Fostamatinib Research Articles

Avatrombopag Plus Fostamatinib Combination Efficacy and Safety in Patients with Immune Thrombocytopenia

INTRODUCTION Avatrombopag (AVA) is a thrombopoietin receptor agonist (TPO-RA), approved for the treatment of immune thrombocytopenia (ITP), as second line in subjects with chronic ITP unresponsive to other treatments. Global response rate of AVA is 69% with a mean duration of 12.4 weeks in its pivotal study 1. The combination of TPO-RA plus immunosuppressive/immunomodulatory drugs could optimize treatment results in ITP, addressing different pathophysiological pathways 2. Among the most widely used immunomodulatory drugs in these circumstances are steroids, azathioprine and mycophenolate. Fostamatinib (FOS) is a splenic tyrosine kinase (SYK) inhibitor. FOS blocks the cascade of signals mediated by SYK after the activation of FcγRs, reducing macrophage activity, proliferation of B lymphocytes and production of antibodies 3. We present the experience in the combined use of AVA with fostamatinib in non-responders to said TPO-RA, an experience not reported to date. METHODS Retrospective, multicenter, international, observational, non-interventional study in patients diagnosed of primary ITP who have received treatment with AVA and FOS in combination between August 2022 and June 2023. We included patients who have not reached platelets >30x10e9/L after at least two weeks of treatment with daily 40mg of AVA, and FOS was prescribed in combination in these circumstances. Epidemiological characteristics, type of ITP, previous treatments received, starting dose, response, concomitant ITP treatment and toxicity are collected. ITP definition and response criteria are based on Provan et al 4: Response (R) as platelets 30-100x10e9/L and complete response (CR) as platelets > 100x10e9/L. Data are described in percentages for the categorical variables and in medians and ranges for the quantitative ones. RESULTS In the period of time evaluated, a total of 55 patients received treatment with AVA in Spain and Norway. The Norwegian data was acquired from the Norwegian ITP registry. In 16 of 55 patients (29%), there was no response after 2 or more weeks with AVA 280 mg weekly. In 6 of these patients, FOS was combined with AVA at a dose of 280mg weekly. Table 1 describes the characteristics of the 6 patients treated with the combination. Median time from initiation of AVA to combination with FOS was 14 days (Range: 14-21 days). The overall response of the combination was 100% (1 R, 5 CR). Median time to R was 25 days and to CR 31 days. Table 2 describes the characteristics of each patient's response. With a median follow-up from the start to last follow up of treatment in combination was 212 days (Range: 45-313 days), there was no relapse. Tapering of AVA and/or FOS was attempted in 5 patients by reducing the dose of FOS in 1 patient and the dose of AVA in 4. In patients 1 and 4, AVA was stopped, but this resulted in drop in the platelets counts. CR was achieved after reintroduction AVA in combination. With regard to toxicity, in the 6 patients treated with the combination AVA plus FOS, only two adverse events were described, both non-serious. One case of headache encountered with the use of AVA, before the initiation of FOS. The other event, was WHO grade 2 liver toxicity attributed to AVA. Hypertransaminasaemia was resolved after the interruption of avatrombopag for 6 days and reduction of AVA from 140mg to 60mg weekly. CONCLUSIONS In subjects with a lack of response to thrombopoietin analogues, the combination with immunosuppressants is an alternative to consider. The combination of avatrombopag and fostamatinib has been shown to be effective and safe, although longer series are needed to support these data. Bibliography 1. Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479-490. 2. Arai Y, Jo T, Matsui H, et al. Comparison of up-front treatments for newly diagnosed immune thrombocytopenia -a systematic review and network meta-analysis. Haematologica. 2018;103(1):163-171. 3. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. 4. Provan D, Arnold DM, Bussel JB, et al Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817

Fostamatinib or Thrombopoietin for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost

Introduction: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment starts with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT), and avatrombopag (AVA), or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness, and cost of care between fostamatinib and the TPOs were evaluated in a real-world setting. Methods: A retrospective analysis of 17 community hematology practices across the USA was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions, and corticosteroids. Multivariable logistic regression analysis was used to compare PLT-related endpoints between agents. Results: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127, and 44 patients who received FOS, ELT, ROM, or AVA, respectively. At month six, there were no significant differences between FOS and the TPOs in terms of the proportion of patients with the PLT count being ≥30 × 103/μL, ≥50 × 103/μL as well as the proportion of patients whose PLT levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7%, and 11.4% in the ELT, ROM, and AVA groups. The mean cost per patient with FOS was $99,209 (95% CI: $59,595–$115,074), compared to $92,426 (95% CI: $68,331–$115,519), $108,482 (95% CI: $84,782–$132,182), and $131,050 (95% CI: $83,327–$179,897) for ELT, ROM, or AVA, respectively. Conclusions: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs, and cost effectiveness.

