Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy

Abstract

Numerous studies suggest that the majority of amyloid- (A) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-A (pE-A, including N3pE-A40/42 and N11pE-A40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with K values ranging between 20 and 65 nM. Chronic oral treatment of hAPPxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-A levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for A cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.

Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study

“…1 . The pGlu-Aβ-seeded Aβ oligomers possess a very high synaptotoxic, neurotoxic and proinflammatory potential in in-vitro and animal models [ 8 , 9 ]. pGlu-Aβ-seeded oligomers strongly suppressed LTP in brain slices, an indicator of synaptic impairment [ 8 ].…”

“…pGlu-Aβ-seeded oligomers strongly suppressed LTP in brain slices, an indicator of synaptic impairment [ 8 ]. In a translational study in an AD animal model, PQ912 significantly rescued impaired spatial learning and memory at a dose which achieved between 50 and 70% QC inhibition in the spinal fluid [ 9 ]. pGlu-Aβ has been shown to induce changes in the secondary and tertiary structure of oligomers and these changes most likely are responsible for the increased synaptotoxic propensity of pGlu-Aβ-containing aggregates [ 8 , 10 , 11 ].…”

“…Consequently, long-term inhibition of QC activity would allow synaptic regeneration and reduced neuronal death rates which should manifest clinically as a reduction in cognitive decline and lower rates of clinical disease progression. PQ912, an inhibitor of QC, has undergone rigorous preclinical and clinical investigations including in-vitro and in-vivo animal and phase 1 studies [ 9 , 13 ] and is a first-in-class QC inhibitor in clinical development. This phase 2a study had the objective to investigate the highest PQ912 dose that was used in an earlier phase 1 study of the same compound [ 13 ], to evaluate safety and tolerability signals in treatment-naïve subjects with mild cognitive impairment (MCI) due to AD or mild dementia due to AD after 12 weeks of treatment and also to evaluate the usefulness of various efficacy measurements for future studies using longer treatment durations.…”

Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation

“…The N-terminal pGlu3-modification enhances the formation of hydrophobic Aβ oligomers that have been found to be particularly synapto/neurotoxic [34][35][36][37][38] . Blocking the generation of pGlu3-Aβ peptides via glutaminyl cyclase (QC) inhibitors has been shown to attenuate AD-like pathology and to rescue cognitive function in mice 39,40 . A first QC inhibitor, PQ912, has completed early clinical trial in AD patients 41,42 and is currently entering advanced clinical development.…”

Scalable, FACS-Free Genome-Wide Phenotypic Screening

“…Using a different CD47 antibody (B6H12), we confirmed that overall CD47 protein expression and cell surface localization were not decreased upon transduction with sgRNAs targeting QPCTL (Figures 2D, E; Figure S4). We then tested two small molecule inhibitors of QPCTL, SEN177 29 and PQ912 [30][31][32] , to validate that the enzymatic activity of QPCTL is required for the observed loss of CC2C6 binding, but not B6H12 binding (Figures 2D, F, G;…”