Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors. Immune thrombocytopenia (ITP) is an autoimmune disease that usually happens when your immune system mistakenly attacks and destroys platelets, which are cells that help blood to clot. Individuals with ITP can experience easy or excessive bruising and bleeding. Scientists have identified that an enzyme called spleen tyrosine kinase (SYK) is involved in numerous biological processes that are associated with the immune system response, inflammation, and some types of cancer in humans. Therefore, it has become a target for new drugs which inhibit the action of SYK. In this review article, the authors provide a summary of the biological properties and actions of SYK and its involvement in various diseases, discuss information about drugs that have been developed as SYK inhibitors for the treatment of ITP, and consider other potential uses for drugs that inhibit SYK. Although several drugs are being developed, the only SYK inhibitor that is currently available for the treatment of ITP is a drug called fostamatinib. In patients with ITP, including those who no longer respond to other treatments, fostamatinib has been shown to improve platelet counts and reduce bleeding events. Researchers are also currently investigating the use of drugs that inhibit SYK, including fostamatinib, for the potential treatment of other diseases associated with inflammation (e.g. rheumatoid arthritis, COVID-19), autoimmunity (e.g. warm autoimmune hemolytic anemia), and blood cancers (e.g. lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia). eng

Paradigm shift in ITP treatment patterns in the era of the COVID-19 pandemic -opportunity to study real world outcomes from an established platform: Update from UK Adult ITP registry

Background: The SARS-CoV- 2 pandemic has led to changes in the way we manage autoimmune disease such as immune thrombocytopenia (ITP). Immunosuppression is a risk factor for severe COVID-19 and also leads to reduced vaccine responses. Medical therapy for ITP is broadly divided into immunosuppressive or that which stimulates megakaryopoeisis. Aim(s): To assess changes in medical therapy for ITP during the SARS-CoV- 2 pandemic using data from the UK adult ITP registry Methods: The UK registry of primary adult ITP (https://www.qmul. ac.uk/itpre gistr y/), one of the largest internationally, produces annual treatment reports on therapy use, trends and to identify cohorts for study. We reviewed data from annual reports to assess treatment changes. Result(s): At the time of analysis, there were 4503 patients in the registry: 224 diagnosed with ITP in 2019, 105 in 2020 and 97 in 2021 (median age 57y, 59y and 55y respectively). Table 1 shows changes in treatment 2019-2021. Most patients still received steroids as part of the treatment for ITP acutely. IVIG use remained static between 2019 and 2021. For diagnoses made between 2019 and 2021 all patients received at least 1 treatment. Immunosuppressive therapy use reduced from pre-2019 levels (data not tabulated) where almost 23% patients received rituximab and 18% MMF to 0% and 3% respectively by 2021. Use of TPO-RA increased, from 33% in 2019 to 43% in 2021. Median time to starting TPO-RA was 3.76 months (IQR 1.317,9.225) in 2019 reducing to 0.985 months (IQR 0.58,1.465) in 2021. Platelet response criteria will undergo analysis once additional data entry has taken place. Conclusion(s): Steroids continue to be used acutely for most ITP patients but TPO-RA are being used ahead of other immunosuppressive therapy in line with interim NHSE pandemic policy. Most patients entered received at least one line of treatment -likely reflecting those frequently attending sites to access healthcare.

Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.

Ultrasound characteristics, serum biochemistry and outcome of ectopic pregnancies presenting during COVID-19 pandemic.

OBJECTIVE: To describe and compare the characteristics of ectopic pregnancies (EPs) in the year prior to vs during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This was a retrospective analysis of women diagnosed with an EP on transvaginal sonography conducted at a center in London, UK, providing early-pregnancy assessment, between 1 January 2019 and 31 December 2020. Women were identified via the Astraia ultrasound reporting system using coded and non-coded outcomes of EP or pregnancy outside the uterine cavity. Data related to predefined outcomes were collected using Astraia and Cerner electronic reporting systems. Main outcome measures included clinical, ultrasound and biochemical features of EP, in addition to reported complications and management. RESULTS: There were 22 683 consultations over the 2-year period. Following consultation, a similar number and proportion of EPs were diagnosed in 2019 (141/12 657 (1%)) and 2020 (134/10 026 (1%)). Both cohorts were comparable in age, ethnicity, weight and method of conception. Gestational age at the first transvaginal sonography scan and at diagnosis were similar, and no difference in location, size or morphology of EP was found between the two cohorts. Serum human chorionic gonadotropin (hCG) levels at the time of EP diagnosis were higher in 2020 than in 2019 (1005 IU/L vs 665 IU/L; P = 0.03). The proportions of women according to type of final EP management were similar, but the rate of failed first-line management was higher during vs before the pandemic (16% vs 6%; P = 0.01). The rates of blood detected in the pelvis (hemoperitoneum) on ultrasound (23% vs 26%; P = 0.58) and of ruptured EP confirmed surgically (9% vs 3%; P = 0.07) were similar in 2019 vs 2020. CONCLUSIONS: No difference was observed in the location, size, morphology or gestational age at the first ultrasound examination or at diagnosis of EP between women diagnosed before vs during the COVID-19 pandemic. Complication rates and final management strategy were also unchanged. However, hCG levels and the failure rate of first-line conservative management measures were higher during the pandemic. Our findings suggest that women continued to access appropriate care for EP during the COVID-19 pandemic, with no evidence of diagnostic delay or an increase in adverse outcome in our population. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