RWD137 A Real-World Comparative Effectiveness Analysis of Fostamatinib Vs. Thrombopoietic Receptor Agonists (TPOS) for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients

Chronic immune thrombocytopenia purpura (ITP) is an acquired autoimmune disease characterized by antibody-induced platelet (PLT) destruction, leading to a reduction in the number of circulating PLTs. Initial treatment is with corticosteroids. In patients who become resistant to corticosteroids, the TPOs, consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety and effectiveness between fostamatinib vs. the TPOs was evaluated in a real-world setting.

Characterisation of Platelet Sensitivity in Severe COVID-19

Background: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterised by a hyperinflammatory and prothrombotic state. In the most severe cases, patients can develop lung complications such as pneumonitis and acute respiratory distress syndrome, frequently complicated by venous and arterial thrombosis. Recent studies suggest that platelets play a role as immune mediators, and may therefore contribute to the development of hyperinflammation and thrombosis in severe COVID-19 patients. The expression and signalling of Glycoprotein VI on platelets are dependent on its association and cross-linking with the dimeric Fc receptor γ-chain, which, upon platelet activation, leads to a signalling cascade involving the Spleen Tyrosine Kinase (SYK). Fostamatinib, a potent SYK inhibitor, has been approved for treatment of Immune Thrombocytopenia (ITP), and has been implicated in abrogating thrombosis by mitigating SYK signalling in platelets. We have recently shown that SYK inhibition can abrogate the thrombosis caused by cross-linking of COVID-19 antibodies. In this study, we assessed platelet reactivity using the Platelet Phenomic Analysis (PPAnalysis), which identifies platelet sensitivity and functional response as independent measures of platelet reactivity by flow cytometry. We hypothesised that platelets in patients with severe COVID-19 are hypersensitive to platelet agonists, in particular to the collagen-related peptide agonist, which involves the SYK pathway of platelet activation. Methods: Patients with COVID-19 pneumonia, recruited to the Multi-Arm Trial of Inflammatory Signal inhibitors for COVID-19 (MATIS) clinical trial - an interventional study assessing the impact of Fostamatinib (FOS) or Ruxolitinib (RUX) against Standard of Care (SOC) to prevent escalation of COVID-19 from moderate (WHO grades 3 and 4) to severe (WHO grade 5) - were included in this study, REC reference 20/HRA/2618. Samples were collected in citrated vacutainers, taken at day 0, before starting study medication or SOC, and at days 7, 14 and 28, where possible. Samples were processed immediately to obtain platelet-rich plasma (PRP). PRP was labelled with fluorescein isothiocyanate (FITC)-conjugated anti-fibrinogen and PE-Cy5-conjugated P-Selectin antibodies, and stimulated with increasing concentrations of the platelet agonists, adenosine diphosphate (ADP; 0.03-30 µM), collagen-related peptide (CRP; 0.003-3 µg/mL), and thrombin receptor activator peptide 6 (TRAP-6; 0.05-15 µM). Changes in platelet sensitivity, measured as LogEC50, were analysed using R. Results: 40 of 182 patients recruited into MATIS were included. A total of 50 COVID-19 samples (24 at day 0, 14 at day 7, 2 at day 14, and 10 at day 28) and 59 healthy control samples were processed using PPAnalysis. The 24 samples taken at day 0 showed extensive variability in platelet sensitivities between the responses to 3 agonists, with outliers both above and below the 95% centile of controls: 0-4% (P-Selectin response) and 13-42% (fibrinogen response) of patients displayed higher platelet sensitivity (below the 95% centile for controls), and 4-42% (P-Selectin response) and 8-16% (fibrinogen response) had lower sensitivity (above the 95% centile for controls), (Figure 1). Of the 9 patients with samples also taken at day 7, no patients showed an increase in platelet sensitivity from the P-Selectin response to all agonists. 5 patients showed reduced sensitivity. 2 patients in this cohort required non-invasive ventilation (NIV). Conversely, fibrinogen response to all agonists showed increased sensitivity at day 7 in 6 patients, with 1 patient requiring NIV, and reduced sensitivity was observed in 2 patients, both requiring NIV (Figure 2). Conclusions: Patients with severe COVID-19 display a large variability in platelet function, with either higher or lower platelet sensitivity to the agonists at day 0 when compared to controls. This implicates a role for aberrant platelet reactivity in COVID-19 and its associated prothrombotic state, and could contribute to the morbidity and mortality of patients. Interpretation of day 7 results at present is limited due to small numbers. However, it does show utility of the PPAnalysis, as a useful tool in the stratification of different patient cohorts, and in studying the associations between platelet function and disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A NF-κB-Based High-Throughput Screening for Immune Adjuvants and Inhibitors.

