Periodic Reporting for period 2 - QSPainRelief (Effective combinational treatment of chronic pain in individual patients, by an innovative quantitative systems pharmacology pain relief approach.)
Periodo di rendicontazione: 2021-07-01 al 2022-12-31
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 model to quantitate drug effects on relevant brain neuronal networks, to adequately predicts clinical outcome. This platform will include patient characteristics (sex, disease status and genotypes), and predict and rank efficacy and tolerability of a wide range of analgesic and other centrally active drug combinations. The best combinations will be validated in a suitable animal model, in clinical studies in healthy volunteers, in 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 2 GA meetings were successfully held. 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.
WP2- QSPainRelief model platform development. Neural circuit models for analgesia, abuse liability, sedation & cognitive impairment all have their first versions. The LeiCNSPK3.0 and LeiCNSBK1,0 models predicted CNS target site concentrations and target-binding kinetics) for ~100 opioids and augmentation drugs for use in the neural circuit models.
WP3- Data collection and data management. An updated DMP and database are available. Apart from historical clinical data and collected data on plasma pharmacokinetics, CNS receptor expression and receptor occupancy data of our selected drugs, data produced by WP5, WP6, and WP7 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, online patient questionnaire data on preferences on (side) drug effects will be collected and used, and compound A was selected by combined expertise. The MVR model is ready to analyse clinical data.
WP5- Cellular signalling and pathway analysis. Modeling indicated the potential existence of MOR-CB1 heteromers and needs to be validated in vitro. A binding kinetic model was developed for orthosteric and allosteric binding with rate constants instead of equilibrium constants. In vitro work on mouse, rat and human brain cells indicated species and brain location dependent mRNA target expression and signal transduction differences, for control, and acute and chronic morphine exposure, with/without pregabalin.
WP6 – Preclinical in vivo validation of QSPainRelief predictions. Studies with morphine and pregabalin were performed in male and female control and neuropathic pain mice. Without neuropathy mice showed a preference for the pregabalin over saline, indicating drug-abuse liability. With neuropathic pain mice showed higher pregabalin self-administration than saline, indicating analgesic effect. A decrease of self-administration by morphine +/- pregabalin, indicated a sedative effect of morphine. Dose selection of compound A2 (THC) for use in the mouse operant model is ready.
WP7- Clinical efficacy and adverse effects of analgesic treatments in healthy subjects. QSPainRelief-novelA with nociceptive tests, and a CNS test battery on cognition and neurophysiology in healthy volunteers with morphine + pregabalin was completed. Pregabalin+ morphine induced superior analgesic effects over pregabalin alone and placebo, without potentiation of cognitive side effects. This indicates this combination as an opioid-sparing treatment.
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 (180) had to be reduced (30). As alternative, QSPainRelief-patientSTRAT was developed as an online questionnaire for 150 patients, to obtain data to be used for patient stratification. QSPainrelief-POPQUEST: 217 patients were recruited and 116 patients completed.
WP9- Dissemination, Training and Exploitation. QSPainRelief’s social media presence kept active. The website was updated. QSPainRelief partners gave multiple lectures and poster presentations at scientific meetings. Two papers were published. Four masterclasses were held and recorded (website, YouTube channel). Two mentor-mentee sessions were held. Monthly, ECS journal club meetings were held. The 2nd dissemination performance evaluation was completed. The IIB updated the exploitation plan.
WP10- Ethical considerations. The 2nd Interim report on ethics monitoring for pre and clinical studies was finalized. QSPainRelief received authorization to perform a) clinical experimentation 2 in WP8; b) preclinical experimentation in WP6; and c) clinical experimentation1 in WP7. On 28th Sep 2022, we a meeting with our SEAB, for feedback on the QSPainRelief work. Governance framework update is ready.
WP11- Ethics requirements. All ethical requirements were fulfilled in time already in the first reporting period.
WP1- Project management. 2 SC and 2 GA meetings were successfully held. 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.
WP2- QSPainRelief model platform development. Neural circuit models for analgesia, abuse liability, sedation & cognitive impairment all have their first versions. The LeiCNSPK3.0 and LeiCNSBK1,0 models predicted CNS target site concentrations and target-binding kinetics) for ~100 opioids and augmentation drugs for use in the neural circuit models.
WP3- Data collection and data management. An updated DMP and database are available. Apart from historical clinical data and collected data on plasma pharmacokinetics, CNS receptor expression and receptor occupancy data of our selected drugs, data produced by WP5, WP6, and WP7 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, online patient questionnaire data on preferences on (side) drug effects will be collected and used, and compound A was selected by combined expertise. The MVR model is ready to analyse clinical data.
WP5- Cellular signalling and pathway analysis. Modeling indicated the potential existence of MOR-CB1 heteromers and needs to be validated in vitro. A binding kinetic model was developed for orthosteric and allosteric binding with rate constants instead of equilibrium constants. In vitro work on mouse, rat and human brain cells indicated species and brain location dependent mRNA target expression and signal transduction differences, for control, and acute and chronic morphine exposure, with/without pregabalin.
WP6 – Preclinical in vivo validation of QSPainRelief predictions. Studies with morphine and pregabalin were performed in male and female control and neuropathic pain mice. Without neuropathy mice showed a preference for the pregabalin over saline, indicating drug-abuse liability. With neuropathic pain mice showed higher pregabalin self-administration than saline, indicating analgesic effect. A decrease of self-administration by morphine +/- pregabalin, indicated a sedative effect of morphine. Dose selection of compound A2 (THC) for use in the mouse operant model is ready.
WP7- Clinical efficacy and adverse effects of analgesic treatments in healthy subjects. QSPainRelief-novelA with nociceptive tests, and a CNS test battery on cognition and neurophysiology in healthy volunteers with morphine + pregabalin was completed. Pregabalin+ morphine induced superior analgesic effects over pregabalin alone and placebo, without potentiation of cognitive side effects. This indicates this combination as an opioid-sparing treatment.
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 (180) had to be reduced (30). As alternative, QSPainRelief-patientSTRAT was developed as an online questionnaire for 150 patients, to obtain data to be used for patient stratification. QSPainrelief-POPQUEST: 217 patients were recruited and 116 patients completed.
WP9- Dissemination, Training and Exploitation. QSPainRelief’s social media presence kept active. The website was updated. QSPainRelief partners gave multiple lectures and poster presentations at scientific meetings. Two papers were published. Four masterclasses were held and recorded (website, YouTube channel). Two mentor-mentee sessions were held. Monthly, ECS journal club meetings were held. The 2nd dissemination performance evaluation was completed. The IIB updated the exploitation plan.
WP10- Ethical considerations. The 2nd Interim report on ethics monitoring for pre and clinical studies was finalized. QSPainRelief received authorization to perform a) clinical experimentation 2 in WP8; b) preclinical experimentation in WP6; and c) clinical experimentation1 in WP7. On 28th Sep 2022, we a meeting with our SEAB, for feedback on the QSPainRelief work. Governance framework update is ready.
WP11- Ethics requirements. All ethical requirements were fulfilled in time already in the first reporting period.
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.