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  • The most common adverse effects were ARIA which occurred at

    2024-04-22

    The most common adverse effects were ARIA, which occurred at higher levels than in any previous anti-Aβ mAb study. ARIA-E was observed at some point during the trial in no participants in the placebo group compared with 1 (3%), 2 (6%), 11 (37%), and 13 (41%) participants receiving 1, 3, 6, and 10 mg/kg aducanumab, with increased incidence in APOE ε4 carriers. Of the 27 participants who developed ARIA-E, 15 (56%) continued treatment (50). Based on the promising interim analysis of the phase 1b study, in August 2015, Biogen launched two identical 18-month pivotal phase 3 studies to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by the CDR-SB. Each trial is enrolling 1350 participants with prodromal or mild AD, as confirmed by Aβ-positive PET (NCT02477800 and NCT02484547).
    Efficacy and Safety of mAbs To date, no mAb targeting Aβ has demonstrated significant efficacy. A meta-analysis of immunotherapies by Penninkilampi et al.(51) broadly found no significant treatment differences for typical primary outcome measures, such as the ADAS-Cog, ADCS-ADL, or CDR-SB. However, as noted by the authors, the divergence of mechanisms would argue for considering these agents individually. Solanezumab and crenezumab—both targeting mid-domain Aβ epitopes—have evidenced some post hoc trends for treatment effects in mild-stage AD 23, 28, 38, 40. Solanezumab has completed phase 3 testing in mild-stage AD without meeting its efficacy end points; however, it continues in preclinical AD trials 31, 32 to see if small effects are amplified with earlier intervention. The most promising results to date have been reported for aducanumab, which demonstrated substantial reductions in Cy5 amine (non-sulfonated) fibrillar Aβ in an early-phase study, accompanied by slowing of clinical decline at higher doses (50). These results have also provided encouragement for gantenerumab, a similar N-terminal antibody, to continue trials using higher doses (35). Overall, the safety and tolerability profile of mAbs targeting Aβ has been acceptable. The aforementioned meta-analysis found no difference between pooled treatment and placebo groups in the incidence of adverse events, serious adverse events, and death (51). ARIA, the most concerning safety issue, occurs with N-terminal mAbs that clear fibrillar Aβ—bapineuzumab, gantenerumab, and aducanumab. ARIA-E is strongly associated with drug dose and APOE ε4 status but is also generally (approximately 78%) asymptomatic and self-limiting 20, 21 and may not require temporary suspension of treatment (20). Serious complications are rare and must be balanced against the alternative outcome of untreated AD. The same frequency of ARIA events that was dose limiting in early trials of bapineuzumab and gantenerumab has more recently—perhaps fortuitously—been tolerated with aducanumab and associated with possible clinical benefit.
    Targets of Anti-Aβ mAbs The lack of efficacy thus far with anti-Aβ mAbs may bolster the case against the amyloid hypothesis of AD (52). However, encouraging results with some antibodies make it equally difficult to dismiss this hypothesis altogether. Converging evidence over the past 2 decades has suggested that the most neurotoxic species of Aβ is the soluble oligomer 1, 53, which has emerged as the central target for disease-modifying treatments, including mAbs. Moreover, transgenic mouse models have suggested that therapeutic interventions reducing fibrillar Aβ at the cost of augmenting soluble species could actually be harmful (54), although mAbs that target fibrils may also target oligomers. In this regard, the clearance of fibrillar Aβ on a PET scan is perhaps not an essential goal of treatment but may occur as an epiphenomenon to the clearance of oligomers. As reviewed by Montoliu-Gaya and Villegas (8), mAbs directed against the N-terminus of Aβ may be most effective in clearing the toxic aggregated species of Aβ. Transgenic mouse models have demonstrated that these antibodies inhibit Aβ aggregation and disaggregate preexisting Aβ fibrils 12, 55, 56. However, as described by Lu et al.(57), using seeded fibril growth from brain extract and data from solid-state nuclear magnetic resonance and electron microscopy, Aβ40 monomers aggregate in oligomers and fibrils with multiples of three units, in which N-termini are exposed, whereas hydrophobic C-termini are inaccessible to antibodies (8). If a similar structure held true for Aβ42, mAbs targeting the N-terminus would likely be most efficient in clearing Aβ oligomers. The success of N-terminal antibodies in clearing aggregated Aβ may also be related to microglial activation and phagocytosis, which is hypothesized to be a common feature of bapineuzumab, gantenerumab, and aducanumab 12, 34, 50, 58.