intervention may yield more substantial benefit. The A4 study (NCT02008357) started in February 2014 and will enroll 1150 cognitively normal individuals 65–85 years of age who have positive Aβ on PET scans (31). The Dominantly Inherited Alzheimer Network (DIAN) selected solanezumab (and gantenerumab, described below) for its phase 2/3 trial in individuals at risk for and with early-stage autosomal-dominant AD (NCT01760005) (32).
    Gantenerumab Gantenerumab (Hoffman-La Roche, Basel, Switzerland), the first fully human IgG1 anti-Aβ mAb, binds a conformational epitope expressed on Aβ fibrils (33). This epitope encompasses both N-terminal (3–12) and central (18–27) SB408124 of Aβ and thus requires that the peptide be folded with the midregion near the N-terminus. In PS2APP transgenic mice, gantenerumab significantly reduced Aβ plaques by recruiting microglia and prevented new plaque formation without altering plasma Aβ levels (33). In phase 1 trials in mild to moderate AD, gantenerumab treatment, including up to seven intravenous infusions (60 or 200 mg) every 4 weeks, reduced brain Aβ burden as measured by 11C-PiB PET (34). Gantenerumab was generally safe and well tolerated, but two of six participants in the 200-mg group experienced ARIA-E (34). In 2010, a phase 2 trial of gantenerumab was launched in 360 participants with prodromal AD and CSF evidence of Aβ deposition using doses of 105 mg or 225 mg administered subcutaneously every 4 weeks for 2 years. In 2012, the trial was expanded to a phase 2/3 registration trial of 799 participants (NCT01224106). Co-primary end points included CDR-SB and change in brain Aβ levels on [18F]-florbetapir PET. However, the trial was terminated in December 2014 following an interim futility analysis. At the Alzheimer’s Association International Conference meeting in July 2015, the study results were presented and revealed no significant treatment effects for CDR-SB or change in brain Aβ levels (35). However, post hoc subgroup analyses suggested that participants with fast progression—i.e., participants whose hippocampal volume and CDR-SB score declined most rapidly—may have benefited, especially individuals with higher serum levels of gantenerumab. The incidence of ARIA-E and ARIA-H ranged from 0.4% to 14%, increasing with gantenerumab dose and APOE ε4 status. These results were interpreted as supporting the continuation of gantenerumab trials using higher doses (35). Gantenerumab (along with solanezumab) is also being evaluated by DIAN in a phase 2/3 trial in individuals at risk for and with early-stage autosomal-dominant AD (NCT01760005) (32).
    Crenezumab Crenezumab (MABT5102A; Genentech, Inc., South San Francisco, CA) was engineered on an IgG4 backbone to minimize the activation of Fc gamma receptors (36). In transgenic mice, it reduced the Fc gamma receptor–mediated activation of microglia and triggered less release of the proinflammatory cytokine tumor necrosis factor alpha, thought to contribute to neurotoxicity, as well as ARIA (36). Crenezumab prefers the mid-domain of the Aβ peptide (residues 13–24) (37) and binds multiple conformations of Aβ (monomers, oligomers, fibrils), with a 10-fold higher affinity for oligomers versus monomers 36, 38. The epitope recognized by crenezumab overlaps that of solanezumab, explaining their observed cross-reactivity but not their different binding profiles for various species of Aβ (39). However, Ultsch et al.(37) reported that crenezumab and solanezumab actually target slightly different epitopes (residues 13–24 vs. 16–26, respectively). The authors suggested that solanezumab-bound Aβ possesses an alpha-helical structure between residues 21 and 26, whereas crenezumab-bound Aβ has a random coil structure between residues 21 and 24. They further proposed that the alpha-helical epitope is present in monomeric Aβ but absent from aggregated species, potentially explaining solanezumab’s preference for monomers but crenezumab’s recognition of multiple species, including oligomers (37). Phase 1 studies in mild to moderate AD produced no cases of ARIA-E following single doses (0.3–10 mg/kg intravenously) or multiple ascending doses (0.5–5 mg/kg intravenously) of crenezumab (36), allowing higher doses in phase 2.