PQ912 is an investigational therapy that was being developed by Probiodrug to treat Alzheimer’s disease. In June of 2019, Probiodrug became Vivoryon Therapeutics.
How PQ912 works
PQ912 works to inhibit, or block, glutaminyl cyclase (QC), a protein found at unusually high levels (upregulated) in affected regions of the brain in Alzheimer’s patients. QC promotes the production of a modified, toxic and clumping form of β-amyloid peptide (Aβ) called pyroglutamate-abeta (pGlu-Aβ), which is the main component of the amyloid plaques found in patients’ brains.
PQ912 is a small molecule that binds to QC to prevent the production of pGlu-Aβ and, consequently, the formation of the amyloid plaques that are thought to lead to Alzheimer’s disease. It is the first compound in the class of QC inhibitors that is in clinical development.
A study recently published in the Journal of Pharmacology and Experimental Therapeutics in 2017 investigated the effectiveness of PQ912 in a mouse model of Alzheimer’s disease and showed that PQ912 inhibited QC activity and resulted in a significant reduction of a toxic form of Aβ called pyroglutamyl-Aβ (pE-Aβ). Investigators concluded that a higher than 50 percent inhibition of QC activity in the brain leads to robust treatment effects, at least in mice.
PQ912 in clinical trials
The first clinical trial of PQ912 was a single-center, Phase 1 study in Switzerland involving 108 healthy volunteers. Participants received several oral doses of PQ912 (ranging between 20 and 500 mg), either once or twice a day.
The results of this study were presented at the 2013 Alzheimer’s & Parkinson’s Diseases (AD/PD) Congress and the Alzheimer’s Association International Conference (AAIC), and published in the scientific journal Alzheimer’s & Dementia: Translational Research & Clinical Interventions. They showed that PQ912 reached concentrations in the brain high enough to block QC activity and that it was safe and well-tolerated across all tested doses, with mostly mild or moderate side effects. The most common side effects reported by participants were gastrointestinal problems and headaches.
Another Phase 1 single-center clinical trial (NCT02190708) started in June 2014 in the U.K. This trial included 36 healthy volunteers and investigated potential drug interactions between PQ912 and other treatments given to Alzheimer’s disease patients, including Versed (midazolam) — commonly used to treat sleeping troubles, acute seizures, and severe agitation — and Prilosec (omeprazole), used to reduce the amount of acid produced in the stomach. The aim of this study was to assess whether PQ912 affects the way the body processes certain drugs when they are given at the same time, and possible contraindications for PQ912 use in clinical practice. This study has been completed but results have not been published.
A Phase 2 trial (NCT02389413) called SAPHIR, evaluated the safety and tolerability of 12 weeks of PQ912 treatment twice a day in some 120 patients with early Alzheimer’s disease. Early results were presented at the 2017 Clinical Trials on Alzheimer’s Disease (CTAD) conference and showed that PQ912 was safe, with a frequency of side effects similar to those seen in a placebo group. However, patients given PQ912 had more skin reactions and gastrointestinal problems. In terms of effectiveness, PQ912 inhibited 92 percent of QC activity, and significantly reduced QC levels in the brain. Treated patients also showed an improvement in memory and attention.
Investigators concluded that PQ912’s lower tolerability may require dose adaptations in future studies. But overall, they found the results encouraging since the drug showed beneficial effects in early Alzheimer’s disease, even within a short treatment period. The results were published in Alzheimer’s Research and Therapy in 2018.
These positive results led investigators to start a Phase 2b trial (NCT03919162) to evaluate the safety and efficacy of PQ192 in patients with early AD. The study will aim to enroll 462 patients to be distributed between 3 escalating dosages of the treatment or placebo.
Last updated: Aug. 8, 2019
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