Clinical Trials

Date: 2017-06-11

Type of information: Results

phase: 2a

Announcement: results

Company: Probiodrug (Germany)

Product: PQ912

Action mechanism:

• glutaminyl cyclase inhibitor. PQ912 is a small molecule that targets glutaminyl cyclase, an enzyme that catalyzes the formation of pyroGlu amyloid-beta (ABeta) a highly toxic ABeta variant that is involved in the development and progression of AD. AD is a neurodegenerative disease characterized by deposits of extracellular ABeta plaques in the brain, intraneuronal tangles and cerebral neuronal loss. QC inhibitors address a major pathology associated with AD by inhibiting the formation of ABeta variants which lead to the assembly of highly neurotoxic ABeta-oligomers.  PQ912 is a glutaminyl cyclase (QC) inhibitor for the treatment of AD and it is the first QC inhibitor to enter clinical development.

Disease: Alzheimer’s Disease

Therapeutic area: Neurodegenerative diseases

Country: Belgium, Finland, France, Germany, The Netherlands, Spain, Sweden

Trial details:

• The SAPHIR study is a double-blind, placebo controlled randomised study carried out in 7 European countries at 21 study sites in treatment naïve patients with early Alzheimer’s disease. PQ912 targets inhibition of the Glutaminyl Cyclase (QC) enzyme which reduces production of highly neurotoxic pGlu-Abeta and related oligomers implicated in AD. The study is investigating PQ912 over a treatment period of 12 weeks. The highest dose of 800mg bid PQ912 used in the Phase 1 multiple dose study and showing a very high target occupancy was compared to placebo to identify early efficacy and safety signals to optimally plan future long-term dose ranging studies.
• The primary objective of the SAPHIR study is to investigate the safety of PQ912 in the target population and the secondary objective is to assess the pharmacodynamics profile through various readouts. (NCT02389413)

Latest news:

