BTK inhibition in MS

[frodo]

Bruton’s Tyrosine Kinase Inhibition in Multiple Sclerosis

https://link.springer.com/article/10.10 ... 22-01229-z

Purpose of Review
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton’s Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS.

Recent Findings
There is evidence that some BTKIs cross the blood–brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS.

Summary
Inhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment.

[Petr75]

2024 Apr 24
Institute of Neuropathology, University Medical Center, Georg August University, Germany
BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair
https://pubmed.ncbi.nlm.nih.gov/38656399/

Abstract

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.

[DIM]

Tolebrutinib Can Reverse Multiple Sclerosis-Induced Cerebrospinal Fluid Proteomic Alterations!

https://congress.sanofimedical.com/s3fs ... ations.pdf

[DIM]

Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis!

https://www.sanofi.com/en/media-room/pr ... 00-2938875

[DIM]

The race is on as several drugmakers get closer to the finish line in developing the first Bruton tyrosine kinase (BTK) inhibitor to treat multiple sclerosis (MS). BTK is a nonreceptor enzyme expressed in B cells and myeloid cells, both of which play a significant role in MS pathology. B cells in particular are found in demyelinated areas, chronic plaques and the cerebral spinal fluid of people with MS. These cells release proinflammatory cytokines that contribute to MS symptoms and disease progression. Inhibiting the BTK enzyme can block B cell activation and, drug developers hope, keep the proinflammatory cascade that follows from getting started.

https://www.managedhealthcareexecutive. ... ors-for-ms

[DIM]

HERCULES (clinical study identifier: NCT04411641) was a double-blind randomized phase 3 clinical study evaluating the efficacy and safety of tolebrutinib in participants with nrSPMS. nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) between 3.0 and 6.5, no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Participants were randomized (2:1) to receive either an oral daily dose of tolebrutinib or matching placebo for up to approximately 48 months.

The primary endpoint was 6-month CDP defined as the increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.0, or the increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included time to onset of 3-month CDP as assessed by EDSS score, total number of new or enlarging T2 hyperintense lesions as detected by MRI, time to onset of confirmed disability improvement, 3-month change in 9 hole peg test and T25-FW test as well as the safety and tolerability of tolebrutinib.

https://www.morningstar.com/news/globe- ... -sclerosis

[Petr75]

2025 May 8
Beyond relapses: How BTK inhibitors are shaping the future of progressive MS treatment
https://pubmed.ncbi.nlm.nih.gov/40345950/

Abstract

Multiple sclerosis is a biologically and clinically heterogenous inflammatory demyelinating disease, driven by relapsing and progressive mechanisms, all individuals experiencing varying degrees of both. Existing highly effective therapies target peripheral inflammation and reduce relapse rates but have limited efficacy in progressive MS due to poor blood-brain barrier penetration and inability to address neurodegeneration. Bruton's tyrosine kinase (BTK) inhibitors represent an emerging therapeutic class offering a novel mechanism targeting BTK, which is expressed by both B cells and myeloid cells, including microglia within the CNS. Pre-clinical, Phase II, and Phase III clinical trials have demonstrated promising results in modulating progressive disease in both relapsing and non-relapsing MS patients. In contrast, the evidence regarding impact on relapse biology remains mixed and somewhat inconclusive. This review highlights gaps in current therapeutic strategies, examines the latest evidence for the efficacy and safety of BTK inhibitors in MS, and explores the future landscape of MS treatment.