Extended dosing of monoclonal antibodies in multiple sclerosis

Over the past two decades, treatment options for patients with multiple sclerosis (MS) have increased exponentially. In the current therapeutic landscape, “no evidence of MS disease activity” is within reach in many of our patients. Minimizing risks of complications, improving treatment convenience, and decreasing health care costs are goals that are yet to be reached. One way to optimize MS therapy is to implement personalized or extended interval dosing. Monoclonal antibodies are suitable candidates for personalized dosing (by therapeutic drug monitoring) or extended interval dosing. An increasing number of studies are performed and underway reporting on altered dosing intervals of anti-α4β1-integrin treatment (natalizumab) and anti-CD20 treatment (ocrelizumab, rituximab, and ofatumumab) in MS. In this review, current available evidence regarding personalized and extended interval dosing of monoclonal antibodies in MS is discussed with recommendations for future research and clinical practice

Pharmacodynamic assessment of cell-bound natalizumab on PBMC samples stored in liquid nitrogen

Natalizumab is a monoclonal IgG4 antibody used for treatment of relapsing remitting MS. Natalizumab interferes with lymphocyte migration by blocking alpha-4 integrin (CD49d). Saturation levels of alpha-4 integrin on circulating T cells by natalizumab have been associated with clinical effectiveness of therapy. However, in most cases, measurements have been carried out using freshly isolated PBMCs. The aim of this study was to set up and evaluate a method to measure relative levels of cell-bound natalizumab using frozen PBMC samples. A new method was set up to measure cell-bound natalizumab by flow cytometry on T cell subsets using fully saturated cells as a 100% reference. A comparison was made between spike samples and samples of natalizumab-treated MS patients freshly isolated and stored in liquid nitrogen. Cell-bound natalizumab could be measured (using an anti-IgG4 antibody) on cells stored in liquid nitrogen. Natalizumab was found to slowly dissociate from the cells during isolation and subsequent sample work-up. This dissociation was more pronounced for monovalent natalizumab resulting from Fab arm exchange (the predominant isoform in patients) than bivalent natalizumab straight from the vial. We established a correction factor to account for this phenomenon. The resulting method has good accuracy compared to assessing fresh cells. The inter-assay precision (%CV) is ca. 12% using frozen cells. In conclusion, we established a method to assess relative levels of cell-bound natalizumab on cells obtained from frozen PBMC samples

Pharmacodynamic assessment of cell-bound natalizumab on PBMC samples stored in liquid nitrogen

Natalizumab is a monoclonal IgG4 antibody used for treatment of relapsing remitting MS. Natalizumab interferes with lymphocyte migration by blocking alpha-4 integrin (CD49d). Saturation levels of alpha-4 integrin on circulating T cells by natalizumab have been associated with clinical effectiveness of therapy. However, in most cases, measurements have been carried out using freshly isolated PBMCs. The aim of this study was to set up and evaluate a method to measure relative levels of cell-bound natalizumab using frozen PBMC samples. A new method was set up to measure cell-bound natalizumab by flow cytometry on T cell subsets using fully saturated cells as a 100% reference. A comparison was made between spike samples and samples of natalizumab-treated MS patients freshly isolated and stored in liquid nitrogen. Cell-bound natalizumab could be measured (using an anti-IgG4 antibody) on cells stored in liquid nitrogen. Natalizumab was found to slowly dissociate from the cells during isolation and subsequent sample work-up. This dissociation was more pronounced for monovalent natalizumab resulting from Fab arm exchange (the predominant isoform in patients) than bivalent natalizumab straight from the vial. We established a correction factor to account for this phenomenon. The resulting method has good accuracy compared to assessing fresh cells. The inter-assay precision (%CV) is ca. 12% using frozen cells. In conclusion, we established a method to assess relative levels of cell-bound natalizumab on cells obtained from frozen PBMC samples

Abnormalities and erythroblasts in peripheral blood of multiple sclerosis patients treated with natalizumab

Background: In natalizumab treated patients several hematopoietic abnormalities including erythroblasts, myeloblasts and neutrophilic precursors in peripheral blood have been described. So far, long term effects of the hematopoietic changes have not been reported. Objective: To describe hematopoietic abnormalities in longitudinally monitored MS patients treated with natalizumab. Patients treated with dimethyl fumarate, teriflunomide and fingolimod served as controls. Secondly, the relation between natalizumab serum levels and the occurrence of hematopoietic abnormalities was explored. Methods: 212 natalizumab treated patients were included, 91 patients with available baseline samples (998 follow-up samples) were compared with patients with dimethyl fumarate (n = 166, 1154 samples), teriflunomide (n = 38, 228 samples) and fingolimod (n = 114, 853 samples). One hundred twenty one patients without baseline samples (1952 follow-up samples) were included in the follow-up group. Results: More than half of all natalizumab treated patients developed hematopoietic abnormalities, almost a quarter had erythroblasts. Natalizumab use was associated with an increased risk of developing abnormalities in comparison to oral treatment, with a corrected hazard ratio of 2.3, 10.0 and 8.1 in comparison to fingolimod, dimethyl fumarate and teriflunomide respectively. No difference in developing abnormalities was observed in relation to natalizumab serum concentrations. None of the patients developed a hematologic malignancy during follow up. Conclusion: Hematopoietic abnormalities are common during natalizumab treatment. Given the lack of consequences of this finding during long-term follow-up, it is generally justifiable to refrain from further diagnostic procedures when observing hematopoietic abnormalities in patients using natalizumab

Infusion-related events during natalizumab: No need for post-infusion monitoring

This retrospective cohort study assessed the timing of infusion-related adverse events (IAEs) during natalizumab (NTZ) administration in well-documented relapsing-remitting multiple sclerosis (RRMS) patients who had received NTZ infusions in our centre between 2006 and 2018. In 225 RRMS patients (14,174 NTZ infusions), 276 IAEs (1.95%) occurred in 60 patients. All documented severe IAE occurred during infusion. Of the 19 moderate adverse events, 17 were during infusion. None of the reactions that occurred after the infusion required intervention. These results suggest that post-infusion monitoring is not necessary in patients who do not have an adverse event during infusion

The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing

Natalizumab is efficacious in the treatment of relapsing-remitting multiple sclerosis. All patients receive the same treatment regimen of 300 mg every 4 weeks, despite differences in pharmacokinetics between individual patients. To give neurologists insight into natalizumab concentrations at time of re-dosing, we investigated longitudinal natalizumab concentrations in 80 patients in relation to disease activity, with possible influencing factors. In a prospective observational cohort study, natalizumab trough serum concentrations were measured in 80 patients. Data on demographics, duration of treatment, Expanded Disability Status Scale, clinical exacerbations, brain magnetic resonance imaging (MRI), and body weight were collected. We measured high (≥10 µg/mL) natalizumab trough concentrations in 94% of patients. Intra-individual concentrations were stable. The spread in concentrations was substantial and did not correlate with disease activity. We found a negative association between natalizumab concentration and body weight (β = -0.30, p = 0.010). The majority of patients showed high natalizumab serum concentrations at time of re-dosing. Alternative treatment regimens could lead to more efficient use of natalizumab, but caution is warranted regarding the possibility of recurrence of disease activity. Prospective clinical trials are needed to establish the safety of extended dose intervals in natalizumab treatmen

Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML. Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML. Methods: In a prospective observational cohort study of 219 patients with relapsing-remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups. Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 mu g/mL (standard deviation (SD): 13.4) versus 23.8 mu g/mL (SD: +/- 11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML. Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PM