Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer’s disease

Abstract

Background This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer’s disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration’s approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. Body Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program. Conclusion The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.

Repurposing drugs against Alzheimer’s disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

“…In 2021, the amyloid-lowering monoclonal antibody Aducanumab was debatably approved as an anti-AD causal therapy although it could not reliably slow cognitive decline in AD patients. Similar negative results were obtained in 2022 for Gantenerumab (Bateman et al 2022), whereas very recently, Lecanemab was the first Aβ monoclonal antibody that was shown to slightly delay cognition deficits in early AD patients (van Dyck et al 2023). While the latter study supported a causal connection between Aβ plaque load and decreased cognitive performance in AD patients, it remains to be shown whether Lecanemab can also mitigate clinical meaningful cognitive decline, especially at later disease stages.…”

Monoclonal antibodies treatment for Alzheimer’s dementia – a literature review

“…Gantenerumab, after over two decades of development in the context of scientific discoveries in the field of AD, represents one of the studied molecules for AD. It is a monoclonal antibody that can also be administered subcutaneously [19]. The mechanism of action is through glial recruitment and phagocytosis of the Aβ plaque, resulting in a dose-dependent reduction in the burden at cerebral level of amyloid accumulation.…”

Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

“…76 Notwithstanding, no drug against prion diseases is currently in clinical trials. Despite the recent success in the Alzheimer's field with aducanumab 43 and the potential of gantenerumab, 77 antibodies have limitations as therapeutics, including stability and immunogenicity, 14,15 which can impact clinical efficiency.…”