Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

Catlett, Ian M.; Nowak, Miroslawa; Kundu, Sudeep; Zheng, Naiyu; Liu, Ang; He, Bing; Girgis, Ihab; Grasela, Dennis M.

doi:10.1111/bcp.14290

Cited by 19 publications

(14 citation statements)

References 31 publications

(76 reference statements)

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“…In a double-blind, placebo-controlled, single- and multiple-ascending dose (SAD; MAD) phase I study participants received branebrutinib (SAD: 0.3–30 mg; MAD: 0.3–10 mg) or placebo [ 96 ]. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days post dosing.…”

Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

“…Branebrutinib plasma levels dropped then rapidly with a half-life of 1.2–1.7 h to undetectable levels within 24 h. Btk occupancy in whole blood cells was rapid, with 100% occupancy reached after a single 10 mg dose and was maintained for 24 h. In the MAD study 100% Btk occupancy was maintained with only 3 mg QD. Doses of only ≥1 mg QD branebrutinib providing a Btk occupancy of >90% were projected to be efficacious [ 96 ]. Branebrutinib intake for 2 weeks was well tolerated.…”

Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

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Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

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Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

Section: Btk Inhibitors (Btki)mentioning

confidence: 99%

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Hundelshausen

Siess

2021

Cancers

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“…Branebrutinib is an irreversible, covalent inhibitor of BTK that has shown efficacy in RA and SLE mouse models, reducing clinical signs of disease dose dependently [ 139 ]. This inhibitor was well tolerated in a phase I study with healthy individuals [ 140 ], and these promising results have led to a clinical trial with active SLE, primary SjS, and RA patients, which is currently recruiting patients (NCT04186871).…”

Section: Btk Inhibitors In Clinical Trials Of Systemic Autoimmune Diseasesmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Neys

Rip

Hendriks

et al. 2021

Drugs

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Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by “classical” anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton’s tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.

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“…Two years after the modeling and simulation work was conducted, branebrutinib was nominated as a clinical drug candidate; it had a low clearance and exhibited a good oral bioavailability (46% or higher) in nonclinical species (mouse, rat, dog, and monkey) (Watterson et al., 2019). In the clinic, 90% BTK inactivation was observed in human blood at 24 h after a 3‐mg single oral dose of branebrutinib (Catlett et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

Achieving a low human dose for targeted covalent drugs: Pharmacokinetic and pharmacodynamic considerations on target characteristics and drug attributes

Yang

2021

Biopharm & Drug Disp

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Covalent modifications of off‐target biomolecules remain to be a concern for targeted covalent drugs. To guide the design of targeted covalent drugs in achieving a low human daily dose, a pharmacokinetic/pharmacodynamic (PK/PD) model was established to quantitatively evaluate target characteristics and drug properties that affect the human dose. Target characteristics, such as expression levels, turnover, and degree of inhibition relevant to efficacy, were evaluated systematically using the model. The drug properties including inactivation potency and drug clearance were also examined. Model simulations revealed that the interplay of target characteristics and drug properties governed the human dose. Particularly, the extent and the duration of target inactivation meaningful to efficacy, as well as the target resynthesis rate measured as the target turnover half‐life, needed to be determined. The target information then served as a basis to inform desired drug inactivation potency and PK properties. The model‐based approach provided a theoretical framework in achieving a low human dose of targeted covalent drugs, and the resultant strategy was successfully applied in the early stage of a Bruton's tyrosine kinase covalent inhibitor project that discovered low‐dose branebrutinib. The PK/PD considerations described are also applicable to the drug design for protein degraders that share the same endpoint as targeted covalent drugs in reducing target levels.

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Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants

Cited by 19 publications

References 31 publications

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Achieving a low human dose for targeted covalent drugs: Pharmacokinetic and pharmacodynamic considerations on target characteristics and drug attributes

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