Can γ-secretase modulators stage a comeback? Scientists led by Irene Gerlach at F. Hoffmann-La Roche, Basel, Switzerland, are banking on it. At this year’s CTAD meeting, held October 24-27 in Boston, they reported that RG6289, a second-generation GSM, appeared safe in a Phase 1 trial and shifted Aβ production toward smaller, less-sticky peptides.

Dennis Selkoe, Brigham and Women’s Hospital, Boston, called the data compelling. “As the AD field desperately needs orally available, small-molecule therapeutics to lower amyloid, and potentially prevent AD progression if used early enough, I look forward to the continued development of Roche’s molecule and other well-validated GSM candidates,” he wrote (comment below). Roche plans to start Phase 2 next year.

The trial could re-energize a field that has suffered stinging setbacks. First there were γ-secretase inhibitors, such as semagacestat and avagacestat, which sank once researchers realized that scuttling a protease that processes more than 100 transmembrane proteins was bound to interfere with cognition (Dec 2012 news; Aug 2010 news).

The field pivoted to modulating γ-secretase on the idea of tweaking the enzyme's active site such that it still runs and, in the case of Aβ, runs more efficiently, processing amyloidogenic Aβ42 and Aβ43 into smaller, innocuous peptides such as Aβ37 and Aβ38. In 2001, some non-steroidal anti-inflammatories were reported to act as such, if at low potency (Weggen et al., 2001). Derivatives followed in the 2010s, including those by Chiesi, Forum Therapeutics, and Neurogenetics. None made it to Phase 2.

Scientists then discovered second-generation GSMs, mostly compounds containing an aryl-imidazole group, including Eisai’s E2212, Bristol Myers Squibb’s BMS-932481, and Pfizer’s PF-06648671, which were tested in Phase 1 (Yu et al., 2013; Soares et al., 2016; Ahn et al., 2020). BMS's compound was toxic to the liver. None made it to Phase 2 (for a review see Nordvall et al., 2023). 

What, after all this, rekindled interest? The realization that shorter Aβ peptides are not only less toxic than Aβ42 but protective, paired with clinical benefit seen with amyloid-reducing immunotherapy (Cullen et al., 2022; Jan 2022 news; Jul 2023 news). “Since we now know that Aβ-immunotherapies work, I think the next step is to also have small molecules against Aβ generation, to eventually be used in maintenance therapies after immunotherapy,” wrote Harald Steiner, University of Munich. “One could also think of prevention therapies with GSMs,” he added.  

To hear Gerlach tell it, Roche never gave up on GSMs. “There was a time when the field believed there was no need for them because BACE inhibitors had arrived, but we never took that view,” she told Alzforum.

In 2020 Gerlach and colleagues reported that RO7185876, a novel class of GSM with a triazolo-azepine structure, shifted proteolysis of Aβ toward Aβ37 and Aβ38, at the expense of Aβ42 and Aβ40, both in vitro and in mice (Ratni et al., 2020). This structure avoids the imidazole group that might have caused toxicity of some earlier GSMs, though Gerlach told Alzforum that RG6289 is yet a different molecule. She revealed no further structural details.

Indeed, Roche has divulged little about RG6289 but, at a talk at CTAD, Agnes Portron said that it stabilizes the substrate-secretase interaction and prolongs cleavage, perhaps by preventing the substrate from slipping out of the membrane, as recently reported (Nov 2023 news). In vitro, RG6289 boosted Aβ37 and Aβ38 about sixfold at sub-micromolar concentration. It all but eliminated Aβ40 and Aβ42, without affecting total Aβ production. The compound did not interfere with processing of Notch, a γ-secretase substrate that regulates neurogenesis and other cell proliferation pathways.   

Roche began a Phase 1 trial in 2021, and Portron presented some of the results. This study enrolled 127 healthy volunteers. It is using an adaptive design that increased doses contingent on pharmacokinetic and pharmacodynamic data as it emerged over the course of the trial. Roche split the trial into six parts. Portron showed data from four: single-ascending doses in 18- to 45-year-olds; multiple-ascending doses over two weeks in 18 to 64-year-olds; multiple doses over two weeks in people 64 to 85; and a study on the effect of food intake on pharmacokinetics.

