Improved and tailored therapies for patients with multiple sclerosis

Primary Investigator

Kjell-Morten Myhr

Myhr is senior consultant and professor in Neurology, and has since 2001, directed the multiple sclerosis (MS) research group at Haukeland University Hospital and the University of Bergen (https://www.uib.no/fg/kgj-ms). He has previous chaired the first KG Jebsen centre for medical research, focusing on MS-biomarkers (2011-2016), and has since 2019 been the director of the first Norwegian centre for clinical treatment research, Neuro-SysMed.

The MS research group at Haukeland University Hospital and the University of Bergen has a long-standing tradition, since the early 1970s, for clinical epidemiology and immunology research in MS. This include studies of incidence and prevalence, and risk factors in MS, as well as immunological and genetic analysis of blood, cerebrospinal fluid (CSF) or brain tissue. The focus has been on aetiology, prognosis and pathogenesis of the disease.

Along with the introduction of disease modifying therapies in the early 1990s, we have increasingly organized and participated in national and international multicentre randomized clinical trials. This has naturally led into additional research activity focusing on symptom identification and therapy, rehabilitation, patients reported outcome measures, as well as health economy to evaluate the consequences of the disease to the patients, their families and society. Biomarker detection for early diagnosis, prognosis and treatment response for tailored therapy for individual patients is yet another research topic of the group.

The MS research group is highly dedicated for translational research to improve MS care, with a strong focus on treatment trials and biomarker detection.

The group is currently organizing a randomized clinical trial to evaluate the efficacy and safety of autologous haematological stem cell transplantation (HSCT) compared to standard high-efficacy therapies in MS. Haukeland University Hospital is the national centre for such MS-therapy in Norway, and we have recently reported efficacy and safety data from patients that received HSCT prior to the study start (Kvistad et al., 2019).

Another focus of our group has been B-cell depletion as early high-efficacy therapy in MS. Years before B-cell therapy was approved for MS, off label rituximab has been offered MS patients at Haukeland University Hospital. Based on this experience, a non-inferiority study comparing low-cost rituximab to the approved high-cost ocrelizumab is now underway. We have recently reported real world clinical experience of high efficacy and safety from rituximab therapy in relapsing-remitting MS (RRMS) (Torgauten et al., 2020 submitted).

Other important contributions from our group are milestone articles on axonal transection and cortical pathology in MS (Trapp et al., 1998, Bø et al., 2003a). Moreover reports of modifiable risk factors in MS, including vitamin D (Bjørnevik et al., 2015; Cortese et al., 2015), and bodyweight (Wesnes et al., 2015; Cortese et al., 2018). Importantly, vitamin D and body weight also seem to influence disease progression (Løken-Amsrud et al., 2012, Wergeland et al., 2011, Nystad et al., 2014) and therapy response (Kvistad et al., 2015; Bringeland et al. 2019).

Biomarkers for prognoses and treatment response are other important contributions from our research group. We, and others, have shown that CSF- and serum levels of neurofilament light chain (NFL) predict long-term prognosis (Bhan et al., 2018) and ongoing disease activity (Varhaug et al., 2017) in MS. More recently, we have presented data indicating that receptor occupancy may influence outcome of the high-efficacy natalizumab therapy in MS (Bringeland et al., 2020).

Symptomatic therapy, rehabilitation, patients reported outcomes measures and health economy have likewise been a prioritized area of research. This will further be integrated in the Neuro-SysMed research activity. We were pioneers in quality of life (QoL) research in MS (Nortvedt et al., 1999, 2000). Reports on physiotherapy rehabilitation (Smedal et al., 2011) as well as MS-symptoms related to fatigue (Smedal et al., 2011), sleep disturbances (Lunde et al., 2012) depression (Beiske et al., 2008), cognition (Cortese et al., 2016; Skorve et al., 2020), and bladder & sexual dysfunction (Nortvedt et al., 2007) have been important contributions from our group. Moreover, knowledge of long-terms consequences of the disease for the patients and their family, related to health economy and prognosis are important in the planning of the healthcare services (Svendsen et al., 2012; 2018; Myhr et al., 2001; Lunde et al., 2017; Grytten et al., 2019).

Aims

  • Optimize or develop new treatment strategies in MS
  • Make new therapies early available for Norwegian patients, preferably through participation in randomized clinical trials
  • Define and evaluate biomarkers for early diagnoses, disease classification, prognosis and treatment response to offer tailored treatment for the individual patients

Research

Trials
Principal Investigator: Øivind Torkildsen

The Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease; The OVERLORD-MS study;

B cell depletion therapies (rituximab, ocrelizumab, ofatumumab) are proven highly effective in MS. A very recent Norwegian health technology assessment (HTA) indicates similar treatment effects from rituximab and ocrelizumab – but clearly, state that more data, preferably from a RCT is needed (https://nyemetoder.no/Documents/Rapporter/disease-modifying-treatments-for-relapsing- remitting-multiple-sclerosis-including-rituximab-hta-rapport-2019.pdf/). Rituximab has been used for the treatment of rheumatologically diseases and haematological cancers since 1998, and due to patency expire, costs only a fraction of ocrelizumab. If rituximab proves to have similar effects as ocrelizumab, it may therefore substantially reduce the annual cost for MS-therapy, and give MS-patients access to highly effective treatment at an earlier time point. In this study, we therefore aim to compare the efficacy and safety of rituximab to ocrelizumab for early treatment in MS.

