Bruton's Tyrosine Kinase Inhibitor Research Articles

Second-degree Heart Block in a Patient on Zanubrutinib

Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor recently approved by the Food and Drug Administration for treatment of chronic lymphocytic leukemia (CLL) in January 2023. As a second generation BTK inhibitor, zanubrutinib is more selective for “on-target” BTK and have less cardiac side effects. Although atrial flutter and atrial fibrillation were noted side effects during clinical trials, heart block is not a known side effect. Here we present a case of a patient with CLL on zanubrutinib who presented with a second-degree heart block.

Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents

The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton’s Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.

A Dual-Function CD47-Targeting Nano-Drug Delivery System used to Regulate Immune and Anti-Inflammatory Activities in the Treatment of Atherosclerosis.

Atherosclerosis is a primary contributor to cardiovascular disease. Current studies have highlighted the association between the immune system, particularly immune cells, and atherosclerosis, although treatment options and clinical trials remain scarce. Immunotherapy for cardiovascular disease is still in its infancy. Bruton's tyrosine kinase (BTK), widely expressed in various immune cells, represents a promising therapeutic target for atherosclerosis by modulating the anti-inflammatory function of immune cells. In this study we introduced a polydopamine-based nanocarrier system to deliver the BTK inhibitor, ibrutinib, to atherosclerotic plaques with an active targeting property via an anti-CD47 antibody. Leveraging polydopamine's pH-sensitive reversible disassembly, the system offers responsive, controlled release within the pathologic microenvironment. This allows precise and efficient ibrutinib delivery, concurrently inhibiting the activation of the NF-κB pathway in B cells and the NLRP3 inflammasome in macrophages within the plaques. This treatment also modulates both the immune cell microenvironment and inflammatory conditions in atherosclerotic lesions, thereby conveying promising therapeutic effects for atherosclerosis in vivo. This strategy also provides a novel option for atherosclerosis treatment. This article is protected by copyright. All rights reserved.

Targeting the tumor microenvironment for treating double refractory chronic lymphocytic leukemia

The introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging, which has become refractory or intolerant to both classes of agents, creating an unmet medical need. Here, we propose that the targeted modulation of the tumor microenvironment provides new therapeutic options for this group of "double refractory" patients. Furthermore, we outline a sequential strategy for tumor microenvironment-directed combination therapies in CLL that can be tested in clinical protocols.

Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition

Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition

The impact of Bruton’s tyrosine kinase inhibitor treatment on COVID-19 outcomes in Chinese patients with chronic lymphocytic leukemia

BackgroundImpact of B-cell depletion following treatment with Bruton tyrosine kinase-inhibitors (BTKi) on the outcome of SARS-CoV-2 infection in chronic lymphocytic leukemia (CLL) patients remain controversial. We investigated the impact of BTKi on susceptibility and the severity of COVID-19 in Chinese patients with CLL during the first wave of COVID-19 (Omicron variant).MethodsCLL patients (n=171) visiting the Institute of Hematology, Peoples’ Hospital, China (November 15, 2022- January 20, 2023) were included in the study. Seventeen patients receiving BTKi and venetoclax with or without obinutuzumab were excluded. Data from 117 patients receiving treatment with BTKi were collected using a standardized questionnaire through telephone interviews. Thirty-four patients without CLL-specific treatment served as controls. The data was analysed using IBM SPSS Software version 21 and a P value of <0.05 was considered statistically significant.ResultsThe median age of patients was 67 years and majority were males (n=100). Treatment with BTKi was not associated with higher incidence of COVID-19 (74% [95% Confidence Interval (CI) 60%, 92%]) versus 74% (CI 48%, 100%) without any treatment (P=0.92). Hypoxemia was reported by 45% (32%, 61%) and 16% (4%, 41%) (P=0.01). BTKi was the only independent risk factor of hypoxemia (Hazard Ratio [HR], 4.22 [1.32, 13.50]; P = 0.02). Five (5.7%) patients with COVID-19 under BTKi required ICU admission; 4 of them died. No ICU admissions/deaths were observed in the control group.ConclusionIn Chinese patients with CLL and treated with BTKi experienced more severe lung disease and ICU admissions due to COVID-19 than patients without CLL therapy. Frequency of infections with SARS-CoV-2, however, was not different in patients with or without BTKi treatment.