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

Introduction: Severe COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. This hyperinflammatory syndrome is reflected by the elevation of several inflammatory molecules, such as C-reactive protein (CRP), ferritin, IL-6, troponin, and D-dimer. In a subset of patients, early intervention with signal inhibitors may treat the Covid-19 hyperinflammatory syndrome before the development of acute lung injury and organ failure. We present a summary of a study protocol for a randomised controlled, multi-arm trial with two novel inflammatory signal inhibitors;Ruxolitinib (RUX) and Fostamatinib (FOS) for the treatment of Covid-19 pneumonia. RUX is an oral Janus Associated Kinase (JAK1/JAK2) inhibitor approved for the treatment of splenomegaly, myelofibrosis and polycythaemia vera. Inhibition of STAT3 downregulates IL-6 and IL-23, which are important for the inflammatory effects of Th17 cells. Further, JAK2 inhibition has been shown to reduce levels of TNFa and CRP, as well as reducing viral cellular entry and assembly. FOS is an oral spleen tyrosine kinase (SYK) inhibitor approved for the treatment of chronic immune thrombocytopenia. Studies of severe acute respiratory distress syndrome (ARDS) suggest that the pathogenesis relies on a series of SYK events leading to cytokine and chemokine release. FOS acts by inhibiting SYK activity, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Primary Objective: The primary objective of MATIS is to determine the efficacy of RUX or FOS compared to standard of care (SOC) to reduce the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia at 14 days from baseline. Secondary objectives at 7, 14 and 28 days: - Determine the efficacy of RUX or FOS to reduce mortality - Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO - Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation - Determine the efficacy of RUX or FOS to reduce the proportion of patients suffering significant oxygen desaturation - Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy - Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism COVID-19 pneumonia - Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a modified WHO Ordinal Scale] - Determine the efficacy of RUX or FOS to reduce the level of inflammatory biomarkers - Determine the efficacy of RUX or FOS to reduce the duration of hospital admission - Evaluate the safety of RUX and FOS for COVID-19 pneumonia Study Design: This is a multi-arm, two-stage, open-label, randomised (1:1:1) controlled trial. Participants will be recruited during hospitalisation for COVID-19 in multiple centres in the UK. Eligible participants (table 1) are randomised to one of the three interventions (RUX, FOS, SOC) by a central web-based randomisation service. This uses randomisation sequences with random block sizes, stratified by age (<65 and ≥65 years) and site. The treatment duration is 14 days from baseline. Patients receiving RUX will be administered 10mg BD for Day 1-7 and 5mg BD for Day 8-14. FOS will be administered as 150mg BD day 1-7 and 100mg BD day 8-14. Participants receive follow up assessments on days 7, 14 and 28 after the first dose. Outcomes: Primary endpoints will be assessed with a pairwise comparison (FOS vs SOC and RUX vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a modified WHO COVID-19 Ordinal Score 5, comprising the following indicators of disease severity: - Death - Requirement for invasive ventilation - Requirement for non-invasive ventilation including CPAP or high flow oxygen - O2 saturation < 90% on 60% inspired oxygen Samples size: In stage 1 of this multi-arm study, 171 parti ipants will be randomised (57 per arm). Following an interim analysis, if either intervention shows a signal of efficacy, stage 2 will recruit a further 95 participants per arm (Fig 1). Trial Status: Recruitment is ongoing and commenced 2nd October 2020. Currently 127 patients are recruited and stage 1 is projected to be completed by 1st September 2021. The full protocol can be accessed via the trial's website. [Formula presented] Disclosures: Milojkovic: Novartis: Honoraria, Speakers Bureau;Incyte: Honoraria, Speakers Bureau;Bristol-Myers Squibb: Honoraria, Speakers Bureau;Pfizer: Honoraria, Speakers Bureau. Cooper: Principia and Sanofi: Consultancy;Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. OffLabel Disclosure: Fostamatanib - is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase (SYK). In the context of treating COVID-19, Fostamatanib acts by inhibiting SYK activist, blocking the production and release of cytokines induced via C-lectin receptors and Fc receptor activation, ameliorating the cytokine storm which precedes ARDS. Studies of severe acute respiratory syndrome induced by coronavirus, suggest that pathogenesis relies on a series of SYK events. SYK medicates ctuokine and chemokine release, induced by the activation of C-lectin receptors and immunoglobulin Fc receptors, resulting in neutrophil and monocyte lung ingress, sequential activation of neutrophil extracellular traps and activation of lung epithelium and multiple myeloid cell. This is followed by inflammation and tissue destruction that contribute to ARDS. Ruxolitinib - A JAK1/JAK2 inhibitor. JAK and STAT molecules are proteins that trance extracellular stimulation into intracellular signalling, leading to expression of host inflammatory cytokines and a variety of immune cells. In the context of MATIS, we use low dose ruxolitinib to treat COVID-19 by targeting key signalling pathways implicated in the hyper-inflammatory response of patients with COVID-19 infection. The mechanisms of Ruxolitinib to act in COVID-19 is through inhibition of STAT3 activation, down regulating IL-6 and IL-23, signalling important for the inflammatory effects of Th17 cells. Furthermore it leads to reductions of TNFa and CRP.