The nuclear factor-κB (NF-κB) family is crucial for regulating immune and inflammatory responses. The activation of the immune cell signaling pathway usually activates NF-κB, causing a protective immune response. NF-κB can also cause excessive inflammatory responses by activating a cascade reaction of pro-inflammatory mediators such as cytokines. In this study, we used an NF-κB luciferase reporter gene system. Out of more than 800 compounds screened, four NF-κB agonists were identified with strong activity at nontoxic concentrations. Subsequently, the adjuvant effect was verified on mouse bone marrow-derived dendritic cells (BMDCs) and macrophages RAW264.7. It was found that fostamatinib (R788) disodium increased the production of IL-6, IL-12p40, and TNF-α, indicating that R788 disodium could induce the maturation of antigen-presenting cells (APCs). In addition, three compounds were screened to significantly inhibit NF-κB at nontoxic doses, including dehydrocostus lactone (DHL)-a known NF-κB inhibitor. The results showed that DHL significantly reduced the release of LPS-induced inflammatory cytokines (including TNF-α, IL-6, and IL-12). Our findings indicate that the NF-κB-based high-throughput screening can be used to discover potential immune adjuvants and anti-inflammatory molecules.

Evaluating fostamatinib disodium as a treatment option for immune thrombocytopenia in adult patients

ABSTRACT Introduction Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by increased platelet destruction and decreased platelet production, leading to thrombocytopenia with or without bleeding manifestations. The majority of patients experiencing treatment need will eventually need secondary treatment following first-line therapy with steroids. In 2018, the oral spleen tyrosine kinase inhibitor fostamatinib received US Food and Drug Administration approval for ITP patients with an insufficient response to a previous treatment. Areas covered This review outlines pharmacological characteristics of fostamatinib and provides an overview of its efficacy and safety results in phase II and III trials, followed by the expert opinion of the authors. Expert opinion Increasing knowledge on the role of different players and mechanisms in the pathophysiology of autoimmune disorders, in general, and of ITP, in particular, has led to the development of several new treatment options, as illustrated by the introduction of fostamatinib in the treatment of ITP. However, lacking direct comparison with other recent treatment options (in particular, thrombopoietin receptor agonists), its use should be evaluated critically taking into account the unique toxicity and potential drug-drug interaction profile.

Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.

Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the β-hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.

Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles

Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis. This allows for prediction of functions and drug target of a novel drug candidate based on profiles obtained in this study. Results from the study showed that the JAK inhibitors tofacitinib and ruxolitinib formed a robust cluster and were found to have a distinct cytokine profile compared to the other drugs. Another robust cluster included the calcineurin inhibitors cyclosporine A and tacrolimus and the protein kinase inhibitors fostamatinib disodium and sotrastaurin acetate, which caused a strong overall inhibition of the cytokine production. The results of this methodology indicate that cytokine profiles can be used to provide a fingerprint-like identification of a drug as a tool to benchmark novel drugs and to improve descriptions of mode of action.

Fostamatinib for persistent/chronic adult immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by phagocytosis and destruction of autoantibody-coated platelets via spleen tyrosine kinase (Syk)-mediated signal transduction in macrophages. Effectiveness of existing therapies varies, and even leading treatments (e.g., IVIg, splenectomy, rituximab, thrombopoietic agents) do not provide optimal management for a substantial number of patients with chronic ITP. Fostamatinib disodium is an orally-bioavailable investigational agent being developed for treatment of primary persistent/chronic adult ITP. Fostamatinib inhibits FcR-triggered, Syk-dependent cytoskeletal rearrangement during phagocytosis. Promising findings have been described in several autoimmune diseases, including rheumatoid arthritis, and sustained responses with manageable adverse events observed with ongoing treatment in patients with heavily treated chronic ITP. Fostamatinib represents an active therapy targeting a previously unexplored mechanism of ITP pathogenesis.