The role of Bruton's tyrosine kinase in pathogenesis of chronic spontaneous urticaria and the prospects for the use of new treatment.

Chronic spontaneous urticaria is a fairly common disease with an unpredictable course, burdensome symptoms and a significant negative impact on patients` quality of life. Despite the established stepwise approach to treatment with antihistamines in standard and increased dosages, anti-IgE therapy, there remains a portion of patients with unsatisfactory control of urticaria symptoms, with the need to develop drugs that target new therapeutic targets. Mast cells, basophils and B cells are key cells involved in the pathogenesis of urticaria; activation, differentiation, proliferation, cytokine secretion and degranulation in all three types of cells is regulated via Bruton's tyrosine kinase signalling pathway through FcεRI and BCR receptors respectively. Inhibition of Bruton's tyrosine kinase is being developed as a new therapeutic strategy for chronic spontaneous urticaria. Here we present overview of the current understanding of chronic spontaneous urticarial`s pathogenesis, the role of Bruton's tyrosine kinase, the history of medical use of Bruton's tyrosine kinase inhibitors, as well as clinical data on the use of new Bruton's tyrosine kinase inhibitors in patients with chronic spontaneous urticaria who have not achieved adequate disease control with antihistamines.

Meta-analysis of the efficacy and adverse effects of acalabrutinib in the management of relapsed/refractory chronic lymphocytic leukemia

The advent of Bruton tyrosine kinase inhibitor (BTKi) therapy with ibrutinib introduced a highly effective targeted therapy in the management of chronic lymphocytic leukemia (CLL). However, due to the adverse effect profile some patients cannot tolerate this novel therapy. Newer, more potent and targeted BTK inhibitors such as acalabrutinib have been developed. Acalabrutinib is an irreversible and second generation BTKi that covalently inhibits BTK with greater selectivity than ibrutinib. As novel BTKis are developed, a greater understanding of their efficacy and adverse effect rates can assist clinicians and patients in the shared clinical decision-making process. A search was conducted using the PICOS model and PRISMA guidelines. PubMeb, Embase, and Cochrane Library databases were searched using the keywords: Acalabrutinib, Acalabrutinib Monotherapy, Tyrosine Kinase Inhibitor, and Relapsed/Refractory (R/R) CLL. After initial literature review 12 studies were chosen for evaluation in this meta-analysis. Meta-analysis and follow up meta-regression models were completed. The results were as follows: ORR 82% (95% CI 74%–90%, I2 = 84.14%, p < 0.01), CR 4% (95% CI 2%–6%, I2 = 0.00%, p = 0.99), mortality rate 12% (95% CI 6%–19%, I2 = 87.23%, p < 0.01), mortality rate due to adverse effect 7% (95% CI 3%–10%, I2 = 67.67%, p = 0.01), mortality due to pneumonia 2% (95% CI 1%–3%, I2 = 0.00%, p = 0.43), mortality due to CLL progression 4% (95% CI 2%–6%, I2 = 61.03%, p = 0.04), neutropenia (≥ grade 3) 18% (95% CI 15%–20%, I2 = 0.00%, p = 0.70), thrombocytopenia (≥ grade 3) 7% (95% CI 4%–11%, I2 = 54%, p = 0.09), anemia (≥ grade 3) 9% (95% CI 6%–12%, I2 = 36.93%, p = 0.18), pneumonia (≥ grade 3) 10% (95% CI 6%–14%, I2 = 66.37%, p = 0.02) and atrial fibrillation 7% (95% CI 3%–11%, I2 = 80.13%, p = 0.00). The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

Racial and ethnic characteristics and outcomes of patients diagnosed with CLL/SLL in the United States.

