Accepted Manuscript Title: Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis Author: Jennifer A. Whang Betty Y. Chang PII: DOI: Reference:

S1359-6446(14)00122-6 http://dx.doi.org/doi:10.1016/j.drudis.2014.03.028 DRUDIS 1382

To appear in: Received date: Accepted date:

14-3-2014 31-3-2014

Please cite this article as: Whang, J.A., Chang, B.Y.,Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis, Drug Discovery Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.03.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis Pharmacyclics, Inc., 999 East Arques Avenue, Sunnyvale, CA 94085, USA Corresponding author: Chang, B.Y. ([email protected])

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Jennifer A. Whang and Betty Y. Chang

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The function and role of Bruton’s tyrosine kinase (BTK) in human B cell development was demonstrated by its association with X-linked agammaglobulinemia (XLA) manifested by a substantial reduction in immunoglobulins and B cells. BTK has a crucial role in pre-B cell receptor (BCR) and BCR signaling during normal B cell development and activation. Aberrant BCR signaling is associated with autoimmune diseases, such as rheumatoid arthritis (RA). In addition, BTK is also expressed in myeloid cell populations, including monocytes, macrophages, neutrophils and mast cells. These innate cells infiltrate the synovial cavity and produce inflammatory cytokines, aggravating arthritic symptoms. In myeloid cell populations, BTK functions downstream of the Fc! recepto rs (FcR) and Fc receptors (FcR) [1,2]. In the absence of BTK, FcR-mediated functions, such as cytokine production, are impaired. In addition, Xid mice, which have a mutation in BTK, have decreased susceptibility to developing collagen-induced arthritis (CIA) [3]. Given that BTK is involved in multiple signaling pathways downstream of the BCR and FcR, it is an attractive therapeutic target for RA.

Introduction

Pathogenesis of RA

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The dysregulation of the immune system can result in abnormal immune responses against self-tissues, leading to the development and pathogenesis of autoimmune diseases. A combination of genetics and environmental factors has been attributed to autoimmune disorders, but the triggers that initiate the disease are unknown. RA is one of many autoimmune diseases characterized by unusual T cell activation and B cell function, circulating autoantibodies and increased pro-inflammatory cytokines. All these factors contribute to the clinical manifestations of RA, which include synovial hyperplasia, pannus formation, cartilage damage and joint destruction [4]. Persistent inflammation localized in the joints consequently leads to systemic complications affecting numerous organs, including but not limited to the brain, liver and lungs [4]. Therefore, it is of great interest to identify a therapeutic target that can attenuate the actions of multiple factors contributing to RA pathogenesis.

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The effector functions of immune cells contribute to the pathogenesis of RA. Infections and tissue injury are hypothesized to initiate the disease. The initiation of RA involves the presentation of self-antigens, leading to the activation of T and B lymphocytes. Activation of the adaptive immune response results in cytokine secretion and autoantibody production, which promotes inflammation. Furthermore, interactions between T and B cells in the synovium are capable of sustaining cell activation. Persistent inflammation occurs as a result of the formation of immune complexes that activate synovium-infiltrating myeloid cells, which include monocytes, macrophages, neutrophils, dendritic cells and mast cells. The release of proinflammatory cytokines and matrix metalloproteases by activated T cells and myeloid cells causes cartilage damage and joint destruction. The destruction of tissue causes the release of additional self-antigens, further potentiating the disease. Finally, chronic inflammation induces bone erosion through osteoclast activation [5]. Given the abundance of T cells in the synovial cavity and their ability to activate B cells during RA, this cell population has been an attractive target for RA therapy. Although the blockade of T cell co-stimulation is an approved therapy (Table 1), the depletion of T cells has exhibited little therapeutic value in RA [6]. Alternatively, B cell function and autoantibody production have also been demonstrated to contribute to disease progression. Thus, therapies directly or indirectly targeting B cells have been developed in an attempt to attenuate disease progression. In particular, depletion of B cell populations improved clinical symptoms and indicated a crucial role for B cells in promoting RA [7]. The crucial role of B cells in the development of RA is demonstrated by the therapeutic benefit exhibited following B cell targeting, either through cell depletion or targeting B cell survival factors. To prevent the production of autoantibodies, the elimination of the autoreactive B cell population was proposed. The absence of B cells prevents the development of arthritis in the CIA model, an animal model of RA dependent on cellular and humoral immunity to initiate disease [8]. In patients with RA, the depletion of B cells with rituximab improved clinical symptoms in patients unresponsive to antitumor necrosis factor (TNF) therapy or methotrexate treatment [7,9,10]. Rituximab is a chimeric monoclonal antibody that targets CD20+ B cells and facilitates antibodydependent cell-mediated cytotoxicity, thus depleting the autoreactive cell population [11]. BTK regulates B cell development and activation