Real-Time Monitoring and Control of Critical Process Impurities during the Manufacture of Fostamatinib Disodium

Process analytical technology (PAT) was used to probe, monitor, and control the formation of process impurities during the synthesis of a pharmaceutical intermediate at 600 kg input scale. An accurate determination of end of reaction (EoR) was vital in limiting side-products, and a novel inline UV/vis-based approach was used where more traditional EoR techniques had failed.

THU0097 Systematic review of the safety of protein kinase inhibitors in clinical trials in rheumatoid arthritis

BackgroundThe safety profile of the protein kinase inhibitors (PKI) in trials for Rheumatoid Arthritis (RA) is unknownObjectivesTo describe the safety profile of PKI in trials for RA.MethodsSystematic review of all...

Attacking MALT1 for ABC-DLBCL therapy

Diffuse large B-cell lymphoma (DLBCL) comprises the largest group of non-Hodgkin lymphoma (NHL). DLBCL can be classified according to their cellular origin and patients with the activated B-cell (ABC) subtype have an inferior prognosis relative to those with the germinal center B-cell (GCB) subtype. Constitutive anti-apoptotic NF-κB signaling is a hallmark of ABC-DLBCL. NF-κB activation is caused by chronic active B-cell receptor (BCR) signaling or constitutive MYD88 signaling. Oncogenic mutations that contribute to pathogenesis of ABC-DLBCL tumors have been identified in critical components of both pathways (Figure ​(Figure1)1) [1]. Figure 1 Oncogenic mechanisms and target directed therapeutic approaches in ABC-DLBCL Target directed approaches for ABC-DLBCL therapy have largely focused on the inhibition of upstream protein kinase [2]. Chronic BCR signaling engages the adaptors CD79A and CD79B in a Syk-dependent mechanism. Syk is constitutively active in many B-cell lymphomas and a clinical phase I/II trial using the Syk inhibitor fostamatinib disodium (FosD, AstraZeneca) shows some response also in DLBCL patients. However, most oncogenic mutations in ABC-DLBCL occur further downstream revealing that Syk may not be an optimal target. Downstream of CD79A/B, Btk and PKCβ bridge proximal BCR signaling events to the CARMA1 (CARD11)-BCL10-MALT1 (CBM) complex. Over 20% of ABC-DLBCL tumors carry oncogenic mutations in CD79A/B. Indeed, the irreversible Btk inhibitor ibrutinib (PCI-32765, Pharamcyclics) and the panPKC inhibitor sotrastaurin (STN) are inhibiting the outgrowth of CD79 mutant ABC-DLBCL in preclinical models [3, 4]. Furthermore, positive clinical responses in a phase II trial were reported in relapsed/refractory DLBCL with the selective PKCβ inhibitor enzastarin (LY317615, Eli Lilly) [5]. However, none of these potential drugs is able to target ABC-DLBCL tumors with lesions downstream of PKCβ or in parallel pathways, such as CARMA1 of MYD88, respectively. Downstream of PKCβ the CBM subunit MALT1 has attracted great attention as a potential therapeutic target [6]. MALT1 serves a dual role in NF-κB signaling in response to antigen receptor stimulation. MALT1 is an adaptor that recruits and activates the IκB kinase (IKK) complex, the gatekeeper of canonical NF-κB. In addition, MALT1 is a paracaspase with a caspase-like proteolytic activity that is required for full NF-κB signaling and survival of ABC-DLBCL cells. MALT1 cleaves and thereby inactivates negative regulators of canonical NF-κB, such as the tumor suppressor A20 and the NF-κB subunit RelB which both counteract pro-survival functions of canonical IKK/NF-κB signaling. Two classes of MALT1 inhibitors have now been identified that effectively and selectively inhibit the growth of ABC- but not GCB-DLBCL in vitro and in vivo [7, 8]. Interestingly, the compounds are inhibiting MALT1 by two very different mechanisms. Fontan et al have identified a structurally new small molecule inhibitor (MI-2) that is covalently modifying catalytic center of MALT1 [7]. MI-2 was tolerated in mice at the effective dose without obvious signs of toxicity. Usually, irreversible inhibitors require optimal pharmacokinetic properties for clinical development, but recent advances for instance on the irreversible Btk inhibitor ibrutinib reveal that a clinical use may be possible. In a parallel study, we have identified the phenothiazines-derivatives (PD) thioridazine, mepazine and promazine as reversible MALT1 inhibitors [8]. PD are not targeting the active site of MALT1, but exhibit a non-competitive, allosteric mode of action. Mepazine, thioridazine and promazine have a long medical history as antipsychotics and sedatives drugs used for the treatment of psychiatric disorders. Well-established toxicokinetics and pharmacokinetics suggest that targeting MALT1 for cancer therapy by this class of compounds may be safe and feasible. Further, medicinal chemistry could be used to generate novel PD that are more potent MALT1 inhibitors, while reducing their neurological effects. Taken together, both studies demonstrate that MALT1 inhibition is a promising strategy for the treatment of ABC-DLBCL. In fact, targeting MALT1 may possess some advantages over the inhibition of upstream protein kinases. MALT1 inhibition also affects survival of CARMA1 mutant ABC-DLBCL. Further, with an occurrence of 29% the MYD88 mutation L265P is the most frequent oncogenic mutation in ABC-DLBCL. 65% of the MYD88-mutant ABC-DLBCL tumors carry additional mutations in CARMA1 or CD79A/B and MALT1 inhibitors are toxic to ABC-DLBCL with aberrant activation of both pathways [7, 8]. Thus, MALT1 inhibition indeed holds great promises for the treatment of the majority of ABC-DLBCL. Research on ABC-DLBCL provides a paradigm for the power of using advanced diagnostic tools (e.g. gene expression profiling and genome sequencing) to classify lymphoma entities and to identify specific oncogenic lesions. In parallel the generation of target directed therapeutics will promote the development of more personalized treatment protocols. Because of the various oncogenic lesions and the possibilities of drug resistances, there cannot be enough ‘smart’ drugs for ABC-DLBCL therapy. In the future, combinatorial treatment protocols may certainly enhance anti-tumor efficacy of the single agents that are currently in preclinical and/or clinical development.

