Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study

Piasecka-Stryczyńska, Karolina; Rejdak, Konrad; Dyroff, Martin C.; Hyvert, Yann; Holmberg, Kristina; Mandel, Matthew; Cunha, Carolina Maria Pires; Mitchell, David; Martin, Emily C.; Montalbán, Xavier

doi:10.1016/j.msard.2021.103001

Cited by 11 publications

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“…Their use has mainly been indicated for various B cell malignancies but also for chronic graft-vs-host disease. Of the inhibitors currently being developed, 6 are or will be tested for their efficacy in MS. Evobrutinib, tolebrutinib, fenebrutinib, and remibrutinib have already reached or will soon enter phase 3 clinical testing, and 2 more inhibitors, orelabrutinib and BIIB091, are currently being tested in phase 2 and phase 1 clinical studies (Table 1). Most of the compounds bind BTK in an irreversible manner; however, fenebrutinib and BIIB091 are reversible inhibitors that bind BTK noncovalently.…”

Section: Btk Inhibitors In Clinical Use and Developmentmentioning

confidence: 99%

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

2023

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ImportanceCurrently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell–depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell–directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK).ObservationsBTK is centrally involved in the B cell receptor–mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety.Conclusions and RelevanceWhile the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.

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Section: Btk Inhibitors In Clinical Use and Developmentmentioning

confidence: 99%

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

2023

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“…Tolebrutinib shows increased CNS penetrance, higher potency and faster reaction rates of BTK inhibition compared with both evobrutinib and fenebrutinib 178 . For evobrutinib, cerebrospinal fluid (CSF) concentrations measured at 2-3 h post-dose were lower than the IC 50 of the compound, suggesting that therapeutic concentrations were not reached (although efficacy studies would be necessary to confirm this) 179 . By contrast, CSF concentrations of tolebrutinib exceeded the IC 90 2 h after administration of a single 120-mg dose in healthy human volunteers in a phase I double-blind, placebo-controlled study 151,180 .…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Bruton tyrosine kinase inhibitors for multiple sclerosis

et al. 2023

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Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the bloodbrain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical An overview of BTK inhibitorsIn 1952, the paediatrician Ogden C. Bruton described an 8-year-old boy with 'complete absence of gamma globulin with otherwise normal serum proteins and recurrent pneumococcal sepsis' 54 . The inherited immunodeficiency described by Bruton was termed X-linked agammaglobulinaemia (XLA). In the early 1990s, the BTK gene (encoding BTK) Key points• Bruton tyrosine kinase (BTK) is an important intracellular signalling molecule involved in regulating the maturation, proliferation, survival and activation of B cells and myeloid cells.• BTK inhibitors might concurrently target adaptive and innate immune mechanisms in the periphery and central nervous system (CNS).• This ability makes BTK inhibitors a promising therapeutic approach for relapsing and progressive forms of multiple sclerosis (MS).• Preclinical studies show that BTK inhibition can suppress key pathological features of MS, including B cell activation, CNS lymphocyte infiltration, leptomeningeal inflammation, pro-inflammatory microglial activation and demyelination.• The efficacy and safety of five BTK inhibitors are currently being evaluated in clinical trials in patients with relapsing and progressive MS.• The BTK inhibitors under investigation in clinical trials differ in their selectivity, mode of binding, target occupancy, inhibitory potency and CNS penetrance.Review criteria PubMed was searched between 10 November 2021 and 5 May 2022 using terms related to BTK (Bruton's tyrosine kinase, BTKi*, BTK inhibit*, Bruton's tyrosine kinase inhibit*) in combination with the following terms: MS OR multiple sclerosis, immune cell*, cancer OR tumour OR tumour OR malignanc*, immune deficienc* OR immune disease* OR immunodeficienc*, mechanism of action OR MOA, B cell OR microglia OR macrophage, pharmacodynamic* O...

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“…[12][13][14][15] Evobrutinib is an orally administered, CNS-penetrating, highly selective, covalent BTK inhibitor, with a low potential for off-target-related adverse effects. [16][17][18] The covalent binding of evobrutinib to BTK results in continued target inhibition even after it has been cleared from the circulation (geometric mean half-life ~2 hours), but due to the continuous turnover of endogenous BTK protein, this inhibition is reversable following drug withdrawal. 19 20 In preclinical studies, evobrutinib has been demonstrated to decrease the activation, proliferation and cytokine release of B cells, as well as inhibit proinflammatory macrophage differentiation.…”

Section: Multiple Sclerosismentioning

confidence: 99%

“…Evobrutinib is an orally administered, CNS-penetrating, highly selective, covalent BTK inhibitor, with a low potential for off-target-related adverse effects 16–18. The covalent binding of evobrutinib to BTK results in continued target inhibition even after it has been cleared from the circulation (geometric mean half-life ~2 hours), but due to the continuous turnover of endogenous BTK protein, this inhibition is reversable following drug withdrawal 19 20.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis

Montalbán

Wallace

Genovese

et al. 2022

J Neurol Neurosurg Psychiatry

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ObjectiveAnalyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials.MethodsPhase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs).ResultsData from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083 due to MS trial design: n=49 received both placebo (W0–24) and evobrutinib 25 mg (W25–48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients.ConclusionsThis is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications.Trial registration numbersNCT02975349,NCT03233230,NCT02975336.

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Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study

Cited by 11 publications

References 0 publications

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

Bruton tyrosine kinase inhibitors for multiple sclerosis

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis

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