• • On June 11, 2017,  Probiodrug announced first line results of its Phase 2a SAPHIR study in early Alzheimer’s disease patients. The primary objective of the SAPHIR study was to investigate the safety and the tolerability of PQ912. Secondary objectives were to assess early effects of PQ912 on the exploratory endpoints NTB, EEG, cerebro-spinal fluid (CSF) biomarkers related to the QC-inhibition (mechanism of action) and to the AD pathology. Results presented here are for the Intention to treat (ITT) population based on a ‘complete case’ analysis.
• A total of 120 patients were randomised in the SAPHIR study, 60 to the placebo arm and 60 to PQ912 arm. Treatment arms were well balanced with respect to age, gender, disease severity and APOE4 status. The mean MMSE (Mini-Mental State Examination) score at baseline was 25.5 (min-max 21-30).
• Safety and tolerability results (primary objective): There were no statistically significant differences of PQ912 vs placebo between the number of patients experiencing an adverse event (PQ912 n=49, placebo n=45) or the number of patients with a serious adverse event (PQ912 n=8; placebo n=5). Patients in the treatment arm did show a significantly higher discontinuation rate due to SAE or grade 3 adverse events compared to patients in the placebo arm (PQ912 n=6; placebo n=0, p=0.027) and the total number of patients non-adherent to randomised treatment for any reason was higher in the treatment arm (PQ912 n=26; placebo n= 2; p<0.01). Skin and gastrointestinal organ system related adverse events were observed in a higher frequency in the PQ912 arm compared to placebo and occurred in the majority in the first half of the treatment period. Dose reductions prescribed by the investigator were identical in the treatment and the placebo arm (both n=5).
• Results of the secondary exploratory endpoints: Molecular biomarkers in the CSF: CSF analyses showed a highly significant QC inhibition (p=0.001), corresponding to a calculated target occupancy of 92% (median), which was achieved in patients with last drug intake within 24 hours before CSF sampling. A decrease in pGlu-Abeta oligomers in the CSF was observed in the treatment arm whereas pGlu-Abeta oligomers increased in the placebo arm. This directional change demonstrates, together with the significant QC-enzyme inhibition, a strong and robust target engagement.
• There was a strong trend for reduction in the level of neurogranin, a marker of synaptic dysfunction in the ITT population in the treatment arm compared to placebo (p=0.1), which became significant if 3 patients starting prohibited concomitant medication during the study were excluded (p=0.046, a 5% absolute reduction of baseline in neurogranin observed in the treatment arm). There was also a strong trend in the mean reduction of YKL 40, a biomarker of inflammation, in the PQ912 arm compared to placebo (p= 0.07, 5% absolute reduction of baseline–level in the treatment arm).
• EEG: The analysis of the EEG power spectra showed a significant reduction of theta power in the PQ912 arm compared to placebo (p=0.002). Slow wave theta activity is reported to increase with the onset and progression of AD. Further analysis of functional connectivity and EEG network parameters is pending.
• Neuropsychological test battery (NTB): Patients in the placebo arm showed overall a stable performance with no or marginal change between baseline and week 12. Performance on the ‘One Card Back Test’, an assessment of working memory showed a statistically significant effect in favour of PQ912 (p=0.05, Cohen’s d = 0.24) while the ‘Detection Test’ an assessment of attention, also showed a meaningful improvement under PQ912 (Cohen’s d=0.20) although not sufficient to reach statistical significance. Performance on the five other cognitive assessments, as well as on their aggregate scores, were not influenced by treatment with PQ912 for 12 weeks (Cohen`s d < 0.2).
• Additional analysis comprising all endpoints, further CSF biomarker and subpopulations will continue during the next several months and the full results of the SAPHIR study are intended to be reported at scientific congresses and published in scientific journals. The results will guide the design of future studies of PQ912 and support the use of lower doses of PQ912 still reaching relevant target occupancy of the QC enzyme, as well as the option to introduce a titration phase for the 800 mg bid dose.
• • On April 7, 2017, Probiodrug announced that the Last Patient’s Last Visit (LPLV) occurred on 5 April 2017 in the currently running Phase 2a SAPHIR study investigating the QC-inhibitor PQ912 in patients with early AD. The study randomized 120 patients in seven countries at 21 investigational sites. Key results for the primary endpoint of safety/tolerability and for components of the three exploratory endpoints - cognition, EEG/fMRI and the main molecular biomarkers are expected to be communicated in early June 2017. Additional information resulting from further data mining including correlation analysis between elements of the safety and efficacy readouts and a set of additional exploratory biomarkers will be available later in the year.
• • On January 9, 2017, Probiodrug announced that recruitment for the Phase 2a SAPHIR study has been completed in mid-December 2016. A total of 120 patients have been randomised, surpassing the 110 patients planned in the study protocol. In this study Mini-Mental State Examination (MMSE) and the Cogstate neuro-psychological tests are monitored blindly every 30 patients to ensure consistency and reliability of ratings. First blinded results at baseline show that the mean MMSE scores from the 120 randomised patients is 25.3, the mean age is 73 years and gender distribution is 64 female and 56 male. Current results indicate a low variability and therefore the high quality of the assessments being used. Full unblinded results of the SAPHIR study are expected in the second quarter of 2017.
• • On December 8, 2016, Probiodrug announced that the study design of the ongoing Phase IIa SAPHIR trial comparing PQ912 to placebo has been presented as a poster at the 9th Clinical Trials on Alzheimer’s disease (CTAD) meeting in San Diego, USA. The SAPHIR study has been designed and is conducted in collaboration with Philip Scheltens, M.D., Ph.D., the VUmc Amsterdam (NL) and the CRO Julius Clinical ( NL).
