End-of-Dose Phenomena Observed With Multiple Sclerosis Medication Ofatumumab

Steffen Pfeuffer, MD

In a small-scale study of 103 patients with multiple sclerosis (MS), findings showed that more than one-third of this group experienced end-of-dose phenomena (EOD) with ofatumumab (Kesimpta; Novartis), an FDA-approved disease-modifying therapy. Overall, the presence of EOD was associated with higher baseline disability, longer disease duration, and older age, raising the importance of careful examination for EOD for patients on this medication.

Senior investigator Steffen Pfeuffer, MD, head of the Neurological CSF Laboratory at the University of Giessen, and colleagues screened all eligible patients from the University Hospital Giessen for abundance of EOD using a questionnaire already established in the SATURATE-MS study (NCT05701423). The study, dubbed ABANDONED-MS, patients were assessed during week 4 of a treatment course (considered “off phase”) and week 1 of a subsequent course (“on-phase”) on neuropsychiatric outcomes, Multiple Sclerosis Functional Composite (MSFC), and Expanded Disability Status Scale (EDSS) scores.

Presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held September 18-20 in Copenhagen, Denmark, results showed that 35 of the 103 patients (34%) experienced EOD with ofatumumab. Most commonly, patients reported fatigue (27%), cognitive impairment (19%), and gait difficulties (16%). In addition, patients with EOD displayed worse performance in some subcategories of neuropsychiatric testing and reported decrease quality of life. There was no substantial differences in depletion of CD19+ B cells among EOD and non-EOD-patients.

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Ofatumumab, approved to treat relapsing forms of MS, has been on the market since 2021. It acts as a fully-humanized monoclonal anti-CD20 antibody constructed with recombinant DNA techniques and is designed to selectively target CD20-expressing B-cells. Following cell surface binding, ofatumumab selectively depletes CD20-expressing B-cells through antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis.

A 2024 study assessing wearing-off effect in MS medications showed that patients taking ofatumumab, given as a once monthly subcutaneous injection had a 18.2% lower odds of the wearing-off effect as compared with ocrelizumab (Ocrevus; Roche)-treated patients. This finding was particularly interesting in that prior data suggested that both ofatumumab and ocrelizumab provide rapid and sustained B-cell depletion. All told, the lower incidence of wearing-off effect among ofatumumab-treated patients potentially suggested additional effects of B cell depletion that in some way differ between ocrelizumab and ofatumumab versus possibly a placebo effect from more frequent dosing of the ofatumumab.²

The study, published in the Multiple Sclerosis Journal: Experimental, Translational, and Clinical, assessed 258 qualifying responses from a tertiary MS center who were taking either natalizumab, ocrelizumab, ofatumumab, or rituximab. Of these, 141 (54.7%) reported the wearing-off phenomenon. Overall, the patient-reported wearing-off effect was seen least frequently with ofatumumab, and after correction for potential confounders, ofatumumab was the only treatment that had lower odds of the phenomenon relative to ocrelizumab.

To date, ofatumumab has shown promising real-world efficacy in comparison with other approved disease-modifying therapies (DMTs). A study presented at the 2024 American Academy of Neurology Annual Meeting evaluated the persistence of ofatumumab compared with self-injectable or oral DMTs. For ofatumumab vs self-injectable DMTs, respectively, 80.8% vs 56.7% were persistent at 6 months and 74.5% vs 43.2% were persistent at 12 months (both comparisons, P <0.001). For ofatumumab vs oral DMTs, respectively, 81.9% vs 77.8% were persistent at 6 months and 76.3% vs 64.6% were persistent at 12 months (both comparisons, P = 0.002).³

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REFERENCES
1. Winter P, Wolff S, Doerr J, et al. Abundance and impact of end-of-dose symptoms among patients receiving Ofatumumab for treatment of active disease in multiple sclerosis (ABANDONED-MS). Presented at: ECTRIMS Congress; September 18-20, 2024; ABSTRACT P1586/196
2. Marian LM, Harris KA, Conway DS. The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis. Mult Scler J Exp Transl Clin. 2024;10(2):20552173241251707.
3. Hersh C, Gorritz M, Chen CC, et al. Real-world persistence of ofatumumab vs self-injectable or oral disease-modifying therapies in patients with multiple sclerosis. Presented at: 2024 AAN Annual Meeting. ABSTRACT P5-6.012