The study results of the ULTIMATE I + II study on the effect of the monoclonal antibody Ublituximab compared to Teriflunomide on the effect in relapsing MS were already communicated at ECTRIMS 2021. They were also recently presented again at the meeting of the American Academy of Neurology (AAN). Therefore, you can currently find many contributions on this topic on the internet and in the medical trade press. A good opportunity to also take a position on this new antibody in the MS-DocBlog. Ublituximab is like Rituximab (only off-label use) and the approved active ingredients Ocrelizumab and Ofatumumab a therapeutic antibody that is directed against the surface protein CD20 on B lymphocytes and leads to a depletion of these important white blood cells mainly in the bloodstream. The concept is therefore already well known – and quite successful in the therapy of relapsing MS, especially for the treatment of highly active courses. In addition, an effect on the (early) primary chronic progressive MS could also be shown for Ocrelizumab.
Further development Ublituximab
B-cell depletion is therefore “in vogue” – and therefore further developments in this therapy segment can be expected. Ublituximab represents such a further development. It is a therapeutic antibody for the treatment of relapsing MS, which has been “glycoengineered”. “Glycoengineering”, also called “glycodesign”, refers to the targeted modification of sugar chains (technical term: modification of glycosylation) on a protein (antibodies are proteins), in order to achieve a better effectiveness of the protein (in the case of Ublituximab the antibody) for example.
In order to better understand the concept of “glycoengineering”, it is useful to recall the structure of antibodies (see illustration). The antibody protein, in simplified terms, has the shape of a Y. The top two legs of the Y are the variable parts of the antibody (also called Fab region). They recognize the target structure and are different for each antibody. The foot of the Y is referred to as the Fc region and is (simplified) the same in most antibodies. The Fc region of the antibody is the site where, for example, “killer cells” or factors of the complement system are attracted. Changes to the Fc region of an anti-CD20 antibody can thus increase the efficiency of the antibody in B-cell depletion. In the specific case of Ublituximab, the Fc fragment was designed to increase the efficiency of so-called cell-mediated cytotoxicity (ADCC – antibody dependent cellular cytotoxicity).
So – after this somewhat complicated, but necessary introduction, let’s take a look at the study results – especially of course with the question of whether the new design leads to better efficacy.
Studies confirm the efficacy of B-cell depletion in MS
Ublituximab was (as already mentioned above) tested in two similar phase III studies (ULTIMATE I + II) compared to Teriflunomide. As in most MS studies, the annual relapse rate was the primary endpoint. The annual relapse rate could be reduced by about 50-60% compared to Teriflunomide in both studies. This result is quite comparable to the results of Ofatumumab, which was also tested against Teriflunomide. And Ocrelizumab also showed a comparable relative risk reduction in its studies compared to Interferon-beta 1a.
As for the important secondary endpoint of disability progression, no significant difference between Ublitiuximab and Teriflunomide could be shown, although noticeably few patients in both test groups had any progression at all within the study program. It is worth mentioning that significantly more patients who received Ublituximab showed an EDSS improvement – although this was only a tertiary endpoint of the study. The results on the reduction of inflammatory foci in the MRI were again very pleasing. Here, a clear superiority over the comparison substance was shown.
Thus, the Phase 3 studies with Ublituximab also underscore the good effect of B-cell depletion in MS. The results are comparable to the effects of Ofatumumab and Ocrelizumab in their respective approval studies.
Also in terms of the safety profile, no new aspects are revealed. The most common side effects of Ublituximab were infusion reactions, but these were mostly mild or moderate. Serious side effects occurred in 6.22% of the Teriflunomide patients and in 9.5% of the Ublituximab patients, with a slight preponderance of infections when administering the antibodies. It should also be mentioned that a total of three deaths occurred in the study program, which were due to inflammatory diseases. In one of these cases, a possible connection with the study drug Ublituximab was seen. Such cases can occur, but they should remind us that despite all recognition of the effectiveness of B-cell depleting therapies, the issue of infection must be kept in mind.
Last but not least, it is worth mentioning that the maintenance dose of Ublituximab could apparently be given without problems within an hour – and short infusion times are of course always welcome from the patient’s side. Overall, however, this aspect will have to be looked at more closely in practice.
