Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MultipleMS (Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalised medicine)

Teaser

Multiple Sclerosis (MS) is an immune-mediated disease and a leading cause of non-traumatic disability in young adults in Europe, affecting ~2.3 million persons worldwide. It is a lifelong disease that strikes individuals, predominantly women, in their most productive years...

Summary

Multiple Sclerosis (MS) is an immune-mediated disease and a leading cause of non-traumatic disability in young adults in Europe, affecting ~2.3 million persons worldwide. It is a lifelong disease that strikes individuals, predominantly women, in their most productive years with an unpredictable and progressive disability that affects all areas of life and includes physical disability, cognitive impairment and fatigue. The complex interactions between genetic and non-genetic factors produce heterogeneities in patients as reflected in the diversity of pathophysiology, clinical manifestations, response to therapies, disease development and progression. MS cannot be cured but there are several available disease modifying treatments (DMTs) that can reduce disease activity in RRMS patients. However, the majority of RRMS patients eventually convert to a secondary progressive form of MS (SPMS) for which there is no approved treatment today.

The overall annual cost for MS is estimated to be € 15.5 billion in Europe including direct medical costs (pharmaceutical and non-pharmaceutical), direct non-medical costs (such as informal care, devices and adaptations), and finally indirect costs (such as productivity losses due to sick leave, incapacity to work and early retirement). The cost of MS increases with increasing disability reaching an annual cost of € 60.000 for patients who have reached progressive stage of disease, with the largest part being indirect costs. Hence, MS is one of the most expensive chronic diseases even compared to many diseases with higher prevalence.

The aim of MultipleMS is to develop novel personalised medicine approaches for MS patients. To this end we will identify a combination of evidence-based selection of clinical, biological, and lifestyle features that can predict the clinical course, stratify patients based on their risk and the therapeutic response to the existing DMTs in a real-world setting, and to gain in-depth knowledge of distinct pathogenic pathways to allow identification of targets for novel treatments.

The overall objectives of MultipleMS are:
• To stratify MS patients according to differential disease etiology, disease severity and progression, and DMT response.
• To identify and validate novel biomarkers to guide stratification of patients according to disease etiology, disease severity and progression and DMT response.
• To identify targets and interventions for new precise therapies.
• To develop guidelines for a new precision medicine using biomarker guided DMT placement and monitoring in clinical settings.
• To exploit and disseminate resulting biomarkers, guidelines and therapeutic targets.

Work performed

Considerable effort have been put into establishing the project as fully compliant with GDPR. This has involved institution of novel data and material transfer agreements and it is also permeating the handling of data in the whole consortium.

Two database solutions have been established for both exiting retrospective and new prospective cohort data, with secured authentication system. All partners have supplied clinical and genetic data from retrospective cohort and harmonization and quality control of the data is currently being performed. Considerable work has been put into planning how radiological image data will be handled and upload of images to the database with Qmenta has been initiated. In parallel, further analyses methods have been developed and implemented by several MultipleMS partners. In local analyses, genetic associations to severity of MS and cerebrospinal fluid biomarkers have been performed. Plasma neurofilament has been determined for a large number of MS cases and it has been shown that it can be used as a prognostic marker of response to treatment as well as disability progression. Significant method developments both regarding laboratory procedures, especially with regard to novel classes of biomarkers as well as immunophenotyping, and data analyses have been performed.

A protocol for the prospective study has been established and the study has been initiated at all centres in 8 EU countries (102 patients completed their baseline visit). A tool to monitor patient recruitment and data entry into the database was established as well as a biomaterial repository. The logistics and SOPs were developed for the sampling and storage of biomaterial and quality control experiments were performed with samples obtained from all clinical sites to ensure that the SOPs work well in a multi-center setting.

A systematic review of published MS guidelines regarding use of biomarkers in clinical practise has been performed. A survey was developed to understand differences and similarities of clinical practice of MS neurologists across Europe and to assess their willingness to use biomarkers in every day clinical practice.

We have established communication and dissemination channels, e.g. an official MultipleMS website, Facebook-page and Twitter account, which are available to all MultipleMS members and open for the public. A Stakeholder Forum was developed containing contact information of relevant stakeholders, such as pharmaceutical companies, (clinical) research associations, governmental bodies, non-governmental organisations, patient organisations and health professionals. Via this forum, stakeholders are informed about the project’s development and can provide feedback to the consortium. A Stakeholder workshop was arranged in London in May 2018 with participants from 18 different organizations/companies, where the aim was to inform key stakeholders in the MS field about the objectives and progress of MultipleMS and to consult them on their expectations of MultipleMS to allow for the best translation of project results. A PhD/Postdoc student challenge was organized in Copenhagen 2017 that gathered PhD students and postdocs in addition to a number of PIs in MultipleMS. Each attendee presented their vision on how to best involve and reach patients in the development and implementation of project results. This challenge was supported by Novartis.

Final results

To create strategic global synergies, MultipleMS includes 22 partners and covers not only the necessary clinical, biological, and computational expertise, but also includes six industry partners ensuring dissemination and exploitation of the methods and clinical decision support system. Moreover, the pharmaceutical industry partners provide expertise to ensure optimal selection and validation of clinically relevant biomarkers and new targets. Our conceptual personalized approach can readily be adapted to other immune-mediated diseases with a complex gene- lifestyle background and broad clinical spectrum with heterogeneity in treatment response. MultipleMS therefore has a potential implication on European policies, healthcare systems, innovation in translating big data and basic research into evidence-based personalized clinical applications.

The project has already resulted in several new collaborations including the EU-STANDS4PM project and several initiated collaborations with other consortia active in the MS field such as IMSGC.

Website & more info

More info: https://www.multiplems.eu/.