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

Abstract

Background: PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests.

Methods: This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses.

Results: There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of > 90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study.

Conclusions: The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study.

Trial registration: Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.

Trial registration: ClinicalTrials.gov NCT02389413.

Keywords: Alzheimer’s disease; Glutaminyl cyclase inhibitor; PQ912; Phase 2a.

Conflict of interest statement

Ethics approval and consent to participate

Twenty-one centers in Europe (Belgium, Finland, France, Germany, Spain, Sweden and The Netherlands) participated in the study. The independent ethic committees at each site approved the protocol and amendments and the informed-consent documentation. All subjects and their caregiver provided written informed consent to participate in the study. The study was conducted in compliance with the declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines.

Consent for publication

All authors approved the final version of the manuscript for submission.

Competing interests

PS has received consultancy/speaker fees (paid to the institution) from Eli-Lilly, GE Healthcare, Novartis, Probiodrug, Biogen, Roche, TauRx and EIP Pharma; he holds no stocks or options in Probiodrug. TG reported as an investigator and the national coordinating investigator for Germany in this trial; outside the submitted work he received consulting fees from Actelion, Eli Lilly, MSD, Novartis, Quintiles and Roche Pharma, lecture fees from Biogen, Lilly, Parexel and Roche Pharma, and grants to his institution from Actelion and PreDemTech. AAG received research support from Probiodrug and received research support from Boehringer Ingelheim via the VUmc Alzheimer Center. CET has functioned on advisory boards of Fujirebio and Roche, received nonfinancial support in the form of research consumables from ADxNeurosciences and Euroimmun, and performed contract research or received grants from Janssen Prevention Center, Boehringer, Brainsonline, AxonNeurosciences, EIP farma and Roche which are all unrelated to the present work. JH has in the past 2 years received honoraria and/or consulting fees from 23andMe, AbbVie, Access to Quality, AlzCure, Amgen, Anavex, Astellas Pharma, AstraZeneca, Avonex, Avraham, Axon, Axovant, Biogen Idec, Boehringer Ingelheim, Bracket, C4X Discovery, Cambridge Brain Sciences, Catenion, Cognitive Therapeutics, Compass Pathways, DeNDRoN, Enzymotec, Eisai, Eli Lilly, Forum Pharma, Fresh Forward, GfHEu, Heptares, Janssen AI, Johnson & Johnson, Kaasa Health, Kyowa Hakko Kirin, LivaNova PLC, Lundbeck, MedAvante, Merck, MyCognition, Neurocog, Neurotrack, Novartis, Nutricia, Pfizer, Prana Biotech, Probiodrug, Prophase, ProStrakan, Regeneron, Reviva, Roche, Sanofi, Servier, Shire, Takeda, TCG, TransTech Pharma and Velacor. IL is an employee and shareholder of Probiodrug. NDP serves on the advisory board of Boehringer Ingelheim and Probiodrug, and is a member of the DSMB of Abbvie’s M15-566 trial; he has received consultancy or speaker fees from Sanofi, Takeda, Janssen and Novartis; and he is CEO and co-owner of the Brain Research Center, Amsterdam. The remaining authors declare that they have no conflicts of interest.

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Figures

Fig. 1

Schematic drawing of QC inhibitor approach. pGlu-Aβ is posttranslationally formed by QC from N-terminally truncated Aβ versions carrying a glutamate at position N3 and N11. pGlu-Aβ seeds Aβ oligomers which are highly synaptotoxic and neurotoxic. Aβ amyloid beta, pGlu pyroglutamate, QC glutaminyl cyclase, sAPPβ soluble amyloid precursor protein beta

Fig. 2

CONSORT flow diagram. AD Alzheimer’s disease, AE adverse event, CSF cerebrospinal fluid, EEG electroencephalography, ITT intention to treat, mITT modified intention to treat, MRI magnetic resonance imaging, NTB Neuropsychological Test Battery, PP per protocol

Fig. 3

a Time to nonadherence. Intent to treat population. b Time to start of TEAEs of skin and subcutaneous tissues disorders . Intent to treat population

Fig. 4

a Glutaminyl cyclase activity (mU/L): change from baseline at end of treatment. Per protocol population. b In-vivo target occupancy calculated from PQ912 levels. PQ912 treated, per protocol (PP) population

Fig. 5

Magnitude of impairment on individual neuropsychological tests at baseline assessment (Cogstate). Impairment defined as group mean performance expressed standardized score (z) using age-matched normative data (mean and SD). ISLT International Shopping List Task, OCL One Card Learning

Fig. 6

Dose–response curve for PQ912 with regard to target (QC enzyme) occupancy. bid twice daily, QC glutaminyl cyclase