Periodic Reporting for period 3 - QSPainRelief (Effective combinational treatment of chronic pain in individual patients, by an innovative quantitative systems pharmacology pain relief approach.)
Berichtszeitraum: 2023-01-01 bis 2024-06-30
About 20% of Europeans suffer from chronic pain, and ~60% of these patients experience inadequate pain relief from currently available analgesic drug therapies and/or suffer confounding adverse effects. Our vision in the QSPainRelief consortium is that novel drug combinations with improved analgesic and reduced adverse effects can be identified and assessed by mechanism-based Quantitative Systems Pharmacology in silico modelling, being far cheaper and less time-consuming than clinical trials. We develop an in silico QSPainRelief platform, integrating 1) the physiologically based pharmacokinetic model to quantitate and adequately predict drug pharmacokinetics in human CNS, 2) target-binding kinetic models, 3) cellular signaling models and 4) a neural circuit models to quantitate drug effects on relevant brain neuronal networks, to adequately predict clinical outcome. This platform will include patient characteristics (sex, disease status) and predict and rank efficacy and tolerability of a wide range of analgesic and other centrally active drug combinations. Selected drug combinations are studied in a suitable animal model, and clinically, in healthy volunteers and clinical practice. Quantitative insights and confirmed effective combinational treatments will result in a game-changer by improving the management of pain in individuals and stratified sub-populations of chronic pain patients and reduce the large burden on health-care providers greatly. This will increase the understanding of chronic pain in general and trigger the development of even better combination therapies in the future.
We continue to make good progress across Workpackages, despite the impact of the Covid pandemic.
WP1- Project management. 2 SC and 1 GA meetings were successfully held, also with the SEAB. The PMO held frequent TCs to monitor progress of the project (with the SC) and to prepare the outline and minutes of the meetings and maintained regular communication with the EC. Bi-weekly TC were held with the coordinator. The QSPainRelief intranet KEYWAYS keeps all documents and information on Milestones & Deliverables. A no-cost extension was prepared and submitted.
WP2- QSPainRelief model platform development. Neural circuit models for analgesia, abuse liability, sedation & cognitive impairment all have their advanced versions. The LeiCNSPK3.0 and LeiCNSBK1,0 models predicted CNS target site concentrations and target-binding kinetics) for ~100 opioids and augmentation drugs, for different doses, for use in the neural circuit models.
WP3- Data collection and data management. The updated DMP and database were reviewed and improved. Historical clinical data and collected data on plasma pharmacokinetics, CNS receptor expression and receptor occupancy data of our selected drugs, and data produced by WP5, WP6, and WP7 are in part uploaded, and the newer data are in the process of being uploaded.
WP4- In silico computations and risk benefit analysis. Lack of physiological patient data (WP8) restricted further development of the CUI model. Instead, an online patient questionnaire was developed. Data on preferences on (side) drug effects will be collected and used. ,Also, a draft CUI Shiny app (in R software) is designed that allows interactive adjustment of weights and stratifications and easy communicating and sharing of results and alternative outcomes. The MVR model is ready to analyse clinical data.
WP5- Cellular signalling and pathway analysis. The in silico predicted existence of MOR-CB1 heteromers was demonstrated to exist in vitro. In silico approaches (further) assessed time dependency of receptor binding kinetics, allosterism, cooperation and formation of heteromers. In vitro work was performed on mRNA target expression and signal transduction differences, for control, and acute and chronic morphine exposure, with/without THC..
WP6 – Preclinical in vivo validation of QSPainRelief predictions. Studies with morphine +/`pregabalin and morphine +/- THC in male and female control and neuropathic pain mice are completed. A decrease of self-administration by morphine +/- THC, indicated a sedative effect of morphine. Studies for morphine +/- fluvoxamine are in progress.
WP7- Clinical efficacy and adverse effects of analgesic treatments in healthy subjects. QSPainRelief-novelB with nociceptive tests, and a CNS test battery on cognition and neurophysiology in healthy volunteers with morphine + fluvoxamine was completed. Collected data re currently being processed.
WP8- Calibration and evaluation of the QSPainRelief platform using CNS biomarkers in real world patients. QSPainRelief-patientCNS was impacted by the covid pandemic (also post pandemic). The number of patients had to be reduced, and in today’s clinical practice drug combinations are exceptional, so recruitment criteria were adapted to single drug treatment. Alternative sources of clinical data is further searched on. A complementary clinical study in patients about to undergo thoracotomy was performed to study. mechanisms contributing to the development of persistent pain after surgery. The REDcap platform for online data collection was setup, including online versions of all questionnaires
WP9- Dissemination, Training and Exploitation. QSPainRelief’s social media presence kept active. The website was maintained. QSPainRelief partners gave multiple lectures and poster presentations at scientific meetings, and 7 new papers were published, A patient event was held. One new masterclass was held and recorded (website, YouTube channel). Two mentor-mentee sessions were held. Frequent ECS journal club meetings were held. The IIB updated the exploitation plan to be discussed soon.
