Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Hoffmann-La Roche
This second-generation γ-secretase modulator is in development for the treatment of Alzheimer's disease. The rationale is that, unlike γ-secretase inhibitors, which inhibit the enzyme complex outright, modulators shift APP cleavage toward production of shorter Aβ peptides and away from production of longer, aggregation-prone peptides such as Aβ42 and Aβ43, while sparing γ-secretase's physiological cleavages of substrates such as notch (e.g. Wolfe, 2007; Trambauer et al., 2020; Weber et al., 2022).
γ-Secretase modulators are intended to slow amyloidogenesis, not plaque removal (e.g., Brendel et al., 2015).
No information about this new molecule is published. In a presentation at the October 2023 CTAD, the company claimed that RG6289 stabilized APP at the active site, increasing odds of processivity in APP cleavage. Roche reported a potency of below 10 nM for γ-secretase modulation of APP cleavage, and no effect on processing of other substrates. In vitro, RG6289 reduced production of Aβ42 and Aβ40, and proportionally increased Aβ38 and Aβ37. The drug showed dose-dependent γ-secretase modulation in rodents and primates.
Prior studies have reported on the binding characteristics of experimental γ-secretase-modulating compounds (Ebke et al., 2011; Lübbers et al., 2011; Cusulin et al., 2019; Ratni et al., 2020; Rodriguez-Sarmiento et al., 2020; Ratni et al., 2021).
No trials are registered in clinicaltrials.gov, but Roche indicates in its fall 2023 development pipeline that RG6289 underwent a 127-person, first-in-human trial starting in 2021. The study included single and multiple ascending dosing in healthy young adult volunteers, and 14 days dosing in healthy elderly adults. Aβ peptides were measured in plasma and, in some people, in CSF. According to results that were presented at the October 2023 CTAD conference, RG6289 was safe. Most adverse events were mild and their frequency did not increase with dose. Pharmacokinetics were linear, plasma concentration increased with dose, was barely affected by eating, and was adequate for once-daily oral dosing. The drug achieved CNS levels comparable to free plasma concentrations. RG6289 dose-dependently reduced CSF Aβ42 and Aβ40 and increased Aβ38 and Aβ37. Reductions in plasma Aβ42 correlated with CSF changes.
Last Updated: 03 Nov 2023
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