Background

PQ912 is an inhibitor of glutaminyl cyclase (QC), a metalloenzyme that is upregulated in the brain 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 story; Morawski 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 news story; Schilling et al., 2008).

Findings

The first clinical trial of PQ912 was not listed in clinicaltrials.gov; 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 story. 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 discontinations. PQ912 inhibited QC activity in CSF by 92 percent. It appeared to slightly decrease pyroglutamate Ab oligomers in CSF, though CSF Ab 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 clinicaltrials.gov and EU Clinical Trials Register.

Clinical Trial Timeline