Background This study was designed to compare outcomes among patients by race and ethnicity in the post-covalent Bruton tyrosine kinase inhibitor (cBTKi) treatment era. Methods A nationwide electronic health record (EHR)-derived de-identified database was utilized that included patients diagnosed with CLL from 2013-2022 who received systemic therapy for their disease. Use of cBTKi therapy, time to next treatment or death (TTNT-D), and overall survival (OS) were compared by race in unadjusted (Kaplan-Meier method) and adjusted analyses (Cox proportional hazards regression). Results This study included 4,572 White (71.8%) and 558 Black (8.8%) patients with CLL; 270 were Hispanic or Latino (4.2%). Patients who were Black were significantly younger, more were female, had later stage disease, were of lower socioeconomic status (SES), more likely to have unmutated immunoglobulin heavy chain gene (IGHV) and to havereceived cBTKi therapy than White patients (all p≤0.002). SES was also significantly different by ethnicity. TTNT-D and OS were not different by race in either unadjusted or adjusted analyses (all p>0.05). Conclusion In unadjusted and adjusted analyses, TTNT-D and OS were not different by race. These data did not identify racial healthcare disparities in the era following the introduction of cBTKi therapy despite differences in baseline characteristics.

Clinical characteristics and prognosis of patients with newly diagnosed primary central nervous system lymphoma: a multicentre retrospective analysis.

Bruton's tyrosine kinase inhibitors (BTKi) exhibit superior efficacy in relapsed/refractory primary central nervous system lymphoma (PCNSL), but few studies have evaluated patients with newly diagnosed PCNSL, and even fewer studies have evaluated differences in efficacy between treatment with BTKi and traditional chemotherapy. This study retrospectively analyzed the clinical characteristics of 86 patients with PCNSL and identified predictors of poor prognosis for overall survival (OS). After excluding patients who only received palliative care, 82 patients were evaluated for efficacy and survival. According to the induction regimen, patients were divided into the traditional chemotherapy, BTKi combination therapy, and radiotherapy groups; the objective response rates (ORR) of the three groups were 71.4%, 96.2%, and 71.4% (P = 0.037), respectively. Both median progression-free survival and median duration of remission showed statistically significant differences (P = 0.019 and P = 0.030, respectively). The median OS of the BTKi-containing therapy group was also longer than that of the traditional chemotherapy group (not reached versus 47.8 (32.5-63.1) months, P = 0.038).Seventy-one patients who achieved an ORR were further analyzed, and achieved an ORR after four cycles of treatment and maintenance therapy had prolonged OS (P = 0.003 and P = 0.043, respectively). In conclusion, survival, and prognosis of patients with newly diagnosed PCNSL are influenced by the treatment regimen, with the BTKi-containing regimen showing great potential.

Outcomes of younger patients with mantle-cell lymphoma experiencing late relapse (>24 months): the LATE-POD study.

Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from the initial MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are established standard treatment at first relapse, but their effectiveness as compared to chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes amongst patients at first, late-POD beyond 24 months. Patients treated upfront with BTKi were excluded. The primary objective was progression-free survival from time of second-line therapy (PFS-2) of BTKi versus CIT. After accrual, all patients were prospectively followed-up. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 (range:19-70) years and 77% were males. Median follow-up from time of first relapse was 53 months (range:12-144). Overall, 114 patients had second-line BTKi, while 271 had CIT, consisting of rituximab-bendamustine (R-B, n=101), R-B and cytarabine (R-BAC, n=70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone-CHOP- or platinum-based, n=100). The two groups were balanced for clinicopathological features, and median time to first relapse (48 months for both). Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT [not reached-NR vs 26 months, respectively, P=.0003], and overall survival [NR and 56 months, respectively, P=.03]. Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio-HR, 0.41 for R-B, 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in BTKi-naïve MCL patients.

Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib.

Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from relapsed/refractory CLL patients in ELEVATE-RR (NCT02477696) (median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 (66%) acalabrutinib-treated and 11 (37%) ibrutinib-treated patients (median variant allele fraction [VAF]: 16.1% vs 15.6%). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, while neither mutation occurred with ibrutinib. L528W and A428D co-mutations presented in one ibrutinib-treated patient. Pre-existing TP53 mutations were present in 25 (53.2%) acalabrutinib-treated and 16 (53.3%) ibrutinib-treated patients at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF: 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and one ibrutinib-treated patient had emergent TP53/BTK co-mutations. Emergent PLCG2 mutations occurred in 3 (6%) acalabrutinib-treated and 6 (20%) ibrutinib-treated patients. One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.

Multi-phased Kinetics and Interaction of Protein Kinase Signaling in Glycoprotein VI-Induced Platelet αIIbβ3 Integrin Activation and Degranulation.

Platelet glycoprotein VI (GPVI) stimulation activates the tyrosine kinases Syk and Btk, and the effector proteins phospholipase Cγ 2 (PLCγ2) and protein kinase C (PKC). Here, the activation sequence, crosstalk, and downstream effects of this Syk-Btk-PKC signalosome in human platelets were analyzed. Using immunoblotting, we quantified 14 regulated phospho-sites in platelets stimulated by convulxin with and without inhibition of Syk, Btk, or PKC. Convulxin induced fast, reversible tyrosine phosphorylation (pY) of Syk, Btk, LAT, and PLCγ2, followed by reversible serine/threonine phosphorylation (pS/T) of Syk, Btk, and downstream kinases MEK1/2, Erk1/2, p38, and Akt. Syk inhibition by PRT-060318 abolished all phosphorylations, except Syk pY352. Btk inhibition by acalabrutinib strongly decreased Btk pY223/pS180, Syk pS297, PLCγ2 pY759/Y1217, MEK1/2 pS217/221, Erk1/2 pT202/Y204, p38 pT180/Y182, and Akt pT308/S473. PKC inhibition by GF109203X abolished most pS/T phosphorylations except p38 pT180/Y182 and Akt pT308, but enhanced most Y-phosphorylations. Acalabrutinib, but not GF109203X, suppressed convulxin-induced intracellular Ca2+ mobilization, whereas all three protein kinase inhibitors abolished degranulation and αIIbβ3 integrin activation assessed by flow cytometry. Inhibition of autocrine ADP effects by AR-C669931 partly diminished convulxin-triggered degranulation. Kinetic analysis of GPVI-initiated multisite protein phosphorylation in human platelets demonstrates multiple phases and interactions of tyrosine and serine/threonine kinases with activation-altering feedforward and feedback loops partly involving PKC. The protein kinase inhibitor effects on multisite protein phosphorylation and functional readouts reveal that the signaling network of Syk, Btk, and PKC controls platelet granule exocytosis and αIIbβ3 integrin activation.

A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

Zanubrutinib is effective in non-germinal-center B-cell-like diffuse large B-cell lymphoma with mutated CD79B, high TCL1A expression, or over- expressed MYC/BCL-2

To evaluate the effects of gene mutations on Bruton tyrosine kinase inhibitor, zanubrutinib’s effectiveness in patients with diffuse large B-cell lymphoma (DLBCL), we examined pooled data from four single-arm studies (BGB-3111-AU-003 [NCT02343120], BGB-3111-207 [NCT03145064], BGB-3111_GA101_Study_001 [NCT02569476], BGB-3111-213 [NCT03520920]; n = 121). Objective response rate (ORR) was higher, though not statistically significant, in patients with activated B-cell-like (ABC)- and unclassified DLBCL (42.9% [21/49]) versus those with germinal-center B-cell-like DLBCL (14.3% [1/7]; p = 0.15). Patients with CD79B mutations had better ORR (60%) versus patients with wild-type alleles (25.9%, p < 0.01). Higher TCL1A expression correlated with better zanubrutinib response (p = 0.03), longer progression-free survival (p = 0.01), and longer overall survival (p = 0.12). TCL1A expression was higher in ABC-DLBCL (p < 0.001) and MYD88/CD79B-mutated subtypes (p < 0.0001). Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.