Highly Specific Inhibitor for Syk Induces Chronic Lymphocytic Leukemia Cell Apoptosis,

Abstract 3875The antibodies expressed by CLL cells are highly selected, implicating a role for antigen in the pathogenesis of this disease. The B-cell receptor (BCR) for antigen may become engaged by microbial or self-antigens to induce activation of downstream adapter/signaling molecules. This, either alone or in concert with activation of other receptors, can induce CLL-cell expression of genes encoding proteins involved in cell survival or proliferation, e.g. c-MYC, potentially enhancing the tendency for disease progression. Our prior studies found that ZAP-70 in CLL cells enhanced BCR signaling, which might account for the relatively aggressive clinical behavior of patients who have CLL cells that express this protein. Although transduction of ZAP-70-negative CLL cells with vectors encoding ZAP-70 enhanced BCR signaling, we found this effect did not require an active ZAP-70 kinase domain. Instead ZAP-70 apparently acts as an adaptor protein that facilitates recruitment/activation of Syk, which in turn serves as the principal kinase responsible for initiating BCR signaling. As such, inhibitors of Syk could be useful therapeutically, as indicated by a clinical study demonstrating that one Syk inhibitor, fostamatinib disodium (R406/R788), has activity in the treatment of patients with this disease. However, at concentrations of fostamatinib required for clinical activity this drug also can inhibit several kinases other than Syk, including Lck, JAK, and Flt3, making it difficult to conclude that the activity of this drug solely was due to its capacity to inhibit Syk. Coffey and colleagues developed a series of highly potent and selective small molecule Syk inhibitors. One of these inhibitors, PRT060318, is a highly specific inhibitor of Syk that is more selective than fostamatinib. We examined whether this specific Syk inhibitor could affect BCR signaling and CLL-cell survival. We evaluated the effect of PRT060318 on BCR signaling by calcium influx induced through surface IgM ligation. We found that PRT060318 inhibited IgM induced BCR signaling with an IC50∼200nM. CLL cells that express ZAP-70 (n=13) or that lacked expression of this kinase (n=10) were treated with 5 μM PRT060318 and examined for cell viability 24 hours later. The average viability of CLL cells that expressed ZAP-70 was significantly lower (70.4 ± 16.1) than that of CLL cells that lacked expression of ZAP-70 (93.6 ± 9.0) (P<0.01), revealing that PRT060318 had greater activity in inducing apoptosis of CLL cells that had high-level expression of ZAP-70. Moreover, Syk inhibition abrogated the capacity of surface IgM ligation to enhance CLL cell survival, the viability of CLL cells treated with PRT060318 and anti-μ (38.8 ± 5.4) was significantly lower than CLL cells with anti-μ stimulation after 48 hours (64.0 ± 6.0) (P<0.01, n=3). PRT060318 also inhibited the capacity of marrow stromal cells to support the survival of CLL cells in vitro (35.3 ± 5.2 vs. 61.8 ± 4.7) (P<0.01, n=4). These results indicate that selective Syk inhibition by PRT060318 can induce apoptosis in CLL cells, has greater activity against CLL cells that express ZAP-70 and might be most active in treating patients with aggressive disease characteristics. Disclosures:Coffey:Portola Pharmaceuticals Inc.: Employment. Carson:Wintherix: Equity Ownership. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Research Funding; Amgen: Research Funding.

