The Annual American Association of Neurology Junket is upon us and starts at the Weekend, NDG is there and may post us some of the stories but the abstracts are out now. What tickles your fancy about the important stories? I will be posting some abstraxts over the coming days that come from AAN 2026.
We have made a hypothesis of the value of memory B cell depletion to control relapsing MS. Agents that do this work, those that don’t don’t and those that don’t do it very well are no so great. This has been associated with efficacy. However we/I have been told that Brutons trysosine kinase inhibitors do not deplete B cells…but the quick retort now is that Brutons tyrosine kinase inhibitors have not worked in relapsing MS so evobrutinib and tolebrutinib have failed so I guess the question is what does fenebrutinib do. No in could be argued that the people in the trials were not that active and so teriflunomide (the comparator) did better than expected. However at least for evobrutinib the imaging data was not good enough. A reduction of about 70% compared to placebo is in beta interferon/glatiramet territory which is not good enough as the B cell depleters can achieve a 90-95% inhibition.
Here they tell us that they have looked at the effect of tolebrutinib and they tell us there is no marked effect on monocytes, neutrophils or lymphocytes…who cares we need to know what happens to the B cells and B cell subsets. B cells are about 20% of lymphocytes and memory cells are about 20% of the 20% so about 5%. But as I say tolebrutinib failed to exhibit impact over teriflunomide. So is the idea intact. Or who it be that as BTK inhibits signalling it doesnt need to affect cell numbers.
When BTK inhibitors were developed it was to target B cells and here they say the antibody IgG levels do not drop. But they do not really drop in a 2 year trial with CD20-depleters either as this is not long enough. IgM stayed within normal limits
Blood Levels of Immune Cells, Immunoglobulins, and Platelets in the Phase Three HERCULES and GEMINI Trials of Tolebrutinib in Non-relapsing Secondary Progressive Multiple Sclerosis and Relapsing Multiple Sclerosis
Celia Oreja Guevara1, Amit Bar-Or2, Heinz Wiendl3, Ho Jin Kim4, Sana Syed5, Zhixing Xu5, Wendy Vargas5, Christina Maxwell5, Agnes Hincelin-Mery5, Biljana Djukic5, Timothy Turner5, Jiwon Oh6, Robert Fox7
1Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 2University of Pennsylvania, 3University of Freiburg, 4National Cancer Center, 5Sanofi, 6St Michael’s Hospital, 7Cleveland Clinic
Objective:To evaluate changes in blood immune cell populations, immunoglobulin levels, and platelet counts in the phase 3 HERCULES and GEMINI tolebrutinib trials.
Background:Tolebrutinib is an oral, brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor thought to modulate persistent immune activation within the CNS, including disease-associated microglia and B cells. In phase 3 pivotal trials, tolebrutinib treatment reduced the risk of disability accumulation versus placebo in non-relapsing secondary progressive MS (nrSPMS), and versus teriflunomide in relapsing MS (RMS) though not superior in reducing annualized relapse rate (primary endpoint).
Design/Methods: HERCULES (NCT04411641)and GEMINI 1 and 2 (NCT04410978, NCT04410991) were phase 3, double-blind trials of tolebrutinib 60 mg once daily with food. In HERCULES, participants with nrSPMS were randomized 2:1 to receive tolebrutinib or placebo. In GEMINI 1 and 2, participants with RMS were randomized 1:1 to receive tolebrutinib or teriflunomide (14 mg once daily), each with matching placebo. Blood samples were collected at baseline and during double-blinded treatment. Samples were analyzed to determine immunoglobulin (IgG, IgM) levels via immunoturbidimetry and the complete blood count, including leukocyte, total lymphocyte, neutrophil, monocyte, and platelet counts.
Results:Over 42 months, mean leukocyte, total lymphocyte, neutrophil, and monocyte counts remained stable and within normal ranges in the tolebrutinib, placebo, and teriflunomide groups. Mean IgG levels remained overall stable and within normal range, and mean IgM levels remained within normal range in all treatment groups over the duration of the trials. Mean platelet counts remained within normal range.
Conclusions: Mean levels of immune cells, immunoglobulins, and platelets remained stable overall and within normal ranges in participants treated with tolebrutinib over the duration of the HERCULES and GEMINI trials. These findings support the safety profile of tolebrutinib as an immunomodulatory agent that does not deplete circulating leukocytes, immunoglobulins, or platelets.
Source: multiple-sclerosis-research.org