Alzheimer'sProbiodrug AG, a biopharmaceutical company developing novel therapeutic solutions to treat Alzheimer’s disease (AD), has announced that data from an extensive phase 1 study with PQ912, its lead glutaminyl cyclase (QC) inhibitor for the treatment of AD, have been published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

PQ912 is a first-in-class competitive inhibitor of glutaminyl cyclase, essential for the formation of pyroglutamate-Amyloid-beta (pGlu-Abeta). pGlu-Abeta seeds Abeta oligomers which, owing to their hypertoxicity, are regarded as the key culprits behind AD.

In the published data, more than 200 young and elderly healthy volunteers were included in a single- and multiple-ascending dose design. PQ912 was found to be safe and well tolerated; the maximum tolerated dose was not reached. The study also evaluated pharmacokinetic parameters of the compound as well as the extent of QC inhibition in the cerebral spinal fluid (CSF), which is a measure for QC-inhibition in the brain.

Based on the data obtained in CSF, the dose dependent target inhibition could be reliably determined and was used for dose selection in the current phase 2a trial. The study was conducted with Covance in Switzerland and the UK.

Dr Inge Lues, Chief Development Officer at Probiodrug and first author of the paper, said: “This is groundbreaking data as for the first time a compound targeting glutaminyl cyclase (QC) enzyme inhibition has been assessed in man for the inhibition of pyroglutamate-amyloid-beta (pGlu-Abeta) formation and thus potentially the treatment of AD.”

“The primary objective of our ongoing Phase IIa study (SAPHIR) is to evaluate the safety of PQ912 in the AD patient population. Exploratory readouts are also included to investigate the hypotheses that inhibition of QC interferes with AD pathology. Beside sensitive cognitive measures to capture acute cognitive improvement, we are also measuring by means of EEG and functional MRI any effects on synaptic plasticity and neuronal connectivity, the physiological basis of memory and learning. In addition, we will introduce a set of biomarkers closely related to the concept, Abeta Oligomer- and pE-Abeta levels in CSF to learn about their potential as AD biomarkers,” added Lues.

Dr Konrad Glund, CEO of Probiodrug and co-author, added: “The publication of the Phase I results in a peer-reviewed journal marks an important milestone for Probiodrug. The company has progressed the project from the discovery of QC as the enzyme responsible for modifying truncated Abeta into pGlu-Abeta to the current stage. The resulting data provide the basis for testing the attractive hypothesis of inhibiting QC as a treatment for AD in patients, which we are currently evaluating in our Phase IIa study.”

“This concept of preventing the formation of pGlu-Abeta via QC inhibition as a treatment for AD addresses exclusively toxic Abeta species, and is unique and differentiated to any other Abeta focused therapeutic concept,” he added.

The article, “A Phase I Study to Evaluate the Safety and Pharmacokinetics of PQ912, a Glutaminyl Cyclase Inhibitor, in Healthy Subjects, can be found here: http://dx.doi.org/10.1016/j.trci.2015.08.002.