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Name: RG6289
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, 2007Trambauer et al., 2020Weber et al., 2022).

Multiple studies have tied the ratio of short to long Aβ peptides to AD pathogenesis (e.g., Jan 2022 newsApr 2022 news).

γ-Secretase modulators are intended to slow amyloidogenesis, not plaque removal (e.g., Brendel et al., 2015).

Previously, a first generation of γ-secretase modulators had failed over toxicology problems (e.g., Aug 2008 newsDec 2008 newsApr 2011 newsNolte et al., 2021).

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., 2011Cusulin et al., 2019Ratni et al., 2020Rodriguez-Sarmiento et al., 2020Ratni et al., 2021).


No trials are registered in, 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 (Nov 2023 conference news, abstract).

At the March 2024 AD/PD meeting in Lisbon, Roche presented the protocol for GABriella, a Phase 2a safety and biomarker study that is to begin in the first half of 2024. The multicenter international dose-finding trial will recruit 245 amyloid-positive volunteers who are cognitively normal or have mild cognitive impairment. The trial targets people expected to be rapidly accumulating brain amyloid, with a lower cutoff of 24 centiloids and only 15 percent of the baseline population allowed to have greater than 100 centiloids. Participants will be randomized to one of three doses or placebo for 72 weeks, against primary endpoints of safety, tolerability, and change in amyloid PET. Secondary outcomes include pharmacokinetics, and pharmacodynamic measures of change in Aβ monomers in CSF and blood. For exploratory endpoints, the study will assess multiple CSF and plasma biomarkers of Aβ, tau, neurodegeneration, synaptic integrity, and inflammation, as well as imaging biomarkers, and cognitive measures (AD/PD presentation).

Last Updated: 03 May 2024


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News Citations

  1. Second-Generation γ-Secretase Modulator Heads to Phase 2
  2. Does More Aβ38 Mean Less Cognitive Decline in Alzheimer’s?
  3. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  4. Chicago: Flurizan Postmortem
  5. Eibsee: Keynote on Anti-amyloid Drugs, Prevention
  6. Barcelona: Allosteric γ Modulation Moves Toward Clinic

Paper Citations

  1. . gamma-Secretase modulators. Curr Alzheimer Res. 2007 Dec;4(5):571-3. PubMed.
  2. . Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  3. . γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing. J Cell Mol Med. 2022 Feb;26(3):880-892. Epub 2021 Dec 20 PubMed.
  4. . Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment. Mol Psychiatry. 2015 Oct;20(10):1179-87. Epub 2015 Jun 9 PubMed.
  5. . Proceedings of the 2020 Classic Examples in Toxicologic Pathology XXVII. Toxicol Pathol. 2021 Aug;49(6):1206-1228. Epub 2021 Jul 14 PubMed.
  6. . Novel γ-secretase enzyme modulators directly target presenilin protein. J Biol Chem. 2011 Oct 28;286(43):37181-6. PubMed.
  7. . Aminothiazoles as γ-secretase modulators. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6554-8. Epub 2011 Aug 19 PubMed.
  8. . Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer's disease iPSC-derived neurons and mice. Mol Cell Neurosci. 2019 Oct;100:103392. Epub 2019 Aug 2 PubMed.
  9. . Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease. ACS Med Chem Lett. 2020 Jun 11;11(6):1257-1268. Epub 2020 Apr 27 PubMed.
  10. . Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere. J Med Chem. 2020 Aug 13;63(15):8534-8553. Epub 2020 Aug 4 PubMed.
  11. . Phenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer's disease. RSC Med Chem. 2021 May 26;12(5):758-766. Epub 2021 Apr 12 PubMed.

External Citations

  1. abstract
  2. AD/PD presentation

Further Reading


  1. . Modulators and inhibitors of gamma- and beta-secretases. Neurodegener Dis. 2006;3(4-5):290-7. PubMed.
  2. . γ-Secretase Modulator in Alzheimer's Disease: Shifting the End. J Alzheimers Dis. 2012 Jan 1;31(4):685-96. PubMed.
  3. . Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention. J Exp Med. 2021 Apr 5;218(4) PubMed.
  4. . Monitoring of chronic γ-secretase modulator treatment by serial amyloid-PET. Mol Psychiatry. 2015 Oct;20(10):1141. PubMed.