Search

Abstract Objective Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open‐label, multicenter, Phase 1b, dose‐finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825). Methods Patients with relapsing or primary progressive multiple sclerosis (aged 18–65 years; Expanded Disability Status Scale score 0.0–6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration–time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose‐continuation phase. Results Eighty‐eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data. Interpretation Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option.

Abstract Objective Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well‐developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of “brain age” analysis on disability in MS using a large, real‐world dataset. Methods Brain age analysis is predicated on the over‐estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. Results MS was associated with advanced predicted brain age cross‐sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. Interpretation Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation.

Abstract Objective Evaluation of serum neurofilament light chain (sNfL), measured using high‐throughput assays on widely accessible platforms in large, real‐world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high‐throughput, scalable immunoassay. Results Elevated sNfL levels for age (sNfL‐E) were found in 1238 MS participants (17.8%). Factors associated with sNfL‐E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease‐modifying therapy was associated with lower odds of sNfL‐E. MS participants with sNfL‐E exhibited worse neurological function (patient‐reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short‐term rates of whole brain atrophy in sNfL‐E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL‐E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age‐normative sNfL Z‐scores as a continuous variable. Interpretation Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.