One of the most exciting topics of large international congresses is the outlook for new therapies that may be able to bring added value in the future. As an immunological treatment strategy, we will probably hear a lot about so-called Bruton Tyrosine Kinase Inhibitors (BTKi) in the coming years, which are currently being tested in large Phase III study programs.
However, in the case of MS, not only relapses/inflammatory activity are a major problem, but above all the slowly progressing disability. The progression of disability is seen as an expression of neurodegeneration in the central nervous system – and this raises the question of drugs that can protect nerve cells – we speak of neuroprotection – and thus prevent neurodegeneration.
Neuroprotection and Remyelination
It is known that intact myelin can protect nerve cells – hence there is interest in drugs that can repair the myelin sheath after its destruction. This repair process is also referred to as remyelination. A few years ago, it was found that an antibody against the molecule Lingo-1 can promote the remyelination of nerve cells. This antibody is called Opicinumab and has been tested in various studies for optic neuritis and relapsing MS. The results of the AFFINITY study (Part 1) with Opicinumab were presented at ECTRIMS 2021. Unfortunately, the study did not meet its primary endpoint (reduction of disability progression). In certain subgroups (older patients, patients with longer disease duration, patients with higher EDSS score), statistically significant differences were shown in the accumulation of disability. However, no MRI endpoint was achieved. Thus, the story of Opicinumab in MS is not over, but the data are not really encouraging.
Perhaps another substance capable of promoting remyelination may make a name for itself in the future. This is Bexarotene, an agonist of the Retinoid X Receptor, which plays an important role in myelinization. In a study with 26 patients per treatment arm, the effect of Bexarotene compared to placebo on visually evoked potentials (VEP) and certain MRI parameters was investigated. In this study, an effect on visually evoked potentials and the MTR (magnitization transfer ratio) in a specific brain area could now be demonstrated in the subgroup of younger patients (< 42 years). This is certainly a good start for this substance, but further studies are definitely needed.
Goal not yet achieved
Elezanumab is a monoclonal antibody against the “repulsive guidance molecule A(RGMa)”, which inhibits the sprouting of axons and remyelination. Elezanumab is therefore supposed to have a neuroprotective effect and promote the repair of the myelin sheath. This substance was tested in two double-blind Phase II studies (Radius-R and Radius-P) in patients with relapsing and progressive MS. To make it short, both studies were negative, all endpoints were missed.
This selection of substances shows how difficult it is to achieve the goal of remyelination and neuroprotection. The path is long and rocky. That’s why it’s so important to currently protect the nerve cells of MS patients with what works best at the moment, namely effective inflammation inhibition.
