Six trials to Watch. Four for BTKi, CD40-CD40L and CD19 and here they are sold as inhibitors of progressive disease, but in reality they are all B cell inhibitors. BTKi may not be B cell depleters and so far two have been abit not good in relapsing disease and two are not being tested in progressive MS. CD40 signalling is needed for B cell activity blocking CD40L will achieve this and CD19 depletion is not that much different from CD20 depletion. CD40Ligand and BTK can be found in antigen presenting cells. However the question would be… Do they offer more than CD20 depletion? Clearly BTKi may not offer more in relapsing disease although head to head haven’t been done. The days of trials against teriflunomide should have been numbered many years ago. Surely it is unacceptable to use a comparitor that is inferior to anti-CD20 depletion… Neuros/Regulators need to get a backbone to stand up to pharma…however will it frighten pharma off…Alot of money would be spent to show it is no better….however other issues other than relapse efficacy can be improved
Rocca MA, Preziosa P, Filippi M. Progressive multiple sclerosis: Six trials to watch. Med. 2026;7(1):100960. doi: 10.1016/j.medj.2025.100960.
Emerging therapies for progressive multiple sclerosis (PMS) increasingly target CNS-compartmentalized inflammation driving progression independent of relapse activity. Six pivotal trials are evaluating Bruton’s tyrosine kinase inhibitors, CD40-CD40L blockade, and CD19-directed CAR-T cells. Together, these studies may establish mechanism-based strategies to modulate microglia and B cell pathology, redefining treatment of progression and addressing a major unmet clinical need.
Introduction: Traditional disease-modifying therapies (DMTs) reduce relapse frequency in relapsing-remitting multiple sclerosis (MS) but have a limited impact on relapse-independent progression, underscoring the need for novel therapies. Bruton’s tyrosine kinase inhibitors (BTKis), with dual immunomodulatory effects and central nervous system penetration, offer a promising alternative for comparison with established agents such as teriflunomide.
Methods: We systematically searched PubMed, Embase, and Cochrane CENTRAL up to June 2025 for randomized controlled trials (RCTs) comparing BTKis with teriflunomide in patients with relapsing MS. The primary outcome was confirmed disability worsening (CDW) at 3 and 6 months. Secondary outcomes included annualized relapse rate (ARR), magnetic resonance imaging (MRI) lesion activity, and adverse events. Random-effects meta-analyses were performed using hazard ratios (HRs), rate ratios, risk ratios, and mean differences, as appropriate.
Results: Four RCTs with 4136 participants were included. ARR was similar between the groups (Rate Ratio: 1.03; 95% CI: 0.90-1.19). BTK inhibitors reduced the risk of 3-month CDW compared with teriflunomide (HR: 0.81; 95% CI: 0.67-0.97) but not 6-month CDW (HR: 0.88; 95% CI: 0.63-1.24). The slight but significant difference in new T1 gadolinium-enhancing lesions favored teriflunomide (MD: 0.20; 95% CI: 0.15-0.25), whereas no difference was found in new or enlarging T2 lesions (MD:0.07; 95% CI:0.85 to 0.71). The incidence of serious adverse events was comparable between the groups (RR: 1.13; 95% CI: 0.92-1.40).
Conclusion: Compared with teriflunomide, BTK inhibitors were associated with a reduced risk of short-term disability progression, whereas no differences were observed in relapse rates, MRI activity, or safety outcomes.
The BTKi havn’t been that good certainly in relapsing MS and the FDA think that there is a side effect issue notably liver toxicity and so it is not trivial and is a class effect meaning all of them with show this effect…not surprising as the liver is filled with macrophases expressing BTK
Sobral MVS, de Oliveira HM, Neto APM, Fagundes TP. Efficacy and safety of Bruton’s tyrosine kinase inhibitors compared to Teriflunomide in relapsing multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. 2026 Jan 5;107:106974.
Introduction: Traditional disease-modifying therapies (DMTs) reduce relapse frequency in relapsing-remitting multiple sclerosis (MS) but have a limited impact on relapse-independent progression, underscoring the need for novel therapies. Bruton’s tyrosine kinase inhibitors (BTKis), with dual immunomodulatory effects and central nervous system penetration, offer a promising alternative for comparison with established agents such as teriflunomide.
Methods: We systematically searched PubMed, Embase, and Cochrane CENTRAL up to June 2025 for randomized controlled trials (RCTs) comparing BTKis with teriflunomide in patients with relapsing MS. The primary outcome was confirmed disability worsening (CDW) at 3 and 6 months. Secondary outcomes included annualized relapse rate (ARR), magnetic resonance imaging (MRI) lesion activity, and adverse events. Random-effects meta-analyses were performed using hazard ratios (HRs), rate ratios, risk ratios, and mean differences, as appropriate.
Results: Four RCTs with 4136 participants were included. ARR was similar between the groups (Rate Ratio: 1.03; 95% CI: 0.90-1.19). BTK inhibitors reduced the risk of 3-month CDW compared with teriflunomide (HR: 0.81; 95% CI: 0.67-0.97) but not 6-month CDW (HR: 0.88; 95% CI: 0.63-1.24). The slight but significant difference in new T1 gadolinium-enhancing lesions favored teriflunomide (MD: 0.20; 95% CI: 0.15-0.25), whereas no difference was found in new or enlarging T2 lesions (MD:0.07; 95% CI:0.85 to 0.71). The incidence of serious adverse events was comparable between the groups (RR: 1.13; 95% CI: 0.92-1.40).
Conclusion: Compared with teriflunomide, BTK inhibitors were associated with a reduced risk of short-term disability progression, whereas no differences were observed in relapse rates, MRI activity, or safety outcomes.
Source: multiple-sclerosis-research.org