Neurology Central

Are antibodies directed against amyloid-β (Aβ) oligomers the last call for the Aβ hypothesis of Alzheimer’s disease?

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Alzheimer’s disease (AD) is a devastating and incurable age-related neurodegenerative disorder with a long presymptomatic period. The accumulation of the amyloid-β (Aβ) peptide in the brain is believed to be the initial event of the AD process and starts 15–20 years before clinical symptoms occur. During the last 20 years, several compounds were designed to decrease the levels of monomeric, oligomeric, aggregates and Aβ plaques. Drugs have been developed and shown to decrease the Aβ production, antagonize Aβ aggregation or increase Aβ brain clearance.

Unfortunately, all these drugs, including Aβ aggregation inhibitors (tramiprosate, scyllo-inositol, PBT2), Aβ antigens (AN-1792, vanutide, AD02, CAD-106), anti-Aβ monoclonal antibodies (ponezumab, bapineuzumab, solanezumab, gantenerumab and crenezumab), anti-Aβ polyclonal antibody (immunoglobulins), γ-secretase inhibitors (begacestat, semagacestat and avagacestat), γ-secretase modulators (tarenflurbil), β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors (LY2811376, LY2886721, AZD3839, verubecestat, atabecestat and lanabecestat), have failed in clinical trials involving mild-to-moderate AD patients or subjects with mild cognitive impairment (MCI) and biomarker evidence of brain amyloid deposition (prodromal AD). Surprisingly, some drugs (tarenflurbil, scyllo-inositol, semagacestat, avagacestat, AD02, CAD-106 and verubecestat) caused worsening of the cognitive or clinical condition of the patients compared with those treated with placebo.

Recent failures of anti-Aβ drugs for treating AD

Recently, there were three major clinical failures of three BACE inhibitors in patients with mild-to-moderate AD and with prodromal AD. The three drugs were lanabecestat (AZD3293, LY3314814) [1], atabecestat (JNJ-54861911) [2] and verubecestat (MK-8931) [3,4]. The discontinuation of the trials with atabecestat was due to observations of serious elevations in liver enzymes. Conversely, the interruptions of the verubecestat and lanabecestat trials were apparently due to lack of efficacy. The concerning safety profile of atabecestat and verubecestat could be molecule specific, but these data should nevertheless be kept in mind in the evaluation of other trials of BACE inhibitors (elenbecestat, CNP520) that are presently ongoing in subjects at early stages of AD.

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