Fostamatinib boosts QOL in RA

Fostamatinib boosts QOL in RA

The Syk kinase as a therapeutic target in leukemia and lymphoma

Introduction: The B-cell receptor (BCR) delivers antigen-dependent and -independent signals that have been implicated in the pathogenesis of several common B-cell malignancies. Agents that can efficiently block BCR signaling have recently been developed and are currently being evaluated as novel targeted therapies. Among these, agents that inhibit the Syk kinase appear particularly promising in preclinical and early clinical studies.Areas covered: The manuscript provides an overview of recent findings that implicate Syk and the BCR signaling pathway in the pathogenesis of several common lymphoid malignancies. It outlines preclinical and early clinical experiences with the Syk inhibitor fostamatinib disodium (R788) and discusses various options for further clinical development of this compound.Expert opinion: Inhibitors of Syk or other components of the BCR signaling pathway are emerging as an exciting novel class of agents for the treatment of common B-cell malignancies. Future efforts should focus on defining the disease entities that are most likely to benefit from these agents, although considerable evidence is already available to pursue such studies in patients with chronic lymphocytic leukemia. Combinations with chemo-immunotherapy, treatment of early-stage disease and consolidation therapy should all be explored and could lead to the development of novel therapeutic approaches with improved efficacy, tolerability and toxicity profiles.

An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: A three‐month randomized, placebo‐controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies. A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score. The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level. Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.

Fostamatinib disodium

The non-receptor tyrosine kinase Syk has a diverse range of biological functions, including a critical role in the intracellular signalling cascade for the surface immunoglobulin receptor on B lymphocytes, and the Fc receptor expressed on numerous immune effector cells. It is therefore seen as a potential therapeutic target in a variety of conditions, including autoimmune, allergic and malignant diseases. Fostamatinib disodium is the orally bioavailable prodrug of R406, a relatively selective small molecule inhibitor of Syk, that has accordingly shown activity in numerous cell types in vitro, and efficacy in a remarkable range of animal models in vivo, including rodent models of asthma, inflammatory arthritis, lupus, glomerulonephritis, diabetes and lymphoma. Success in these models has translated to phase II clinical trials in autoimmune thrombocytopenia, lymphoma and, most notably, rheumatoid arthritis, in which larger phase III trials are currently in progress. Whilst the diverse biological functions of Syk, coupled to the potential off-target effects of this kinase inhibitor are a source of possible toxicity, the available data thus far augurs well for future clinical use of Fostamatinib in a wide range of human diseases.

Safety and Efficacy of the Newer Biological Therapeutics in the Treatment of Rheumatoid Arthritis

Biological therapies have been a major advance in RA treatment. However, remission or response is not achieved in all patients. Therefore, new drugs seem necessary. Most recent trials have focused in the development of three different groups of molecules: those against commercialized targets but minimizing side effects or improving administration, others molecules against new targets, and a third group including small molecules. Some of them have been shown to be clinically efficacious and safe in RA patients, including: two new anti-TNFα therapies (golimumab and certolizumab pegol), three anti-CD (ocrelizumab, ofatumumab and a SMIP), subcutaneous abatacept, anti-IL17 therapy, tasocitinib and fostamatinib disodium. Therefore, a wide spectrum of new RA therapeutics are promising, but more studies are necessary to confirm these results.

The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling

AbstractInhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a promising therapeutic approach in chronic lymphocytic leukemia (CLL), but experimental in vivo evidence to support this view is still lacking. We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the Eμ-TCL1 transgenic mouse model of CLL. Similarly to human CLL, these leukemias express stereotyped BCRs that react with autoantigens exposed on the surface of senescent or apoptotic cells, suggesting that they are antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that R788 functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of R788 was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed. Collectively, these data provide further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease.