Benjamin Ettle’s research while affiliated with Novartis and other places

Booster vaccinations against SARS-CoV-2 are recommended 6–12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed. Fifteen patients were included. At the time of the first booster vaccination, ten patients were seropositive for neutralizing antibodies, four patients were seronegative, and for one patient, no baseline levels were available. All patients who were seropositive at baseline showed >2-fold increase in neutralizing antibody titers after the first booster and two patients (20%) showed a >10-fold increase. Among seronegative patients, three (75%) had a >10-fold increase in neutralizing antibody titers. Seropositivity was maintained in almost all patients until month 12. One initially seronegative patient had less than 2-fold increase in neutralizing antibody titers after the booster vaccination and can be considered a non-responder. Most patients with continued ofatumumab treatment are able to maintain permanent seropositivity and therefore presumably constant protection against severe courses of COVID-19 if repeated booster vaccinations are applied.

Objective This study aims at understanding the impact of ofatumumab treatment on the development of cellular and humoral immune responses to initial and booster SARS-CoV-2 mRNA vaccines. Methods KYRIOS is an open-label, prospective, two-cohort study at eight sites in Germany including 40 MS patients who receive SARS-CoV-2 mRNA vaccination either before starting ofatumumab treatment (cohort 1) or during stable ofatumumab treatment for at least 4 weeks (cohort 2). The impact of ofatumumab treatment on the proportion of patients having established SARS-CoV-2 reactive T-cells (primary endpoint) and developing SARS-CoV-2 neutralizing antibodies (secondary endpoint) after initial and booster vaccination will be assessed. Additionally, cellular and humoral immune responses will be monitored for up to 18 months and cellular response will be further described by immunophenotyping. Results Results of this second interim analysis show the efficacy of SARS-CoV-2 mRNA vaccines to induce cellular and humoral immune responses in MS patients depending on the timing of ofatumumab treatment initiation. First data indicate that in patients vaccinated during stable ofatumumab treatment, specific immune response is detectable as soon as 1 week after the initial vaccination cycle and further increases afterwards. Conclusions KYRIOS data show for the first time that patients vaccinated during stable ofatumumab treatment can mount immune responses to SARS-CoV-2 mRNA vaccines. The presented data further emphasize the importance of considering both, humoral and cellular immune response, for interpretation of vaccine efficacy.

Background: Few data exist on how ofatumumab treatment impacts SARS-CoV-2 booster vaccination response. Methods: KYRIOS is an ongoing prospective open-label multicenter study on the response to initial and booster SARS-CoV-2 mRNA vaccination before or during ofatumumab treatment in relapsing MS patients. The results on the initial vaccination cohort have been published previously. Here, we describe 23 patients who received their initial vaccination outside of the study but booster vaccination during the study. Additionally, we report the booster results of two patients in the initial vaccination cohort. The primary endpoint was SARS-CoV-2-specific T-cell response at month 1. Furthermore, serum total and neutralizing antibodies were measured. Results: The primary endpoint was reached by 87.5% of patients with booster before (booster cohort 1, N = 8) and 46.7% of patients with booster during ofatumumab treatment (booster cohort 2, N = 15). Seroconversion rates for neutralizing antibodies increased from 87.5% at baseline to 100.0% at month 1 in booster cohort 1 and from 71.4% to 93.3% in booster cohort 2. Of note, 3 of 4 initially seronegative patients in booster cohort 2 and one seronegative patient in the initial vaccination cohort seroconverted after the booster during ofatumumab treatment. Conclusions: Booster vaccinations increase neutralizing antibody titers in ofatumumab-treated patients. A booster is recommended in ofatumumab-treated patients.

Background: It is unclear whether multiple sclerosis (MS) patients receiving ofatumumab mount an immune response after SARS-CoV-2 mRNA vaccination. Methods: KYRIOS is an ongoing, multicenter, open-label, prospective clinical study on immune responses in MS patients after initial or booster SARS-CoV-2 mRNA vaccination prior to (cohort 1) or during (cohort 2) ofatumumab treatment. We report one-week and one-month results of the initial vaccination. A comparison with patients vaccinated while receiving beta-interferon, glatiramer acetate, dimethyl fumarate, teriflunomide or no treatment was included (cohort 3). Results: In total, 11 patients received their initial vaccination during the study. The primary endpoint of SARS-CoV-2-specific T-cells at month 1 was reached by 80.0% of patients in cohort 1 (N = 6) and 100.0% in cohort 2 (N = 5). T-cell reactivity peaked at week 1. All cohort 1 patients reached seroconversion for SARS-CoV-2 neutralizing antibodies at week 1 and month 1. In cohort 2, neutralizing antibodies increased in all patients and exceeded the cut-off for seropositivity in 40.0% of patients at week 1 and 25.0% at month 1. Immune responses in cohort 3 were comparable to cohort 1. Conclusion: Presence of T-cell response and increase in levels of neutralizing antibodies, although less pronounced compared to controls, suggest that MS patients receiving ofatumumab are able to mount an immune response to SARS-CoV-2 mRNA vaccination.

