Neuro-SysMed: A Systems Medicine Approach to Restructure Norwegian Clinical Neurology

Neuro-SysMed is a Centre for Clinical Treatment Research focused on multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia. Hosted by Haukeland University Hospital in collaboration with the University of Bergen and Haraldsplass Deaconess Hospital, the Centre aims to optimize current treatments and develop therapies to slow disease progression, alleviate symptoms, and improve care. The Centre is engaged in 39 clinical studies and research projects across diseases. Multiple Sclerosis (MS) We are conducting 16 studies focusing on efficacy, safety, prevention, and personalized approaches. OVERLORD-MS compares the efficacy and safety of intravenous rituximab (RTX) and ocrelizumab (OCR) in relapsing-remitting MS (RRMS). A subsequent six-month switch study evaluates whether the effect is preserved, after switching from OCR to RTX. All patients are offered inclusion in a dose extension study (REDUCE-MS) evaluating long-term safety and efficacy. Long-term safety and efficacy of rituximab compared to cladribine is analysed in a target trial emulation evaluating high efficacy therapies in RRMS. RAM-MS examines the effect of autologous hematopoietic stem cell transplantation, compared to standard high-efficiency treatments, in RRMS with breakthrough disease activity. Samples from OVERLORD-MS and RAM-MS are used in biomarker studies exploring personalized anti-CD20 (RTX) and HSCT treatments. 3TR-IMI-Horizon assesses biomarkers for disease modifying treatment responses in RRMS. The COVID-19 VACCINE study investigated how MS drugs, especially RTX, affect the clinical and immune effects of COVID-19 vaccination. SMART-MS investigates whether autologous mesenchymal stem cells can repair neurological tissue damage in progressive MS. NORSEMAN-MS investigates whether nicotinamide riboside can slow disease progression in MS-patients experiencing worsening of disability. FlowOX-MS evaluating pulsed negative pressure treatment for leg spasticity and pain in MS, is completed. Antiviral treatment strategies are investigated in the TAF-MS-0 and TAF-MS-1 studies evaluating whether tenofovir alafenamide fumarate (TAF) affects Epstein-Barr virus (EBV) shedding in saliva. Their results will be fed into TAF-MS-2 evaluating whether TAF can influence MS-disease activity measured by PET-imaging of microglia activation. Microglia activation is also studied in chronic active MS-lesions from brain tissue samples. NorseMS tests symptomatic therapy for improving sleep disturbances in MS by Cognitive Behavioural Therapy. Neurodegeneration (PD, Dementia, ALS) We have completed three studies and are running 20 others focusing on neuroprotection, prevention, and personalized approaches. NADPARK and NR-SAFE trials have nominated NAD-replenishment with nicotinamide riboside (NR) as a disease-modifying therapy for PD. NADbrain, exploring the blood and brain kinetics of NAD-precursors was recently completed. NO-PARK, a phase III efficacy trial assessing whether NR treatment can delay neurodegeneration and disease progression in PD, is fully enrolled and to be completed in May 2025. NO-PARK extension assesses the long-term safety and tolerability of NR. N-DOSE and N-DOSE AD will determine the optimal dose of NR for PD and Alzheimer's disease. NADAPT is a phase II trial investigating whether NR can delay the progression of supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBD). SLEIPNIR is a multiarm trial platform aiming to assess target penetration and engagement of potential disease-modifying therapies for PD. HYDRA, a phase III multiarm multistage (MAMS) trial platform, is set to start in 2025, in a consortium with corresponding UK and France initiatives. NADage, assessing the potential of NR treatment in ameliorating age-related frailty and preventing conversion to dementia, received EU funding from the ERA4Health program. NO-ALS investigates whether NR and pterostilbene can slow the progression of ALS, while NO-ALS-II investigates the long-term safety of this treatment. ALS-LTMV quality of life impacts of long-term mechanical ventilation for ALS. STRAT-PARK, a personalized medicine initiative in PD, develops clinical biomarkers to stratify PD with funding from the Michael J Fox Foundation. STRAT-COG is a similar initiative for Alzheimer's disease. NorRBD and NAD-RBD are studies of individuals with prodromal neurodegeneration aiming to enable prevention. DIGI.PARK develops digital measures of treatment response in PD. The ParkOme initiative has mapped molecular profiles from >1,300 brains, with groundbreaking results expected published in Q4 2024. Meanwhile, the mitoPD project identified a novel PD subtype characterized by mitochondrial dysfunction. New therapy identification is ongoing in the PARKdrug and DRONE projects with several hits identified, resulting in new innovation projects and commercialization funding.

Central Nervous System (CNS) diseases affect one in three people during their lifetime and are leading causes of death and disability. Despite more than two centuries of scientific endeavor, minor advances have been gained in understanding and treating most CNS diseases; consequently, patients confront a future of progressive disability and premature death with treatments that are mostly symptomatic. Since demographic studies show that patient numbers will continue to grow, our failure to make any significant impact means that CNS diseases are now the major challenge to health care provision. Our proposed Center for Clinical Research (FKB) will integrate a centralized national hub enabling and supervising clinical trials in neurology and innovative Systems Medicine approaches, to addresses the unmet needs of patients with the most common and debilitating CNS diseases in a systematic and all-encompassing fashion. Our groundbreaking concept comprises four highly integrated and complementary activities: 1) A multidisciplinary Neurological Clinical Trial Unit (NTCU) will enable nationwide access to cutting-edge clinical trials for patients with CNS disorders, investigators/researchers and the industry. 2) Patients recruited to our trials will enter a unique Systems Medicine pipeline, which will provide standardized assessment and precision stratification, followed by highly personalized experimental treatment and care interventions. 3) In parallel, our cutting-edge translational node will integrate the powerful Norwegian registries and cutting-edge networks-biology, emerging from patient samples, with innovative disease models in order to nominate novel therapeutic targets and generate the next generation of therapies. These will be fed back into the clinical node for testing in novel clinical trials. 4) Positive results will trigger our drug development and commercialization pipeline under the leadership of our expert innovation team and infrastructure at the FKB.