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The role of BTK in myeloid cells and FcR signaling

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B cells arise from hematopoietic stem cells in the bone marrow in an ordered process. During differentiation, B cells are regulated by multiple checkpoints to eliminate any potential autoreactive cells. Signals transduced through the BCR are crucial in controlling B cell development and activation. Progenitor cells committed to the B cell lineage differentiate into pro-B cells and subsequently transition to the pre-B cell stage following successful immunoglobulin heavy-chain rearrangement [12]. Surface expression and signaling of the pre-BCR on pre-B cells induces proliferation and expansion. Next, rearrangement of the immunoglobulin light chain produces complete BCR molecules that are expressed on the surface of immature B cells [12]. Cells with strong BCR signaling, because of high-affinity binding, undergo deletion, anergy or receptor editing to limit autoreactive cells [12]. After exiting the bone marrow, immature cells enter the periphery and become mature B cells. The survival of mature B cells in the periphery is dependent on BCR signaling [13,14]. Furthermore, recognition of cognate antigen by the BCR induces cell activation. A proportion of activated cells further differentiate into plasma cells capable of producing antibodies. BCR engagement initiates an intracellular signaling cascade resulting in nuclear factor B (NF-B) and nuclear factor of activated T cells (NFAT) transcriptional activation, leading to the execution of cellular effector functions. Following BCR stimulation, receptor proximal events include the recruitment of BTK to the plasma membrane, and the pleckstrin homology (PH) domain of BTK interacts with phosphatidylinositol-3,4,5-triphosphate (PIP3) [15,16]. Subsequent tyrosine phosphorylation of BTK by the SRC- and spleen tyrosine kinase (SYK) family of kinases, such as LYN, FYN and SYK, fully activates BTK, which results in the activation of downstream signaling pathways leading to NF-B activation (Figure 1) [17]. BTK is a member of the Tec family of nonreceptor protein tyrosine kinases with expression restricted to B cells and myeloid cells [15]. The significant role of BTK in B cells is demonstrated in X-linked agammaglobulinemia (XLA) and X-linked immunodeficiency (Xid) in humans and mice, respectively [16]. Null mutations or point mutations in any domain of BTK cause XLA and result in a block in B cell development at the pre-B cell stage. As a result, peripheral B cell populations and circulating antibodies are deficient in patients with XLA [18]. In a similar manner, Xid mice have a point mutation in the PH domain of BTK [19]. Both Xid- and BTK-deficient mice exhibit a reduction in specific populations of peripheral B cells, but the phenotype in mice is less severe compared with XLA [20,21]. Interestingly, Xid mice have decreased susceptibility to develop arthritis in the CIA model [3]. Alternatively, the overexpression of BTK in B cells enhances BCR-induced activation and is capable of inducing autoantibody production, resulting in the development of autoimmunity [22]. The inhibition of BTK kinase activity in this mouse model prevents the onset of autoimmunity [22]. These results indicate that altering BTK kinase activity can act to target B cells.

