Name: PQ912
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Probiodrug AG


PQ912 is an inhibitor of glutaminyl cyclase (QC), a metalloenzyme that is upregulated in the brains of Alzheimer’s disease patients. QC generates pyroglutamate Aβ, a modified, pathogenic form of the peptide, by catalyzing the cyclization of an exposed glutamate at the N-terminus of Aβ. The enzyme has been reported to be highly expressed in affected cortical regions in AD; the resulting pGlu-Aβ has been found to be toxic, highly aggregation-prone, and a major component of amyloid plaques in humans (see Apr 2008 conference newsMorawski et al., 2014; Frost et al., 2013). 

PQ912 represents a small-molecule approach to reducing pGlu-Aβ generation; an immunotherapy targeting this pathogenic species directly exists, as well (see LY3002813).

In preclinical work, QC inhibitors have been reported to reduce amyloid pathology and improve performance in learning and memory tests in various mouse models (Apr 2008 conference news; Schilling et al., 2008).


The first clinical trial of PQ912 was not listed in; however, its results were presented at the 2013 AD/PD conference in Florence, Italy. In a single-center Phase 1 study in Switzerland, 108 healthy volunteers up to age 50 received once- or twice-daily doses ranging from 20 to 500mg of PQ912, either in liquid or pill form; 28 received placebo. The drug’s half-life in CSF was reported to be longer than in plasma, with CSF concentrations a third of those in blood. The concentration that was reached in CSF blocked QC activity. The compound's pharmacokinetic and pharmacodynamic properties reportedly were dose-proportional; for details see Mar 2013 conference news. In this trial, PQ912 appeared safe and well-tolerated up to the highest dose tested. As presented at the subsequent 2013 AAIC conference in Boston, PQ912 was also safe in an extension trial evaluating 200 to 300 mg/day in 16 elderly volunteers, as well.  

Many candidate drugs either activate or deactivate enzymes of the P450 detoxification complex in the liver and intestine. To assess this possibility, Probiodrug, via the CRO Covance, started a single-center trial in the United Kingdom in June 2014 that will measure inhibition of CYP3A and CYP2C19 in 36 healthy volunteers. This trial uses the benzodiazepine midazolam and the antacid omeprazole, which are metabolized by CYP3A and CYP2C19, respectively, as probes to measure whether PQ912 affects P450.

From March 2015 to April 2017, the Phase 2 SAPHIR trial evaluated a 12-week course of twice-daily 800 mg PQ912 tablets to placebo. The trial enrolled 120 people with MCI or mild dementia due to AD as ascertained by CSF Aβ levels at screening. It took place in seven European countries. The trial met its primary outcome of safety, with no difference in the frequency of adverse events between the treatment and placebo arms. The treatment group had more skin reactions and gastrointestinal problems than placebo, and more discontinuations. PQ912 inhibited QC activity in CSF by 92 percent. It appeared to slightly decrease pyroglutamate Aβ oligomers in CSF, though CSF Aβ oligomers concentrations are near the assay’s detection limit. The treatment group showed a benefit on working memory and a trend on attention, but no difference on five other neuropsychological tests. On EEG readings, the treatment group showed a reversal of AD-induced changes in theta and alpha rhythms. In CSF, the synaptic marker neurogranin and the inflammatory marker YKL40 trended downward from a known rise in AD. CSF AD biomarkers were unchanged (see Jun 2017 news). Additional analyses will be presented at the 2017 CTAD conference in Boston.​

For all trials, see and EU Clinical Trials Register.

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029
Probiodrug AG NCT02389413


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News Citations

  1. Can Dousing PyroGlu-Aβ Treat Alzheimer’s Disease?
  2. New Alzheimer’s Drug Shows Safety, Hints of Efficacy in Phase 2
  3. Keystone Drug News: Pyroglu Aβ—Snowball That Touches Off Avalanche?

Therapeutics Citations

  1. Donanemab

Paper Citations

  1. . Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer's disease. J Alzheimers Dis. 2014;39(2):385-400. PubMed.
  2. . Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease-Like Transgenic Mouse Models. Am J Pathol. 2013 Aug;183(2):369-81. PubMed.
  3. . Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat Med. 2008 Oct;14(10):1106-11. Epub 2008 Sep 28 PubMed.

External Citations

  2. EU Clinical Trials Register

Further Reading


  1. . Pyroglutamate-Aβ: Role in the natural history of Alzheimer's disease. Int J Biochem Cell Biol. 2010 Dec;42(12):1915-8. PubMed.
  2. . Structural analysis of the pyroglutamate-modified isoform of the Alzheimer's disease-related amyloid-β using NMR spectroscopy. J Pept Sci. 2012 Nov;18(11):691-5. Epub 2012 Sep 24 PubMed.
  3. . Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation. J Neurosci. 2011 Sep 7;31(36):12790-801. PubMed.
  4. . Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 2011 Jun;121(6):705-19. PubMed.
  5. . Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease. Acta Neuropathol. 2010 Aug;120(2):195-207. PubMed.