• The primary objective of the SAPHIR study is to investigate the safety of PQ912 in the target population and the secondary objective is to assess the pharmacodynamic profile. The publication at CTAD reveals that the study applies a series of methodological innovations which in this combination has not been executed before in an early AD study. Specific in and exclusion criteria based on diagnostic biomarkers of Abeta and tau were required to be met by all patients to ensure a high confidence of the diagnosis of early AD. Mini–Mental State Examination (MMSE) and Cogstate test battery assessments at baseline are monitored blindly every 30 patients to ensure consistency and reliability of ratings. A number of exploratory endpoints like EEG, fMRI and a series of CSF based biomarkers including QC-activity, pGlu-Abeta, Abeta oligomers, neurogranin as well as inflammation markers are centrally analysed. Based on an exploratory analysis of 86 randomised patients, a low standard deviation for the Neuro-psychological test battery and functional EEG at baseline has been observed.
• • On March 9, 2015, Probiodrug announced that the first patient has been enrolled in the Phase 2a “SAPHIR” clinical study of its lead product PQ912 at the Alzheimer Center, VU Medical Center (VUmc), Amsterdam. The phase 2a clinical trial ‘Safety and Tolerability of PQ912 in Subjects with Early Alzheimer’s disease (SAPHIR)’ is a randomized, double-blind multi-center study which plans to enrol a total of 110 patients with early stage Alzheimer’s disease. It will be led by internationally renowned experts in AD in five European countries at 14 sites. The primary endpoint of the trial is the safety and tolerability of PQ912 compared with placebo over a three-month treatment period. Additionally, a set of exploratory read-outs comprising cognitive tests, functional assessments by EEG and functional MRI and new molecular biomarkers in CSF will be used to evaluate the compound’s effect on the pathology of the disease. First data of the SAPHIR study are expected mid-2016. The SAPHIR study follows an exploratory Phase I study in which PQ912 was proven to be safe and well tolerated and showed good pharmacokinetic profile resulting in effective brain concentration and target occupancy.
• • On July 10, 2014, Probiodrug announced that Prof. Hans-Ulrich Demuth, co-founder and consultant to the company, will give a talk detailing clinical development of PQ912 at the upcoming Alzheimer’s Association International Conference in Copenhagen, Denmark. The presentation, titled: “Toxic pGlu-Abeta is enhanced and Glutaminyl Cyclase (QC) up-regulated early in Alzheimer's Disease (AD) - Inhibitors of QC Blocking pGlu-Abeta Formation are in Clinical Development,” summarizes target validation and pharmacological studies supporting the treatment of Alzheimer’s disease by lowering modified and toxic pyroglutamated (pGlu) Abeta through the inhibition of glutaminyl cyclase (QC). The presentation provides Phase 1 clinical results and development status of PQ912, the company’s lead QC-inhibitor. These results indicate that QC expression is strongly correlated with the appearance and increase of pGlu-modified Abeta in the brains of AD patients. pGlu-modified Abeta primes formation of mixed Abeta oligomers. Phase 1 single (SAD) and multiple ascending dose (MAD) trials of PQ912 in healthy volunteers were conducted in more than 160 volunteers including Elderly. The studies demonstrated that PQ912 is safe and well tolerated. Dose-proportional pharmacokinetics and a strong pharmacokinetic and pharmacodynamic relationship based on QC inhibition were observed in cerebrospinal fluid, showing an EC50 of 30nM. Probiodrug is now moving full speed ahead in preparing a Phase 2a trial of PQ912 in early AD patients.
• • On July 16, 2013, Probiodrug has provided an update on PQ912, an inhibitor of glutaminyl cyclase (QC) in clinical development for the treatment of individuals with Alzheimer’s disease (AD). QC has been identified as the enzyme responsible for the formation of pyroglutamated (pGlu) toxic Abeta peptides. Numerous studies have elucidated the crucial role of pGlu Abeta peptides in the pathogenesis of AD. Moreover, pGluAbeta species are prominent constituents of plaques associated with AD. PQ912 is currently being tested in an extended Phase 1 clinical trial, results of which have been reported at the recent Alzheimer’s Association International Conference in July 2013 and the International Conference on Alzheimer’s & Parkinson’s Diseases, which took place in March 2013. In these studies, a total of 140 healthy young and elderly volunteers were administered ascending single doses (from 10 to 1800 mg) and multiple twice-daily (BID) doses (from 20 to 500 mg) of PQ912. PQ912 was safe and well tolerated throughout the dose range tested. For healthy non-elderly and elderly volunteers tested, the maximum tolerated dose was not reached during this study. PQ912 exposure increased dose proportionally in these individuals. There were no serious adverse events, no apparent dose related AEs, and no clinically relevant laboratory and ECG findings. The exposure of PQ912 in plasma was increased approximately 2-fold in the elderly study participants compared with the non-elderly at the doses tested, suggesting that PQ912 is not metabolized by the liver in the elderly to the same rate that it is in younger individuals. The half-lives in plasma and cerebrospinal fluid (CSF) were essentially the same in the non-elderly and elderly groups. The plasma and CSF drug concentrations were highly correlated. Average QC-inhibition of 70% in CSF was achieved at 400 mg BID in non-elderly and is estimated to be reached at 300 mg BID in elderly. Probiodrug expects to advance PQ912 into a Phase 2 clinical study in 2014.
• •  On November 14, 2011, Probiodrug has announced top-line results of its Phase 1 single (SAD) and multiple ascending dose (MAD) study of PQ912 in healthy volunteers. The Phase 1 trial, conducted in Switzerland, demonstrated that PQ912 is safe and well tolerated after oral dosing. Dose-proportional pharmacokinetics and a strong pharmacokinetic and pharmacodynamic relationship based on QC inhibition were observed in plasma and cerebrospinal fluid. The combined SAD/MAD study involved 100 volunteers in a blinded, placebo controlled randomized trial.

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