Patients treated with ofatumumab (Kesimpta; Novartis) demonstrated significant decreases in absolute and percent CD19 counts at day 5 of treatment, which persisted through the 90-day period.
In a small interim analysis, treatment with ofatumumab (Kesimpta; Novartis) resulted in decreased cortical grey matter (CoGM) microglial activation among patients with relapsing multiple sclerosis (MS). Notably, investigators observed peripheral CD19+ cell depletion at day 5, and that the results may suggest an indirect, downstream effect of B-cell depletion on microglial activity in this patient population.1
The research presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, included 5 patients with relapsing MS who underwent 20 [F-18]PBR06 PET scans prior to and at days 5, 28, and 90 after initiating ofatumumab. The study cohort had Expanded Disability Status Scale (EDSS) scores of 3.0 at baseline and underwent peripheral CD19 count and clinical evaluations. Lead author Tarun Singhal, MD, MBBS, assistant professor, Harvard Medical School, and colleagues generated individualized z-score maps of brain parenchymal microglial activation by voxel-by-voxel comparison between each subjects PET standardized uptake value ratio (SUVR) images and a control dataset of 9 healthy individuals.
After 90 days of treatment with ofatumumab, mean CoGM glial activity load on PET (GALP) was significant decreased as compared with baseline (0.75 [±0.09] vs 0.93 [±0.06]; –19.4%; P <.05). GALP was calculated as the sum of voxel-by-voxel z-scores of at least 4 in the lesional and perilesional normal-appearing white matter (LWM and P-NAWM), CoGM, and thalamic regions of interest (ROI) in standard atlas space. Mean CoGM-GALP was not significantly decreased at day 5 nor 28. "Further studies on effects of ofatumumab on microglial activation are warranted," Singhal et al concluded.
At day 5, investigators did however observe significant decreases in absolute (11.5 cells/µL [±9.1] vs 256.6 cells/µL [±117.4]; –96%; P = .01) and percentage of CD19+ counts (0.98% [±0.98] vs 14.7% [±8.7]; –93%; P = .02) relative to baseline. Notably, both of these observations persisted at day 90. Over the 90-day treatment period, there were no statistically significance differences in mean GALP scores in thalamic, LWM, and P-NAWM regions, or in clinical measurements (P <.05).
Ofatumumab, a B-cell depleting medication delivered via subcutaneous injection, was approved by the FDA in August 2020 for adultswith relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive MS.2 Since its approval, it has been featured in several post hoc analyses and had several other presentations at AAN 2022.
In a new safety analysis, the therapy was well-tolerated for at least 3.5 years, with no new safety signals. The data stemmed from the ongoing, open-label, umbrella extension ALITHIOS (NCT03650114) and the phase 3 ASCLEPIOS I and II trials (NCT02792218 and NCT02792231).3,4 In ALITHIOS, investigators found a low incidence of serious infections (2.9%; exposure-adjusted incidence rate [EAIR], 1.4) and malignancies (0.6%; EAIR, 0.3) among those with adverse events (AEs; ≥1 AE, 83.8%; EAIR, 148.7) and serious AEs (≥1 serious AE, 9.7%; EAIR, 4.8). After up to 4 years of treatment, levels of immunoglobulin G were stable in ofatumumab-treated patients, while immunoglobulin M decreased, though levels remained within normal ranges. Additionally, there were no associations identified between antibody levels and the risk of serious infection.
In the second analysis, long-term efficacy data suggested that over 4 years of use, the subcutaneous anti-CD20 monoclonal antibody was associated with fewer relapses, as well as a reduced risk of 3-month and 6-month confirmed disability worsening and less disease activity, compared with those who switched therapies.4