Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Background and Aims: ENHANCEwas a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n= 89), 10 mg (n= 89), placebo (n= 87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67xupper limit of normal (ULN), >= 15% ALP decrease from baseline, and total bilirubin <= ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score >= 4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p= 0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 (p= 0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p= 0.0008); 10 mg: 16.7% (p= 0.03); placebo: 4%]. There were no serious treatment-related adverse events.Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Background and Aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p=0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: −3.14 (p=0.02); placebo: −1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p=0.0008); 10 mg: 16.7% (p=0.03); placebo: 4%]. There were no serious treatment-related adverse events. Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated

Rhopalia are integrated parts of the central nervous system in box jellyfish

In cubomedusae, the central nervous system (CNS) is found both in the bell (the ring nerve) and in the four eye-bearing sensory structures (the rhopalia). The ring nerve and the rhopalia are connected via the rhopalial stalks and examination of the structure of the rhopalial stalks therefore becomes important when trying to comprehend visual processing. In the present study, the rhopalial stalk of the cubomedusae Tripedalia cystophora has been examined by light microscopy, transmission electron microscopy, and electrophysiology. A major part of the ring nerve is shown to continue into the stalk and to contact the rhopalial neuropil directly. Ultrastructural analysis of synapse distribution in the rhopalial stalk has failed to show any clustering, which indicates that integration of the visual input is probably spread throughout the CNS. Together, the results indicate that cubomedusae have one coherent CNS including the rhopalia. Additionally, a novel gastrodermal nerve has been found in the stalk; this nerve is not involved in visual processing but is likely to be mechanosensory and part of a proprioceptory system

Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia

10.1371/journal.pone.0128028PLoS ONE105e012802

Sustaining meaningful patient engagement across the lifecycle of medicines: A roadmap for action

Background There is increased recognition that incorporating patients’ perspectives and insights into the medicines development process results in better health outcomes and benefits for all involved stakeholders. Despite the increased interest and the existence of frameworks and practical recommendations, patient engagement (PE) is not yet considered standard practice. The objective of this work was to provide a roadmap to support systematic change in all stakeholder organisations involved in medicines development across Europe, patients and patient organisations, medicines developers, academia, regulatory authorities, Health Technology Assessment bodies, payers, policy-makers and public research funders, to sustain PE practices. Methods A mixed-methods approach was used by the EU-funded Innovative Medicines Initiative PARADIGM Consortium to co-develop the sustainability roadmap including background work to identify success factors and scenarios for sustainable PE. The roadmap development was based on the Theory of Change concept and populated with findings from (1) interviews with national/ and international institutions with the potential to increase PE uptake by other stakeholders; (2) multi-stakeholder workshops and webinars; and (3) consultations with specific stakeholder groups, Consortium members and a consultative body formed by international PE initiatives. Results This roadmap sets strategic goals for the PE community to achieve meaningful and systematic PE through changes in the culture, processes and resources of stakeholder organisations. It brings in key PARADIGM outputs to work in a coordinated fashion with existing frameworks and mechanisms to achieve system-wide sustained PE. Conclusions The roadmap provides a framework for all stakeholders to take collective action within their organisations and across Europe to implement PE in a sustainable manner

Optimising Multi-stakeholder Practices in Patient Engagement: A Gap Analysis to Enable Focused Evolution of Patient Engagement in the Development and Lifecycle Management of Medicines

Background: The PARADIGM consortium aimed to make patient engagement in the development and lifecycle management of medicines easier and more effective for all, with the development of new tools that fulfil robustly defined gaps where engagement is suboptimal. Aims: To generate an inventory of gaps in patient engagement practices and process from existing global examples. Methods: A large set of criteria for effective patient engagement previously defined via a multi-stakeholder Delphi method, were mapped under fourteen overarching themes. A gap analysis was then performed by twenty-seven reviewers against the resulting forty-six mapped criteria, on a sample of seventy initiatives from global databases. Results: An inventory of gaps was identified including contextual information as to why the gaps exist. Our work identified general patterns where patient engagement was suboptimal—defined as; fragmented reporting and dissemination of patient engagement activities, and the fundamental principles defined in frameworks or guidance being poorly adhered to in actual practice. Specific gaps were identified for sixteen criteria. Additionally, it was also common to observe primary aspects of a process were addressed for a given criteria (i.e. training for roles and responsibilities) but a secondary context element was lacking (i.e. making training material accessible/understandable/meaningful to all participants). Conclusion: The results show that the evolution towards meaningful and systematic patient engagement is occurring, yet more importantly they provide clear directional insights to help enhance collaborative practices and co-design solutions. This targeted impact to catalyse a needs-oriented health system that integrates patient engagement at its core is essential

Optimising multi-stakeholder practices in patient engagement: A gap analysis to enable focused evolution of patient engagement in the development and lifecycle management of medicines

Background The PARADIGM consortium aimed to make patient engagement in the development and lifecycle management of medicines easier and more effective for all, with the development of new tools that fulfil robustly defined gaps where engagement is suboptimal. Aims To generate an inventory of gaps in patient engagement practices and process from existing global examples. Methods A large set of criteria for effective patient engagement previously defined via a multi-stakeholder Delphi method, were mapped under fourteen overarching themes. A gap analysis was then performed by twenty-seven reviewers against the resulting forty-six mapped criteria, on a sample of seventy initiatives from global databases. Results An inventory of gaps was identified including contextual information as to why the gaps exist. Our work identified general patterns where patient engagement was suboptimal—defined as; fragmented reporting and dissemination of patient engagement activities, and the fundamental principles defined in frameworks or guidance being poorly adhered to in actual practice. Specific gaps were identified for sixteen criteria. Additionally, it was also common to observe primary aspects of a process were addressed for a given criteria (i.e. training for roles and responsibilities) but a secondary context element was lacking (i.e. making training material accessible/understandable/meaningful to all participants). Conclusion The results show that the evolution towards meaningful and systematic patient engagement is occurring, yet more importantly they provide clear directional insights to help enhance collaborative practices and co-design solutions. This targeted impact to catalyse a needs-oriented health system that integrates patient engagement at its core is essential