Benedict Rauser’s research while affiliated with Vrana GmbH (Germany) and other places

Objective To understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and siponimod treatment. Methods AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment at all. Cohort 1 received SARS-CoV-2 mRNA vaccination while continuing siponimod treatment, cohort 2 interrupted siponimod treatment for a full vaccination cycle and cohort 3 received vaccination during continuous treatment with first-line DMTs (glatiramer acetate, interferons, teriflunomide) or no current treatment. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one and month one and six after initial vaccination cycle and one month after a potential booster vaccination. Results After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients data will be available in early 2022 for all patients at week one and later time points including first booster vaccinations. Conclusions This analysis will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimod treated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

Many challenges exist in the precise diagnosis and clinical management of secondary progressive multiple sclerosis (SPMS) because of the lack of definitive clinical, imaging, immunologic, or pathologic criteria that demarcate the transition from relapsing-remitting MS to SPMS. This review provides an overview of the diagnostic criteria/definition and the heterogeneity associated with different SPMS patient populations; it also emphasizes the importance of available prospective/retrospective tools to identify patients with SPMS earlier in the disease course so that approved disease-modifying therapies and nonpharmacological strategies will translate into better outcomes. Delivery of such interventions necessitates an evolving patient-clinician dialog within the context of a multidisciplinary team.

Background Systematic data are lacking on the immune response toward SARS-CoV-2 mRNA vaccination in SPMS patients on disease-modifying therapies (DMTs). Objective The AMA-VACC clinical trial was designed to characterize immune responses to SARS-CoV-2 mRNA vaccines in siponimod-treated SPMS patients. Design AMA-VACC is an ongoing three-cohort, multicenter, open-label, prospective clinical study. Methods The study included patients at risk for SPMS or patients with SPMS diagnosis. Patients received SARS-CoV-2 mRNA vaccine as part of their clinical routine during ongoing siponimod treatment (cohort 1), during siponimod treatment interruption (cohort 2), or while on dimethyl fumarate, glatiramer acetate, beta-interferons, teriflunomide, or no current therapy (cohort 3). SARS-CoV-2-specific neutralizing antibodies and T-cell responses were measured 1 week and 1 month after the second dose of vaccination. Results In total, 17 patients, 4 patients, and 20 patients were recruited into cohorts 1, 2, and 3, respectively. The primary endpoint of seroconversion for SARS-CoV-2-neutralizing antibodies at week 1 was reached by 52.9%, 75.0%, and 90.0% of patients in cohorts 1, 2, and 3, respectively. For 64.7% of patients in cohort 1, all patients in cohort 2, and 95% of patients in cohort 3, seroconversion was observed at either week 1 or month 1 or both time points. After 1 week, 71.4% of cohort 1, 75.0% of cohort 2, and 85.0% of cohort 3 were positive for either SARS-CoV-2-neutralizing antibodies or SARS-CoV-2-specific T-cells or both. After 1 month, the rates were 56.3%, 100.0%, and 95.0%, respectively. Conclusion The study shows that the majority of siponimod patients mount humoral and cellular immune response under continuous siponimod treatment. The data do not sufficiently support interruption of treatment for the purpose of vaccination. Registration EU Clinical Trials Register: EudraCT 2020-005752-38 ( www.clinicaltrialsregister.eu ); ClinicalTrials.gov: NCT04792567 ( https://clinicaltrials.gov ).

Background: The tailored immunomodulatory treatment strategy for secondary progressive multiple sclerosis (SPMS) depends on disease activity. Objective: To assess the real-world situation in monitoring disease activity in SPMS patients and to identify associations of resulting subgroups with demographics, symptomatology, and therapy Methods: This study included 4,263 SPMS patients from the German MS register (GMSR). For the classification into ‘active’ and ‘inactive’ according to relapse activity and MRI findings during the year prior to the latest clinical visit, we used the following definitions: active - gadolinium enhancing (Gd+)/new T2 lesions or ≥1 relapse, inactive - neither Gd+/new T2 lesions nor relapses. The active, inactive, and unclassifiable patients were compared in terms of clinical data, socio-demographics, symptomatology, healthcare, and DMT. Results: Classification was possible for 1,513 (35.5%) SPMS patients, with 467 classified as active and 1,046 as inactive. For the classification, MRI data was available for 33.2% of the 4,263 patients. Higher MRI frequencies were observed for younger patients (OR 1.22 [1.12,1.33] per 10 years) with short disease duration (OR 1.19 [1.09, 1.30] per 10 years) (p<0.001). Conclusion: MRI coverage was low, especially in elderly SPMS patients. Roughly one third of the SPMS patients presented markers of disease activity in the last year. Overall, the clinical differences (concerning symptomatology and care) between patients with active and inactive SPMS were small.

