Treatment with natalizumab and ocrelizumab in multiple sclerosis: The road towards a personalized approach

In this thesis, our research regarding personalized treatment with natalizumab and ocrelizumab in multiple sclerosis (MS) by extending treatment intervals and the road towards implementation of a personalized approach into clinical practice are outlined. Natalizumab and ocrelizumab are highly effective treatments for reducing disease activity in MS. Both treatments are approved in standard treatment intervals, while biological needs can vary between persons with MS. A personalized approach, in which treatment intervals are tailored based on individual pharmacokinetic (PK) and pharmacodynamic (PD) parameters, might lead the way to optimizing current treatment strategies. Personalizing treatment intervals can reduce treatment burden, potential risks, and healthcare costs. For natalizumab, we detected several factors that can influence natalizumab PK. We found that pregnancy and subcutaneous administration were associated with lower natalizumab drug trough concentrations. These factors are especially important to consider when patients receive extended interval dosing (EID), where the treatment interval of every four weeks is prolonged and drug trough concentrations are lower. It remains important to keep natalizumab drug levels above the therapeutic cut-off to ensure adequate suppression of MS disease activity. Measurement of drug concentrations can provide insight into natalizumab PK. We studied personalized EID of natalizumab by measurement of individual drug concentrations in clinical practice and found that MS disease activity is adequately controlled. We also showed that natalizumab drug concentrations can be reliably measured by a finger prick, providing an alternative route to collect blood samples. After evaluating natalizumab wearing-off symptoms at the end of a treatment cycle, we observed that occurrence of wearing-off symptoms did not increase in the majority of participants in the first year after personalized EID. When discontinuing natalizumab treatment and switching to ocrelizumab, a direct switch is preferred for sustained adequate MS disease suppression compared to an indirect switch with a bridging therapy. After switching, neurologists should be aware of progressive multifocal leukoencephalopathy (PML), which can still develop after discontinuation of natalizumab (carry-over PML). With regard to ocrelizumab, we described the association between ocrelizumab drug concentrations, anti-drug antibodies, and B-cells, enabling physicians to predict optimal treatment intervals more precisely. We also considered ocrelizumab drug concentration as a good predictor of SARS-CoV-2 vaccination response. We studied personalized EID of ocrelizumab based on B-cell counts in clinical practice during the COVID-19 pandemic. The majority of participants was able to extend their treatment interval without increase in short-term MS disease activity. Finally, we studied wearing-off symptoms in persons using ocrelizumab, which also occur frequently during treatment with similar characteristics as natalizumab wearing-off symptoms. Other than BMI, there were no predictors of these symptoms. Informing patients that wearing-off symptoms are most likely not associated with MS disease activity can lower possible uncertainty patients might have regarding EID. To conclude, treatment of MS has become more personalized. The quest for an optimal biomarker for therapeutic drug monitoring and the right therapeutic cut-off for both natalizumab and ocrelizumab continues, with promising study data on its way to influence clinical practice, further paving the road towards a personalized approach.