The majority of Aβ peptides deposited in Alzheimer’s Disease (AD) reveals to be N-terminally truncated and post-translationally modified. Among these modified species, pyroglutamyl-Aβ (pE-Aβ, including N3pE-Aβ<sub>42</sub>) has been identified as particularly neurotoxic. The N-terminal pE-modification renders the peptide hydrophobic, reduces degradation by peptidases and leads to the accumulation of the peptide. It has been shown recently that pE-Aβ is seeding and sustaining the formation of highly neuro-/synaptotoxic oligomers which are assumed to be a key early pathological culprit. After showing that the formation of pE-residues in Abeta is catalyzed by Glutaminyl cyclase (QC), its prevention by inhibiting QC emerged as a potential new disease modifying treatment concept for AD. The identification of our QC-inhibitor PQ912 started out from one of the first potent representatives. The efforts for the improvement of the pharmacological and pharmaco-kinetic profile were supported by structure based design and thermo-dynamic investigations into the inhibitor binding to QC and resulted in an attractive candidate molecule for drug development. After successfully demonstrating efficacy in transgenic AD-mice models by lowering the pE-Aβ content and the improvement of spatial learning and memory, the subsequent Phase I clinical study rendered PQ912 as being safe and well tolerated, demonstrating a dose dependent exposure and high QC-target engagement in the cerebrospinal spinal fluid (CSF). A Phase IIa clinical study treating early AD patients with a high dose of PQ912 (resulting in 90% target occupancy) for 3 month was recently completed. The trial confirmed the phase I findings regarding the target occupancy in the CSF. Moreover, positive exploratory efficacy signals were obtained, all indicating a synapto-protective effect of PQ912. At the biomarker level, a decrease of the number of patients with detectable pEAβ oligomer levels, a reduction of the synaptic marker Neurogranin, and the inflammatory marker YKL-40 was observed. At a functional pharmaco-dynamic level, the theta wave in the qEEG, described to be enhanced in early AD, was found to be significantly reduced. Moreover, the treatment group showed a significant improvement in working memory (‘one card back task’) as well as a trend for an improvement in the attention task. Further clinical studies towards identifying an optimal efficient dose after a longer treatment period are planned.

Inhibition of glutaminyl cyclase as a new concept for the treatment of Alzheimer’s disease: PQ912, the first-in-class QC-inhibitor in clinical development for AD

255th National Meeting (2018)

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