Overall, the drug came with mild adverse events, such as headache, nausea, and diarrhea, many of which were more common in the placebo group. The incidence of adverse events did not go up with dose.

Given by mouth, RG6289 rapidly entered people's plasma, where the drug's concentration fell steadily over the next five days or so, whether it was taken with or without food. Pharmacokinetics suggested a half-life of 13 to 21 hours, which favors dosing once per day. With this daily regimen, RG6289 reached a steady-state concentration in the blood after about seven days. About 3 percent of it reached the CSF, which Portron said was equivalent to the amount of free compound coursing through the blood. CSF samples were collected once from people in the younger multiple-ascending-dose group, once the concentration of the compound in the blood had reached a steady state.  

Analysis of plasma and CSF Aβ42 suggested that the compound had reached its target. Plasma Aβ42 fell in a dose-dependent manner, though Porton did not say what those doses were. Secretase activity outside the brain also releases Aβ from APP, so the measured drop in plasma could be in keeping with modulation of peripheral γ-secretase.

In the multiple-ascending-dose regimen, Roche recorded a dose-dependent tapering of Aβ42 and Aβ40 in the CSF, dropping by 80 percent at the apparent highest dose. Again, Porton disclosed no dose information, nor did Gerlach. Along with these Aβ42 and Aβ40 reductions, CSF Aβ37 and Aβ38 rose in parallel, suggesting modulation of γ-secretase processivity. 

Roche plans to start a Phase 2 trial next year, selecting doses based on the pharmacokinetics of the Phase 1 trial. Gerlach said this would be in people who test positive for amyloid, whether unimpaired or with mild cognitive impairment due to AD. She said details of study design will be presented at a conference early next year. In a poster at CTAD, the scientists hint that the Phase 2 doses will aim to lower plasma Aβ42 by 27 to 66 percent. The authors write that they believe this range defines a positive benefit-to-risk ratio.

One risk people in the field worry about is altered processing of Notch and other substrates. Recently, scientists in Bart de Strooper’s lab at KU Leuven, Belgium, found 85 of these substrates in microglia alone. Indeed, γ-secretase inhibitors (GSIs) profoundly limited microglial responses associated with amyloidosis. Many of these transmembrane proteins signal through their intracellular domains (ICDs), which γ-secretase clips off in an endoproteolytic step that is blocked by GSIs. Modulators, on the other hand, are designed to accelerate carboxypeptidase processing once ICDs have been released.

“There is no concern about negatively affecting signaling functions of γ-secretase as GSIs do, since GSMs do not affect cleavages that generated ICDs,” Steiner explained.

Still, Gerlach and colleagues are testing for effects on the wider γ-secretase proteome. “In a proteomic study using a cell line that expresses substrates endogenously, we have confirmed that the GSI blocked processing of serval substrates, but saw no such effect on any of the investigated substates using our series of GSMs,” Gerlach told Alzforum. Of course, we haven’t investigated all the substrates, but our data show very consistently no effect on other  γ-secretase substrates (non-APP), as expected for a modulator.”—Tom Fagan


  1. Gamma-secretase allosteric modulators of presenilin cleavage function (i.e., GSMs) offer an attractive therapeutic approach for AD. They represent a surgical strike on the presenilin-mediated production of longer, more-self-aggregating Aβ-peptides that can initiate the disease.

    This approach has long been known but has, in my view, received insufficient attention as regards medicinal chemistry, compound development, and clinical trials. The recent presentation at CTAD by Agnes Portron and colleagues of Roche’s Phase 1 data on their new GSM was mechanistically compelling and demonstrated that the compound is worthy of further development, as the authors plan to do in an upcoming Phase 2 trial. 

    As the AD field desperately needs orally available, small-molecule therapeutics to lower amyloid and potentially prevent AD progression if used early enough, I look forward to the continued development of Roche’s molecule and other well-validated GSM candidates.

  2. Since we now know that Aβ-immunotherapies work, I think the next step is also to have small molecules against Aβ generation, for example to eventually be used in maintenance therapies after immunotherapy. One could also think of prevention therapies with GSMs.