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In addition to T and B cells, myeloid cells infiltrate the synovium during RA. These innate immune cells, such as macrophages, mast cells, neutrophils and NK cells, release effector factors exacerbating synovitis [4]. FcRs are expressed on the surface of B cells and myeloid cells and have been demonstrated to have a role during autoimmunity. FcRs recognize and bind the Fc portion of immunoglobulins, and receptor cross-linking by immune complexes stimulates cellular activation, leading to antibody-dependent cellular cytotoxicity, phagocytosis and proinflammatory cytokine production (Figure 1). Internalization and degradation of immune complexes facilitate antigen presentation to T cells, but the inability to eliminate immune complexes can lead to autoimmune disease [23]. Thus, the presence of immune complexes not only indicates autoimmune disease, but also potentiates pathogenesis by stimulating inflammation. Activating FcRs are capable of driving cellular functions whereas inhibitory FcRs block activating signals. Previous studies have demonstrated that a deficiency in activating FcRs protects mice from experimental models of arthritis, whereas deletion of the inhibitory FcRIIB triggers increased susceptibility to arthritis [24–27]. In the CIA model, FcR-deficient mice did not exhibit signs of arthritis, but anticollagen II antibodies were still detected at similar levels to mice that did develop arthritis [25]. This indicated that the adaptive immune response was intact. Similar results were observed in the collagen antibody-induced arthritis (CAIA) model, which bypasses the requirement for T and B cell functions in the induction of arthritis [26]. Again, the absence of FcRs protected mice from disease development [26]. In addition to FcRs, FcR has also been demonstrated to be involved in disease pathogenesis. Decreased susceptibility to arthritis development has been observed in FcR-deficient mice [27]. Unlike FcR-deficient mice, mice with a deficiency in FcR developed arthritis, but the onset of disease was delayed and the severity was reduced [27]. Alternatively, the elimination of FcRIIb, an inhibitory receptor, promoted disease development in both the CIA and CAIA models [24–26]. In the absence of FcRIIb, mice rapidly developed arthritis with signs of cellular infiltration and bone erosion [24–26]. Interestingly, BTK has been demonstrated to function downstream of both the FcR and FcR, and in the absence of BTK, FcR-mediated functions, such as cytokine production, are impaired [1,2]. The activating FcRs contain immunoreceptor tyrosine-based activation motifs, which are also present in the BCR invariant chains, and facilitate the proximal signaling events by the Src and SYK family of kinases (Figure 1). In the case of FcRs, BTK is rapidly activated after receptor activation, and functions in FcR-induced phagocytosis [1]. The role of BTK downstream of the FcRI was demonstrated with Xid and BTK-deficient mice. Whereas mast cell development is not regulated by BTK, its kinase activity is necessary for mast cell function [2]. Cells isolated from Xid or BTKdeficient mice demonstrated a reduced capacity to degranulate and release histamine. Furthermore, the production of proinflammatory cytokines was significantly decreased because of impaired NFAT activation [2].

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Given that BTK functions in both B cells and myeloid cell populations, it is an attractive therapeutic target for RA. In particular, eliminating the kinase activity of BTK would block multiple signaling pathways in different cell populations. Consequently, different factors contributing to the pathogenesis of RA could be simultaneously eliminated by targeting this one kinase. Development of BTK inhibitors for RA

