A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

Lues, Inge; Weber, Frank; Meyer, Antje; Bühring, Uli; Hoffmann, Torsten; Kühn-Wache, Kerstin; Manhart, Susanne; Heiser, Ulrich; Pokorny, Rolf; Chiesa, Joseph; Glund, Konrad

doi:10.1016/j.trci.2015.08.002

Cited by 45 publications

(53 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PQ912 is the first inhibitor of QC that entered clinical development. The results of a comprehensive phase 1 study have been recently published (Lues et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Hoffmann

Meyer

Heiser

et al. 2017

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…PQ912 is the first inhibitor of QC that entered clinical development. The results of a comprehensive phase 1 study have been recently published (Lues et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…1) has been selected as a development candidate based on its excellent overall drug-like profile. PQ912 is a first-in-class inhibitor of glutaminyl cyclases currently in clinical development (Lues et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Hoffmann

Meyer

Heiser

et al. 2017

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…The application of QC inhibitors for the treatment of Alzheimer’s disease has proven to be successful in different transgenic animal models [20,66,67]. One competitive QC inhibitor PQ912 for the treatment of Alzheimer’s disease successfully completed clinical trial phase 1 [68] and currently is tested in clinical trial phase 2 [23]. All known QC inhibitors were synthesized or achieved by structure based design and bioisosteric replacement as well as homology modeling.…”

Section: Discussionmentioning

confidence: 99%

Natural Products from Microalgae with Potential against Alzheimer’s Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors

et al. 2016

View full text Add to dashboard Cite

In recent years, many new enzymes, like glutaminyl cyclase (QC), could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme-inhibiting properties of natural substances are becoming increasingly important. In different studies, the pathophysiology connection of QC to various diseases including Alzheimer’s disease (AD) was described. Algae are known for the ability to synthesize complex and highly-diverse compounds with specific enzyme inhibition properties. Therefore, we screened different algae species for the presence of QC inhibiting metabolites using a new “Reverse Metabolomics” technique including an Activity-correlation Analysis (AcorA), which is based on the correlation of bioactivities to mass spectral data with the aid of mathematic informatics deconvolution. Thus, three QC inhibiting compounds from microalgae belonging to the family of sulfolipids were identified. The compounds showed a QC inhibition of 81% and 76% at concentrations of 0.25 mg/mL and 0.025 mg/mL, respectively. Thus, for the first time, sulfolipids are identified as QC inhibiting compounds and possess substructures with the required pharmacophore qualities. They represent a new lead structure for QC inhibitors.

show abstract

“…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.…”

mentioning

confidence: 99%

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

Hettmann¹,

Gillies

Kleinschmidt

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

In clinical trials with early Alzheimer's patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer's disease (AD). Specific forms of amyloid beta (Aβ) peptides, for example posttranslationally modified Aβ peptides with a pyroglutamate at the N-terminus (pGlu3, pE3), are attractive antibody targets, due to pGlu3-Aβ's neo-epitope character and its propensity to form neurotoxic oligomeric aggregates. We have generated a novel anti-pGlu3-Aβ antibody, PBD-C06, which is based on a murine precursor antibody that binds with high specificity to pGlu3-Aβ monomers, oligomers and fibrils, including mixed aggregates of unmodified Aβ and pGlu3-Aβ peptides. PBD-C06 was generated by first grafting the murine antigen binding sequences onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized and site-specific mutations were introduced to restore original target binding, to eliminate complement activation and to improve protein stability. PBD-C06 binds with the same specificity and avidity as its murine precursor antibody and elimination of C1q binding did not compromise Fcγ-receptor binding or in vitro phagocytosis. Thus, PBD-C06 was specifically designed to target neurotoxic aggregates and to avoid complement-mediated inflammatory responses, in order to lower the risk for vasogenic edemas in the clinic. Alzheimer's disease (AD) is a neurodegenerative disease that accounts for 60-70% of dementia patients. Progressive memory loss, and cognitive dysfunction and premature death 3-9 years after diagnosis are typical for AD 1 and 140 million AD patients or related dementia patients are projected to require treatment and care in 2050 worldwide, generating a major socioeconomic burden 2-5. Currently, the disease is often treated symptomatically with drugs that transiently improve neuropsychiatric symptoms by antagonizing acetylcholinesterase (AChE) or N-Methyl-D-aspartic acid (NMDA) receptor alone or in combinations 6. In contrast, disease-modifying therapies (DMTs) are new therapeutics, which aim at preventing or slowing AD progression by targeting the disease-causing mechanisms of AD 7-9. Most DMTs against AD in late stage clinical development either target amyloid-or tau-related pathologies. These two histopathological hallmarks are identified either as extracellular plaques of aggregated amyloid β (Aβ) peptides or as intracellular aggregation of hyperphosphorylated tau proteins in neurofibrillary tangles 10,11. According to the amyloid hypothesis of AD 11 , proteolytic cleavage of the amyloid precursor protein (APP) results in the generation and accumulation of soluble Aβ monomers that further aggregate into soluble oligomers and fibrils of different sizes and functionalities 12. These soluble aggregates may aggregate further into larger

show abstract

A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

Cited by 45 publications

References 31 publications

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

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

Natural Products from Microalgae with Potential against Alzheimer’s Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors

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

Contact Info

Product

Resources

About