Prolonged remission with ibrutinib maintenance therapy following radiation in a patient with relapsed primary CNS lymphoma.

Background: Treatment for refractory or relapsed primary CNS lymphoma (r/r PCNSL) is challenging. Salvage whole-brain radiation therapy (WBRT) is an option but has a short duration of disease control, so additional treatment modalities are warranted. Case: A 75-year-old female with r/r PCNSL who had multipleprogressions after multiple lines of treatment underwent salvage WBRT. The patient received ibrutinib, a Bruton's tyrosine kinase inhibitor, as maintenance therapy for 18months following WBRT with the intention of increasing survival duration after salvage WBRT. She survived 81months from diagnosis, including 57months after completion of WBRT. Conclusion: Thiscase presentation describes the experience ofusing ibrutinib as maintenance therapy in treating r/r PCNSL after salvage WBRT.

Cardio-Oncology: A New Discipline in Medicine and Its Relevance to Hematology.

Cardio-oncology, a burgeoning subspecialty, addresses the complex interplay between cardiology and oncology, particularly in light of increased cardiovascular (CV) disease mortality in cancer patients. This review provides a comprehensive overview of cardio-oncology with a focus on the therapies used in hematological malignancies. We explore the bidirectional relationship between heart failure and cancer, emphasizing the need for collaborative care. The review discusses risk stratification, highlighting the importance of baseline CV risk assessment and personalized surveillance regimens. Primary and secondary prevention strategies, including pharmacological interventions, are outlined. The review also delves into the cardiotoxicity associated with hematological cancer therapies, focusing on anthracyclines, Bruton kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, CAR-T cell therapy, immune checkpoint inhibitors, multiple myeloma treatments, and hematopoietic stem cell transplantation. We then highlight the high risk of venous and arterial thromboembolisms in cancer patients and the challenges of anticoagulation management in cardio-oncology. Finally, the review touches on the importance of long-term follow-up and appropriate screening in cancer survivors at high risk of CV morbidity and mortality, based on their CV risk profile and the type and dose of cardiotoxic therapies they received such as anthracyclines or high radiation doses.

BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNFα.

Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the impact of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNFα fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNFα did not impact ROS production in healthy neutrophils but prevented exogenous TNFα from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNFα was independent of transcription. Moreover, the addition of TNFα immediately rescued ROS production in IBT-treated neutrophils indicating that TNFα worked through a BTK-independent signaling pathway. Finally, TNFα restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNFα rescues the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

Pharmacology of drugs used in autoimmune dermatopathies in cats and dogs: A narrative review.

Immunosuppressive drugs are the mainstay of treatment for many feline and canine autoimmune skin diseases, either as monotherapy or in combination with other drugs. Treatment with these drugs is often lifelong and may have long-term consequences on the affected animal's overall quality-of-life. Clinicians need to understand the pharmacology of immunosuppressants in planning and executing the treatment regimen for the best possible clinical outcome, as well as reducing the risk of adverse effects. This review paper will focus on the mechanism of action, pharmacokinetics and pharmacodynamics, clinical uses and adverse effects of immunosuppressive drugs used to treat autoimmune dermatoses in cats and dogs. These include glucocorticoids, ciclosporin A, azathioprine, chlorambucil, mycophenolate mofetil, oclacitinib and Bruton's tyrosine kinase inhibitors.