Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Haselmayer, Philipp; Camps, Montserrat; Liu-Bujalski, Lesley; Nguyen, Ngan Thi Kim; Morandi, Federica; Head, Jared; O’Mahony, Alison; Zimmerli, Simone C.; Bruns, Lisa; Bender, Andrew T.; Schroeder, Patricia; Grenningloh, Roland

doi:10.4049/jimmunol.1800583

Cited by 107 publications

(135 citation statements)

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“…Evobrutinib is a highly selective, oral inhibitor of BTK. In human cellular assays, evobrutinib potently inhibits B cell and basophil activation and a range of functions mediated by BCR and FcR induction . Moreover, evobrutinib has shown promising activity in preclinical models in a number of autoimmune diseases .…”

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confidence: 99%

“…In human cellular assays, evobrutinib potently inhibits B cell and basophil activation and a range of functions mediated by BCR and FcR induction . Moreover, evobrutinib has shown promising activity in preclinical models in a number of autoimmune diseases . In a mouse model of interferon‐accelerated systemic lupus erythematosus, evobrutinib was associated with robust reduction in disease activity which correlated with inhibition of B cell function .…”

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confidence: 99%

“…8 Moreover, evobrutinib has shown promising activity in preclinical models in a number of autoimmune diseases. [8][9][10] In a mouse model of interferon-accelerated systemic lupus erythematosus, evobrutinib was associated with robust reduction in disease activity which correlated with inhibition of B cell function. 8 Similarly, in a collagen-induced arthritis mouse model, rheumatoid arthritis-like symptoms were inhibited by evobrutinib.…”

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confidence: 99%

“…[8][9][10] In a mouse model of interferon-accelerated systemic lupus erythematosus, evobrutinib was associated with robust reduction in disease activity which correlated with inhibition of B cell function. 8 Similarly, in a collagen-induced arthritis mouse model, rheumatoid arthritis-like symptoms were inhibited by evobrutinib. 8 Furthermore, in both B cell-dependent 9 and T cell-dependent 10 experimental autoimmune encephalomyelitis mouse models, evobrutinib limited central nervous system inflammation and disease severity suggesting a potentially broader therapeutic benefit in multiple sclerosis (MS) compared with therapeutic agents with modes of action involving B cell depletion alone.…”

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confidence: 99%

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Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker

Martin

Mitchell³

et al. 2019

Clinical Translational Sci

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Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling, and a rational therapeutic target for autoimmune diseases. This first‐in‐human phase I, double‐blind, placebo‐controlled trial investigated the safety, tolerability, pharmacokinetics (PK), target occupancy, and effects on QT interval of evobrutinib, a highly selective, oral inhibitor of BTK, in healthy subjects. This dose escalation trial consisted of two parts. Part 1 included 48 subjects in 6 ascending dose cohorts (25, 50, 100, 200, 350, and 500 mg) randomized to a single dose of evobrutinib or placebo. Part 2 included 36 subjects in 3 ascending dose cohorts (25, 75, and 200 mg/day) randomized to evobrutinib or placebo once daily for 14 days. Safety and tolerability, as well as PK and target occupancy (total and free BTK in peripheral blood mononuclear cells), were assessed following single and multiple dosing. PK parameters were determined by noncompartmental methods. QT interval was obtained from 12‐lead electrocardiogram recordings and corrected for heart rate by Fridericia's method (QTcF). Treatment‐emergent adverse events (TEAEs) were mostly mild, occurring in 25% of subjects after single dosing, and 48.1% after multiple dosing. There was no apparent dose relationship regarding frequency or type of TEAE among evobrutinib‐treated subjects. Absorption was rapid (time to reach maximum plasma concentration (Tmax) ~ 0.5 hour), half‐life short (~ 2 hours), and PK dose‐proportional, with no accumulation or time dependency on repeat dosing. BTK occupancy was dose‐dependent, reaching maximum occupancy of > 90% within ~ 4 hours after single doses ≥ 200 mg; the effect was long‐lasting (> 50% occupancy at 96 hours with ≥ 100 mg). After multiple dosing, full BTK occupancy was achieved with 25 mg, indicating slow turnover of BTK protein in vivo. Concentration‐QTcF analyses did not show any impact of evobrutinib concentration on corrected QT (QTc). In summary, evobrutinib was well‐tolerated, showed linear and time‐independent PK, induced long‐lasting BTK inhibition, and was associated with no prolongation of QT/QTc interval in healthy subjects. Evobrutinib is, therefore, suitable for investigation in autoimmune diseases.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker

Martin

Mitchell³

et al. 2019

Clinical Translational Sci

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“…Bruton's tyrosine kinase (BTK), an important molecule in B cells, has been reported to have multiple pathogenic roles in SLE including B cells differentiation and autoantibodies production [140]. One of the BTK inhibitors, evotrubinib, has been reported to be a promising agent in treating chronic autoimmune disease in mice [141]. Further, BTK inhibition was proven to be effective in improving renal, cutaneous and brain manifestations in a murine model of SLE [142].…”

Section: New Trends In Targeted Therapiesmentioning

confidence: 99%

B cells targeting therapy in the management of systemic lupus erythematosus

Lee

Amengual

2019

Immunological Medicine

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which affects the majority of organs and systems. Traditional therapies do not lead to complete remission of disease but only relieve symptoms and inflammation. B cells are the most important effector cell types in the pathogenesis of SLE. Therefore, therapies targeting B cells and their related cytokines are a very important milestone for SLE treatment. Several biologics that modulate B cells, either depleting B cells or blocking B cell functions, have been developed and evaluated in clinical trials. Belimumab, a fully humanized monoclonal antibody that specifically binds B cells activating factor (BAFF), was the first of these agents approved for SLE treatment. In this review, we explore the currently available evidence in B cell targeted therapies in SLE including agents that target B cell surface antigens (CD19, CD20, CD22), B cell survival factors (BAFF and a proliferation-inducing ligand, APRIL), cytokines (interleukin-1 and type 1 interferons) and co-stimulatory molecules (CD40 ligand). We highlighted the mechanisms of action and the individual characteristics of these biologics, and present an update on the clinical trials that have evaluated their efficacy and safety. Finally, we describe some of the emerging and promising therapies for SLE treatment.

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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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Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Abstract: B cell proliferation, cytokine release, and plasmablast differentiation assays CD19 + B cells were isolated from PBMCs of healthy volunteers by negative selection using the B cell purification kit II (Miltenyi Biotec,

Cited by 107 publications

References 77 publications

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

B cells targeting therapy in the management of systemic lupus erythematosus

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

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