The objectives of this non-inferiority study are to evaluate if rituximab has comparably efficacy and safety as ocrelizumab in the treatment of newly diagnosed patients with MS.
The primary endpoint of the study is the proportion of patients free of new T2 magnetic resonance imaging (MRI) lesions between month 6 and month 24 (two years).

The study (https://clinicaltrials.gov/ & NCT04578639 is approved by the Regional Committees for Medical and Health Research Ethics Western Norway, and the Norwegian Medicines Agency. The first patient will be included in late October 2020 at Haukeland University Hospital.

 

Newsletter 1 (Norwegian)
Newsletter 2 (Norwegian)
Newsletter 3 (Norwegian)
Newsletter 4 (Norwegian)
Newsletter 5 (Norwegian)
Newsletter 6 (Norwegian)
Newsletter 7 (Norwegian)
 

participating centres

  • Haukeland University Hospital, Bergen
  • Oslo University Hospital, Oslo
  • Akershus University Hospital, Lørenskog
  • Stavanger University Hospital, Stavanger
  • St Olav’s Hospital, Trondheim
  • The University Hospital Nord-Norge, Tromsø

funding

  • The Research Council of Norway, Neuro- SysMed
  • Haukeland University Hospital
  • University of Bergen
  • Participating hospitals

Last updated May 11th, 2021 at 11:00 am

Other research
Principal Investigator: Stig Wergeland

MS-SEQ – elucidating the genetic susceptibility of multiple sclerosis by whole exome sequencing

The cause of multiple sclerosis (MS) is unknown, but there is strong evidence for involvement of both genetic and environmental factors. There is a clear heritability in MS, but the genes and variants involved are largely unknown. GWAS studies have provided some insight by identifying genetic markers (> 200) associated with a modified risk for MS. These have generally small effects and mark loci rather that specific genes. Therefore, the genes and biological pathways involved remain largely unmapped. To overcome this limitation, we aim to sequence the complete coding genome (exome) of a large cohort of patients and controls and apply sensitive analyses methods to understand the role of common and rare genetic variation in MS. Unlike GWAS studies, our design will allow the direct identification of genes and molecular pathways involved in the disease and therefor help identify novel therapeutic targets. We therefore aim to map the entire coding genome (exome) of 2500 MS patients and 3500 controls to elucidate the heritability of MS

The objectives are to identify novel genetic risks of MS and possible biomarkers for diagnosis and disease progression, and further exploit the obtained insight of disease mechanisms to identify novel therapeutic targets.

DNA samples from about 2500 MS patients in the Norwegian MS Registry and about 3000 controls, mainly from the HUSK-study (https://husk-en.w.uib.no/) will be analysed by whole exome sequencing and data will be available for analyses from Q4 2020. We will then analyse the data for possible novel genetic risks of MS or possible biomarkers for diagnosis and disease progression, and further exploit the obtained insight of disease mechanisms to identify possible novel therapeutic targets.

Currently, the study is approved by to the Regional Committee for Medical and Health Research Ethics Western Norway, and contract for collaboration with HUSK and the exome sequencing providers is finalized.

SUPPORT ________________________________________________________________

Participating Centres

  • The Norwegian MS Registry
  • Haukeland University Hospital
  • University of Bergen

Funding

  • The Norwegian MS Registry
  • The Research Council of Norway, Neuro-SysMed
  • Haukeland University Hospital
  • University of Bergen

Last updated October 30th, 2020 at 12:13 pm

National and international collaborators

Years of successful MS research have been dependent on extensive local, national and international collaboration. Our network is also important for further research in Neuro-SysMed, and some of our collaborators are listed below:

Dr Kritin Lif Breivik, Førde Hospital, Førde.
Dr Ineke HogenEsch, Haugesund Hospital, Haugesund.
Professor Trygve Holmøy, Akershus University Hospital, Lørenskog,
Dr. Cecilie Jacobsen, Stavanger University Hospital.
Associate Professor Margitta Kampman, University Hospital of North Norway (UNN), Tromsø.
Dr. Kathrine Lian, St. Olavs University Hospital, Trondheim.
Dr Gro Owren Nygård, Oslo University Hospital.

Professor Alberto Ascherio, Harvard School of Public Health, Boston USA.
Professor Frederik Barkhof,
VU Medical Center, Amsterdam, Netherlands and University College London, UK.
Dr. Kjetil Bjørnevik,
Harvard School of Public Health, Boston USA.
Dr. Morten Blinkenberg, Copenhagen University Hospital, Denmark.Professor Jan Lycke, Sahlgrenska University Hospital, Sweden.
Associate Professor Joachim Burman, Akademiska sjukhuset, Uppsala.
Dr. Jeppe Romme Christensen, Copenhagen University Hospital, Denmark.
Professor. Joep Killestein, VUmc, Amsterdam, Netherlands.
Professor Hubert Schrezenmeier Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Ulm, Germany.
Professor Anders Svenningsson, Karolinska Institutet, Stockholm, Sweden.
Professor Minoru Ueda,
University of Nagoya, Japan.
Professor Maura Pugliatti, University of Ferrara, Ferrara, Italy.
Professor Christina Wolfson, McGill University, Montreal, QC, Canada.

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