BACKGROUND A digital tool (Multiple Sclerosis Progression Discussion tool, MSProDiscuss) was developed to facilitate a discussion between a healthcare professional (HCP) and patient in evaluating early, subtle signs of multiple sclerosis (MS) disease progression. OBJECTIVE To report findings on the usability and usefulness testing of the MSProDiscuss tool in the real-world clinical setting. METHODS In this cross sectional, online survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability and usefulness, and integration and adoption into clinical practice to capture their overall experience on using the tool). Responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made. RESULTS In total, 301 HCPs tested the tool in 6974 MS patients, of which 77% were relapsing remitting MS patients including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was 1-4 minutes in 97% (initial) to 98% (final) of the cases. In 94% (initial) to 97% (final) cases, HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions from the tool. HCPs were willing to use the tool again in the same patient 91% (initial) of the cases. MSProDiscuss was useful in discussing MS symptoms and their impact on daily activities (88% initial and 92% final) and cognitive function (79% for both initial and final) and in discussing progression in general (88% initial and 90% final). While completing the final questionnaire, 95% of HCPs agreed that the questions were similar to those asked in regular consultation and the tool helped to better understand the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague, and 86% are willing to integrate it into their clinical practice. CONCLUSIONS MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on disease progression in daily clinical practice. Most HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice.

Background A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression. Objective The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting. Methods In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs’ overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made. Results In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice. Conclusions MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice.

We agree with Kleiter et al. that the conversion of relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) represents a gradual process difficult to detect [1]. Even after years of significant effort defining diagnostic criteria through clinical and radiological data, an early recognition of conversion from RRMS to SPMS and the stratification of RRMS patients with an increased risk of developing disease progression is not clear [1-4]. Due to diverse factors, an uncertain diagnostic period of approximately 3 years has been described [3]. In addition to clinical outcome markers, no definitive imaging or laboratory test informs about the moment when a patient has entered the transitional MS phase [5]. The theory of a diffuse transition phase has been described and may a potential therapeutic opportunity where both RRMS and SPMS disease subtypes overlap for an undetermined period [1, 6]. Numerous compensatory mechanisms may cover the disability progression in this transition phase, making a silent progression with subclinical neurodegenerative process [7]. Nevertheless, the pathogenesis and clinical profile of these patients is far from being completely understood. A recent study with patients with RRMS showed that most of the patients had a disability progression that was independent of relapse activity, challenging current concepts of relapsing and progressive disease [8].

BACKGROUND A high proportion of patients with relapsing remitting multiple sclerosis (RRMS) convert to secondary progressive multiple sclerosis (SPMS) characterized by irreversibly progressing disability and cognitive decline. Siponimod (Mayzent®), a selective sphingosine-1-phosphate receptor modulator, has been recently approved by the EMA for the treatment of adult SPMS patients with active disease, as evidenced by relapses or magnetic resonance imaging features of ongoing inflammatory activity. Approval by the FDA covers a broader range of indications, comprising clinically isolated syndrome, RRMS, and active SPMS. However, treatment effects of siponimod have not been assessed in a structured setting in clinical routine so far. OBJECTIVE The objectives of AMASIA (ImpAct of Mayzent® (siponimod) on secondAry progressive multiple Sclerosis patients in a long-term non-Interventional study in GermAny), a prospective non-interventional study (NIS), are to assess long-term effectiveness and safety of siponimod in clinical routine, and to evaluate the impact of disease burden on quality of life and socioeconomic conditions. Here, we report the study design of AMASIA. METHODS Treatment effects of siponimod will be evaluated in 1500 SPMS patients during a 3-year observational phase. According to the genetic polymorphism of CYP2C9, the initial dose will be titrated to the maintenance dose of 1 mg (CYP2C9*1*3 and *2*3) or 2 mg (all other polymorphisms of CYP2C9 except *3*3 which is contraindicated) taken orally once daily. Primary endpoint is the 6-month confirmed disability progression, as assessed by a functional composite endpoint comprising the expanded disability status scale (EDSS) and the symbol digit modalities test (SDMT) to take appropriate account of cognitive changes and to increase sensitivity. Further measures including MS activity data, assessments of functional domains, questionnaires addressing the patient’s, physician’s, and relatives’ perspectives of disability progression, cognitive worsening, and quality of life as well as socioeconomic aspects will be documented by the MSDS3D system. RESULTS AMASIA is being conducted between February 2020 and February 2025 in up to 250 neurological centers in Germany. CONCLUSIONS AMASIA will complement the pivotal phase-III-derived efficacy and safety profile of siponimod by real-world data and will further evaluate several individual treatment aspects such as quality of life and socioeconomic conditions of patients and care givers. It might help to establish siponimod as promising option for the treatment of SPMS patients in clinical routine.