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Currently, the approved treatments for RA that regulate immune functions are mostly antibody-based therapies (Table 1). At a molecular level, multiple kinases have been implicated at different stages of disease progression, including BTK, SYK and Janus kinase 3 (JAK3). Whereas current therapies for RA primarily target one factor contributing to RA pathogenesis, BTK is an appealing therapeutic target because of its function in multiple signaling pathways downstream of the BCR and FcRs. As a result, the effector functions of numerous cell populations involved in disease progression can be limited by regulating the activity of BTK. Several covalent and noncovalent small-molecule inhibitors for BTK have been developed and demonstrated efficacy in animal models of RA (Table 2). However, only a few of these inhibitors have entered clinical trials for RA. All of the inhibitors listed in Table 2 selectively target the ATP-binding pocket of BTK, and the irreversible inhibitors covalently bind the cysteine residue at position 481 in the active site of the kinase domain [28–32]. The potent inhibition of BTK activity suppresses B cell activation and proliferation [28–36]. Furthermore, FcR signaling is also attenuated in the absence of BTK kinase activity [34,35,37]. Ibrutinib, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one, is an irreversible BTK inhibitor that covalently binds cysteine 481 in the active site [28,33]. The US Food and Drug Administration recently approved ibrutinib (Imbruvica) for mantle cell lymphoma in patients who received at least one prior therapy. Additionally, ibrutinib had exhibited a dose-dependent therapeutic effect in both the CIA and CAIA animal models of RA [28,33,37]. Oral treatment of ibrutinib (12.5 mg/kg) in mice resulted in 85–90% occupancy of BTK and had a robust effect on disease progression characterized by reduced inflammatory cytokines and inflammatory cells in the synovial fluid. Accordingly, a decrease in inflammation correlated with diminished cartilage damage, bone resorption and pannus formation [37]. Furthermore, ibrutinib demonstrated a suppressive effect on FcR- and FcR-mediated cytokine production by monocytes, macrophages and mast cells [37]. These studies indicated that BTK inhibition by ibrutinib is capable of regulating B cell and myeloid cell functions in experimental models of RA. In addition to ibrutinib, three other BTK inhibitors were evaluated in clinical trials. GDC-0834, R-N-(3-(6-(4(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7tetrahydrobenzo[b]thiophene-2-carboxamide, is a reversible ATP-competitive inhibitor that demonstrated a dosedependent inhibition of BTK phosphorylation and BCR- or CD40-induced cell proliferation [29]. In rat CIA models, oral treatment of GDC-0834 (100 mg/kg) significantly reduced (78–88%) clinical symptoms of arthritis exhibiting diminished ankle swelling, synovial inflammation, cartilage damage, and bone resorption when compared with vehicle-treated animals [29]. Phase 1 clinical studies examined the pharmacokinetics of a single-dose of GD-0834 in healthy individuals [38]. In addition to GDC-0834, phase 1 clinical trials have been initiated for HM-71224, another small-molecule BTK inhibitor [39]. However, published reports on this drug are currently not available. CC-292 (AVL-292), N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide, is similar to ibrutinib in that it is also an irreversible BTK inhibitor that forms a covalent bond with cysteine 481, thereby potently inhibiting BTK kinase activity and B cell proliferation [30]. Oral dosing of CC-292 in mouse CIA models revealed a dose-dependent inhibition of RA progression. At a dose of 30 mg/kg, a 95% reduction in clinical score and decreased inflammation, pannus formation, and cartilage and bone damage was observed [30]. In early clinical studies, healthy individuals were treated with a single 2 mg/kg oral dose of CC-292, and pharmacodynamic analysis indicated that BTK occupancy was sustained hours after the drug was undetectable in the plasma [30]. CC-292 has currently progressed into phase 2a clinical studies to evaluate its efficacy as a co-therapy with methotrexate. Currently, CC-292 is the first BTK inhibitor to be tested in patients with RA. Concluding remarks

The impact of the immune system in the pathogenesis of RA has been demonstrated with different therapies that target effector cells of the immune response. Currently, antibody treatments that deplete B cell populations or neutralize cytokines have demonstrated efficacy in the clinic. However, because of the role of multiple immune cell populations during the pathogenesis of RA, a greater therapeutic benefit could be achieved by simultaneously targeting these different effector cells. By targeting a kinase, in particular BTK, with a small-molecule inhibitor, multiple signaling pathways in different cell populations can be regulated with one drug. The challenge to designing an effective small-molecule inhibitor is maintaining potency over time while limiting off-target effects. However, the small-molecule BTK inhibitors have demonstrated selective and potent inhibition of BTK in preclinical studies, and several inhibitors have rapidly progressed towards clinical trials in patients with RA. In addition, several studies have now demonstrated the benefit of inhibiting BTK activity in models of systemic lupus erythematosus [33,40,41]. Future studies on the effectiveness in other autoimmune disorders could further broaden the uses for BTK inhibitors. Conflict of interest statement

J.A.W. and B.Y.C. are employees of Pharmacyclics, and own stocks in the company.

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Table 1. Therapies approved for RA targeting immune effectorsa Target

Approved drugs

Action

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CD20 CD80/CD86 IL-1 IL-6 TNF JAK

Antibody depletion of B cells Fusion protein inhibiting full T cell activation Recombinant IL-1 receptor antagonist Antibody blockade of IL-6 receptor Antibody neutralization of TNF Small molecule JAK inhibitor preventing cytokine production

Abbreviations: IL-1, interleukin-1, IL-6, interleukin-6.

Table 2. BTK inhibitors in development for RAa Chemical structure

Biochemical IC50

Cellular IC50

RA animal model

Irreversible

0.5 nM

Stage for RA

8 nM

CIA, CAIA, Preclinical PCA and RPA

5.9 nM

3 nM

CIA

Phase IIa

Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis.

The function and role of Bruton's tyrosine kinase (BTK) in human B cell development was demonstrated by its association with X-linked agammaglobulinem...
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