As already stated in the previous article “News from ECTRIMS (1)“: We have now become very good at controlling focal inflammation in MS – that is, the inflammatory response triggered by the influx of peripheral immune cells into the central nervous system. We can suppress this pathophysiological process very efficiently with highly effective MS therapies, including anti-CD20 antibodies.
In addition to the focal inflammatory lesions, neuropathological examinations of MS brains also reveal another type of lesion, the so-called chronic-active lesions, which are characterized especially at their edges by the activation of myeloid cells (i.e., macrophages and microglia). The group of Tanja Kuhlmann from Münster recently showed that the width of this border of myeloid cells correlates with the severity of the disease. Accordingly, the processes at the edges of inactive lesions probably play a crucial role in disease progression in MS. Thus, this so-called “non-focal inflammation” (non-focal disease biology) is a very important target for new therapeutic developments.
Tolebrutinib and Paramagnetic Rim Lesions
Some of these chronic-active lesions can now be visualized by modern MRI techniques, which have also been included in the new McDonald diagnostic criteria. The so-called paramagnetic rim lesions (PRL) are based on the representation of iron deposition in myeloid cells, making chronic active lesions visible. A subgroup analysis of the HERCULES study (Tolebrutinib in SPMS) showed that the effect of the BTKi Tolebrutinib on disease progression was most pronounced in the subgroup of patients with the most PRLs. Thus, there is still justified hope that the BTKi have opened the door to the treatment of progressive MS and have an effect on the “non-focal MS biology”.
Frexalimab and Biomarkers
In this context, the substudies on biomarkers from the Phase II study of Frexalimab, an antibody against CD40L, are of interest. CD40L is a surface protein that is important for communication between T cells and myeloid cells. Therefore, in addition to the good clinical results of this Phase II study, the changes in biomarker profiles of adaptive and innate immune cells are noteworthy. It was found that, among other things, the marker for activated macrophages/microglia decreased significantly during the course of the study with the administration of Frexalimab.
Vidofludimus Calcium and Secondary Endpoints
The results of the CALLIPER study on Vidofludimus Calicum were also presented at this year’s ECTRIMS. Much is also expected from this molecule due to its CNS accessibility and the effects on microglial cells mediated by Nurr-1. Unfortunately, the study failed to meet its primary endpoint (reduction of brain atrophy compared to placebo). However, some results on secondary endpoints suggest that this medication also has potential.
However, the studies also show how crucial the choice of the primary endpoint is. This raises the question of whether we are currently working with the right endpoints that are capable of reflecting the essential effects of new substances. We probably need more sensitive measurement methods to better represent the influence on the non-focal biology of MS.
This post was translated from German to English with the help of AI.