    The advantage of these compounds is that lowering of the pathogenic long Aβ species is accompanied by enhanced generation of short ones, which in turn also interfere with aggregation of the long ones, so there is a double positive effect. There is no concern about negatively affecting signaling functions of γ-secretase as GSIs do, since GSMs do not affect the signaling cleavages of γ-secretase mediated by the thus-generated ICDs. Conceptually they should therefore be safe drugs. Also remember that Aβ38 in patients is correlated with delayed disease progression (Cullen et al., 2022).

    So, I think development of GSMs is the best way with regard to using small compounds targeting Aβ formation.


    . Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline. Neurology. 2022 Mar 1;98(9):e958-e967. Epub 2021 Dec 22 PubMed.

  3. As a note of historical clarification, while not mentioned in this article, the first second-generation, non-NSAID, GSMs were discovered by Steve Wagner and me in 2002 at Neurogenetics, Inc., later TorreyPines Therapeutics, Inc. Our original GSM program was supported by Eisai, which then went on to develop its own GSM, E2012, roughly based on our original GSM scaffold. It is worth noting that other second-generation GSM's, used in past or ongoing clinical trials, have also been roughly based on our original TorreyPines Therapeutics' GSM scaffold. It is wonderful to see so many second-generation GSM's being spawned from our original (Kounnas et al., 2010).

    After TorreyPines Therapeutics was acquired in 2009, Steve and I continued to develop and optimize new chemical classes of our original GSM's with support from the NIH and the Cure Alzheimer's Fund, in my laboratory at MGH and at UCSD. Steve Wagner tragically passed away in 2022, but my colleagues and I have actively continued the clinical development of our GSM program. Most recently, I served as the scientific founder of Acta Pharmaceuticals, the corporate sponsor for the IND submission of our lead GSM. We are currently planning Phase 1 clinical trials in partnership with the NIH and Alzheimer's Disease Cooperative Study.

    As many would agree, GSM's represent one of our best hopes to safely and affordably lower the production of Abeta42 for the prevention and treatment of AD. Let us remember the contributions of the late Steve Wagner in the discovery of the first second-generation GSM's.


    . Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron. 2010 Sep 9;67(5):769-80. PubMed.

    . Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species. Biochemistry. 2014 Feb 4;53(4):702-13. Epub 2014 Jan 22 PubMed.

    . Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme. Bioorg Med Chem Lett. 2016 Aug 15;26(16):3928-37. Epub 2016 Jul 6 PubMed.

    . Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606. J Pharmacol Exp Ther. 2017 Jul;362(1):31-44. Epub 2017 Apr 17 PubMed.

    . Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators. Bioorg Med Chem. 2020 Nov 15;28(22):115734. Epub 2020 Sep 1 PubMed.

    . Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention. J Exp Med. 2021 Apr 5;218(4) PubMed.

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Therapeutics Citations

  1. Semagacestat
  2. Avagacestat
  3. PF-06648671
  4. RG6289

News Citations

  1. Drug Company Halts Development of γ-Secretase Inhibitor Avagacestat
  2. Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor
  3. Does More Aβ38 Mean Less Cognitive Decline in Alzheimer’s?
  4. FDA Grants Traditional Approval to Leqembi
  5. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase

Paper Citations

  1. . A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PubMed.
  2. . Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects. J Clin Pharmacol. 2013 Dec 17; PubMed.
  3. . The γ-Secretase Modulator, BMS-932481, Modulates Aβ Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers. J Pharmacol Exp Ther. 2016 Jul;358(1):138-50. Epub 2016 Apr 20 PubMed.
  4. . Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies. Clin Pharmacol Ther. 2020 Jan;107(1):211-220. Epub 2019 Sep 11 PubMed.
  5. . Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease. Front Mol Neurosci. 2023;16:1279740. Epub 2023 Oct 16 PubMed.
  6. . Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline. Neurology. 2022 Mar 1;98(9):e958-e967. Epub 2021 Dec 22 PubMed.
  7. . 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.

External Citations

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Further Reading