WP10- Ethical considerations. The 3rd Interim report on ethics monitoring for pre and clinical studies was finalized. QSPainRelief received authorization to perform a) clinical QSPainRelief-PatientsSTRAT study in WP8; b) preclinical studies in WP6; and c) clinical NovelB study in WP7. SEAB members were invited to the 5th GA meeting, and each periodical SC TCs, and provided regular feedback on the QSPainRelief work.
WP11- Ethics requirements. Nearly all ethical requirements were fulfilled in time already in previous periods (one deliverable is pending).
WP1- Project management. 2 SC and 1 GA meetings were successfully held, also with the SEAB. The PMO held frequent TCs to monitor progress of the project (with the SC) and to prepare the outline and minutes of the meetings and maintained regular communication with the EC. Bi-weekly TC were held with the coordinator. The QSPainRelief intranet KEYWAYS keeps all documents and information on Milestones & Deliverables. A no-cost extension was prepared and submitted.
WP2- QSPainRelief model platform development. Neural circuit models for analgesia, abuse liability, sedation & cognitive impairment all have their advanced versions. The LeiCNSPK3.0 and LeiCNSBK1,0 models predicted CNS target site concentrations and target-binding kinetics) for ~100 opioids and augmentation drugs, for different doses, for use in the neural circuit models.
WP3- Data collection and data management. The updated DMP and database were reviewed and improved. Historical clinical data and collected data on plasma pharmacokinetics, CNS receptor expression and receptor occupancy data of our selected drugs, and data produced by WP5, WP6, and WP7 are in part uploaded, and the newer data are in the process of being uploaded.
WP4- In silico computations and risk benefit analysis. Lack of physiological patient data (WP8) restricted further development of the CUI model. Instead, an online patient questionnaire was developed. Data on preferences on (side) drug effects will be collected and used. ,Also, a draft CUI Shiny app (in R software) is designed that allows interactive adjustment of weights and stratifications and easy communicating and sharing of results and alternative outcomes. The MVR model is ready to analyse clinical data.
WP5- Cellular signalling and pathway analysis. The in silico predicted existence of MOR-CB1 heteromers was demonstrated to exist in vitro. In silico approaches (further) assessed time dependency of receptor binding kinetics, allosterism, cooperation and formation of heteromers. In vitro work was performed on mRNA target expression and signal transduction differences, for control, and acute and chronic morphine exposure, with/without THC..
WP6 – Preclinical in vivo validation of QSPainRelief predictions. Studies with morphine +/`pregabalin and morphine +/- THC in male and female control and neuropathic pain mice are completed. A decrease of self-administration by morphine +/- THC, indicated a sedative effect of morphine. Studies for morphine +/- fluvoxamine are in progress.
WP7- Clinical efficacy and adverse effects of analgesic treatments in healthy subjects. QSPainRelief-novelB with nociceptive tests, and a CNS test battery on cognition and neurophysiology in healthy volunteers with morphine + fluvoxamine was completed. Collected data re currently being processed.
WP8- Calibration and evaluation of the QSPainRelief platform using CNS biomarkers in real world patients. QSPainRelief-patientCNS was impacted by the covid pandemic (also post pandemic). The number of patients had to be reduced, and in today’s clinical practice drug combinations are exceptional, so recruitment criteria were adapted to single drug treatment. Alternative sources of clinical data is further searched on. A complementary clinical study in patients about to undergo thoracotomy was performed to study. mechanisms contributing to the development of persistent pain after surgery. The REDcap platform for online data collection was setup, including online versions of all questionnaires
WP9- Dissemination, Training and Exploitation. QSPainRelief’s social media presence kept active. The website was maintained. QSPainRelief partners gave multiple lectures and poster presentations at scientific meetings, and 7 new papers were published, A patient event was held. One new masterclass was held and recorded (website, YouTube channel). Two mentor-mentee sessions were held. Frequent ECS journal club meetings were held. The IIB updated the exploitation plan to be discussed soon.
WP10- Ethical considerations. The 3rd Interim report on ethics monitoring for pre and clinical studies was finalized. QSPainRelief received authorization to perform a) clinical QSPainRelief-PatientsSTRAT study in WP8; b) preclinical studies in WP6; and c) clinical NovelB study in WP7. SEAB members were invited to the 5th GA meeting, and each periodical SC TCs, and provided regular feedback on the QSPainRelief work.
WP11- Ethics requirements. Nearly all ethical requirements were fulfilled in time already in previous periods (one deliverable is pending).
QSPainRelief expects to provide direct insights on the effectiveness of combinational treatment in chronic pain for pain patients, regulators, and pharma industries. Industries can use these insights to bring the most promising options to the market. We will rank combinations from favorable to unfavorable, as information to physicians, patients, and regulators. The unfavorable combinations should be avoided or carefully monitored. All will directly benefit patients. Further, QSPainRelief develops, demonstrates and makes a mature mechanism-based in silico discovery platform available as a decision-making tool for drug development pipelines in chronic pain. This tool can be exploited for future use by the IP owners and contributes to the leadership and competitiveness of European industries, SMEs, and academia, and ultimately will increase the health and well- being of European citizens.