Hintergrund Es gibt Hinweise darauf, dass bei schubförmiger Multipler Sklerose (Relapsing Multiple Sclerosis; RMS) ein früher Beginn einer hochwirksamen Therapie einer Eskalationsstrategie überlegen sein könnte. Ziel Mit Hilfe einer Kosten-Folgen-Analyse sollen die klinischen und gesundheitsökonomischen Auswirkungen verschiedener Behandlungsszenarien mit Ofatumumab (OMB), Dimethylfumarat (DMF) bzw. Glatirameracetat (GA) simuliert werden: ein sofortiger Behandlungsbeginn mit OMB als Ersttherapie, ein früher Wechsel auf OMB nach einem Jahr unter Behandlung mit DMF oder GA, ein später Wechsel nach 5 Jahren bzw. kein Wechsel. Methodik Der Simulation wurde ein EDSS-basiertes Markov-Modell mit einem Zeithorizont von 10 Jahren zugrunde gelegt. Bei jedem Zyklusübergang waren eine Progression, eine Verbesserung bzw. eine Stabilisierung des EDSS, ein Behandlungsabbruch, Schub oder Tod möglich. Inputdaten für das Modell stammten aus OMB-Studien, einer Netzwerk-Metaanalyse, aus Fachveröffentlichungen und öffentlich verfügbaren Quellen. Ergebnisse Ein später Wechsel auf OMB resultierte im Vergleich mit der sofortigen OMB-Behandlung in einem geringeren Anteil an Patienten mit einem EDSS von 0 bis 3 nach 10 Jahren (∆ –7,5 % DMF; ∆ –10,3 % GA), in mehr Schüben (∆ + 0,72 DMF; ∆ + 1,23 GA) und in geringeren Beschäftigungsquoten (∆ –4,0 % DMF; ∆ –5,6 % GA). Dies gilt ebenso für den Vergleich eines späten mit einem frühen Wechsel. Das Szenario ohne Therapieumstellung führte zu schlechteren Ergebnissen. Die Arzneimittelkosten waren bei sofortiger bzw. früher OMB-Behandlung höher, wurden aber nahezu ausgeglichen durch niedrigere Kosten für die Patientenversorgung (u. a. stationäre bzw. informelle Pflege, gemeinschaftliche und soziale Dienstleistungen) und geringere Produktivitätsverluste. Schlussfolgerung Eine sofortige Behandlung mit OMB bzw. ein früher Wechsel auf OMB führen zu besseren Ergebnissen hinsichtlich Klinik und Produktivität im Vergleich zu spätem oder keinem Wechsel auf OMB. Dabei bleiben die sofortige bzw. frühe OMB-Behandlung nahezu kostenneutral.

Objective To evaluate the 5-year real-world benefit–risk profile of fingolimod in patients with relapsing–remitting MS (RRMS) in Germany. Methods Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional real-world study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively. Results At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with ‘no change’ in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%). Conclusions PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term real-world treatment of patients with RRMS.

Background Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0–3 (Δ − 7.5% DMF; Δ − 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ − 4.0% DMF; Δ − 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.

Background: Fingolimod (Gilenya®) is approved for adult and pediatric patients with highly active relapsing–remitting multiple sclerosis (RRMS). Objectives: The objective was to describe the effectiveness of fingolimod in young adults compared to older patients in clinical practice. Methods: PANGAEA is the largest prospective, multi-center, non-interventional, long-term study evaluating fingolimod in RRMS. We descriptively analyzed demographics, MS characteristics, and severity in two subgroups of young adults (≤20 and >20 to ≤30 years) and older patients (>30 years). Results: Young adults had lower Expanded Disability Status Scale (EDSS) scores compared to older patients (1.8 and 2.3 vs. 3.2) at baseline. The mean EDSS scores remained stable over 5 years in all subgroups. Young adults had higher annual relapse rates (2.0 and 1.7 vs. 1.4) at study entry, which were reduced by approximately 80% in all subgroups over 5 years. The proportion of patients with no clinical disease activity in year 4 was 52.6 and 73.4 vs. 66.9% in patients ≤20, >20 to ≤30 years and >30 years, respectively. The symbol digit modalities test score increased by 15.25 ± 8.3 and 8.3 ± 11.3 (mean ± SD) from baseline in patients >20 to ≤30 and >30 years. Conclusions: Real-world evidence suggests a long-term treatment benefit of fingolimod in young RRMS patients.