Treatment of immune thrombocytopenia (ITP) in the COVID-19 era: Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor

Background : Management of ITP became increasingly challenging during the COVID-19 pandemic. Immunosuppressive treatments increase susceptibility of patients to COVID-19. Therapies increasing the thrombotic risk are suboptimal due to coagulopathy observed with COVID-19. The need to minimize office visits to limit potential viral exposure renders intravenous administration or injections less suitable. Consequently, ITP management requires careful patientcentric consideration during the pandemic. Fostamatinib is a potent oral SYK inhibitor that abrogates SYKmediated destruction of platelets and may abrogate SYK-mediated thromboinflammation. Aims : To evaluate fostamatinib as an ITP treatment during the COVID-19 era. Methods : Review of safety, immunotoxicology, and mechanism of action and administration for fostamatinib. Results : Preclinical studies demonstrated intact innate and humoral responses to immune challenges in fostamatinib (R406) treated rodents. 1 In ITP clinical trials, the incidence of adverse events (including infections) was somewhat higher with fostamatinib vs placebo (83% vs 75%), which is consistent with the 2.4-fold increase in exposure to fostamatinib vs. placebo (29 vs. 12 patient-exposure years, respectively). No patients had opportunistic infections. The rate of thromboembolic events with fostamatinib (0.7% over 5 years) was low compared with similar studies with other ITP treatments (2.6-8.9% over 2-8 years). Office visits can be minimized due to oral administration of fostamatinib and simplified titration: fostamatinib is initiated at 100mg BID and increased to 150mg BID after 4 weeks if needed. Thrombocytosis was uncommon (1.4% over 5 years). Conclusions : Fostamatinib is an immunomodulatory treatment for ITP that may lower the risk of thrombosis. The need for office visits may be reduced due to oral administration, simplified titration, and infrequency of thrombocytosis. Fostamatinib is an appropriate option for the treatment of ITP in the COVID-19 era.

Geographic distribution of patient and physician itp treatment preferences and effect of physician caseload on treatment practices: Results from the itp world impact survey (i-wish)

American Society of Hematology 2019 guidelines for immune thrombocytopenia (ITP) recommend considering individual patient (pt) preference when selecting second-line therapy in adults with ITP. We previously reported pts' and physicians' (MDs') perspectives on ITP treatments (txs) across all countries included in the ITP World Impact Survey (I-WISh), which examined ITP's burden and impact on quality of life (QoL). A better understanding of the geographic differences in pts' and MDs' tx preferences and the effects of MD caseload may reveal areas in which additional discussion and education might be beneficial. Aims: Using I-WISh data, define the geographic distribution of pt and MD tx preferences and the effect of MDs' ITP caseload on their tx practices and attitudes. Methods: I-WISh was an exploratory, cross-sectional 30-minute survey of 1507 pts with ITP and 472 ITP-treating MDs conducted in 13 countries (Dec 2017-Aug 2018). Pts were recruited via MDs and pt advocacy groups (PAGs). A steering group of expert ITP clinicians and PAG leads developed the survey. Pts' and MDs' preferences on tx modalities were evaluated through responses to specific questions. MD caseload was defined as 'low' (≤10 pts currently treated), 'medium' (11-29), or 'high' (≥30). Differences in responses between 'low' and 'high' caseload status were considered meaningful if they differed by >10 percentage points. Results: Mean pt age was 47 years;65% were female. MDs had a mean caseload of 34 current pts with ITP;MDs with 'low', 'moderate', and 'high' caseload status had mean caseloads of 7, 19, and 70 current pts with ITP, respectively. Most pts (90%;n=1360/1507) had a preference for orally administered ITP txs (once [83%] or twice [7%] daily) over an injection;pt preference for oral ITP tx was >85% in countries excluding France (80%), Turkey (77%), and Germany (70%). MDs' (first-choice) preference for orally administered ITP txs (versus subcutaneous [SC] or intravenous [IV] tx) was broadly aligned with that of pts, and was selected by 77% of all MDs (n=365/472). There were distinct geographical differences in MDs' preferred ITP txs when pursuing a tx goal of 'sustained remission': splenectomy was the preferred tx class in Canada (70%), Colombia (48%), and the USA (36%);corticosteroids (CSs) in China (56%) and India (33%);and thrombopoietin-receptor agonists (TPO-RAs) in Egypt (70%), Turkey (57%), the UK (55%), Spain (48%), Italy (43%), France (41%), Japan (39%), and Germany (27%). For pts with persistent/chronic/recurrent ITP, MDs' first-choice preference for oral (vs SC or IV) ITP tx appeared to increase with rising caseload ('low', 'moderate', and 'high' caseload: 68%, 77%, and 87%, respectively). As MDs' caseload increased, shifts in the preferred tx class for the goal of 'sustained remission' were also seen;preference for TPORAs increased (19%→43%) whereas CSs decreased (38%→13%).TPORAs were the overall preferred tx class (Fig. 1). Summary/Conclusion: Both pts and MDs appeared to demonstrate a preference for oral ITP txs over an injection (SC/IV) option, with some geographic differences in preferences. There were also apparent shifts in MD tx preferences with changes in ITP caseload in approaching sustained clinical remission. An important limitation was question phraseology, which did not include factors such as substantial dietary restrictions for oral medications. Also, country sample sizes varied, and data were collected prior to the COVID-19 pandemic: tx preferences may have changed subsequently. Nonetheless, these findings warrant confirmation.

Treatment of immune thrombocytopenia in the covid-19 era: Fostamatinib, an oral spleen tyrosine kinase inhibitor

Background: Management of immune thrombocytopenia (ITP) has become increasingly challenging during the COVID-19 pandemic. Immunosuppressive treatments used to treat ITP can increase the susceptibility of patients to develop COVID-19. Additionally, therapies which increase the risk of thrombosis may not be optimal due to the hypercoagulable state also observed in patients with COVID-19 infection. The need to minimize office visits, to limit potential exposure to the virus, renders therapies requiring intravenous administration or injections as well as treatments requiring frequent titration less suitable. Consequently, ITP management requires careful patient-centric consideration during the pandemic. Aims: To evaluate fostamatinib as an ITP treatment during the COVID- 19 era Methods: Review of the safety data from the phase 3 studies for fostamatinib in ITP as well as titration and mode of administration. Results: Patients (n=146) in the trials had a median age of 53 years (range 20-88), a median of 5 prior ITP treatments, and 229 years of fostamatinib exposure. An increase in platelet count ≥50,000/μL was observed in 54% of patients on fostamatinib treatment. These patients maintained their response to treatment for 86% of treatment days. In the placebo-controlled phase, there was a 2.4-fold difference in duration of exposure to fostamatinib vs. placebo (29 vs. 12 patient-exposure years, respectively). Consequently, the incidence of infections with fostamatinib was somewhat higher than with placebo (27% vs. 21%). The incidence of overall adverse events was similarly higher with fostamatinib vs placebo (83% vs 75%). No patients had opportunistic infections. Office visits can be minimized due to oral administration of fostamatinib and simplified titration. Fostamatinib dosing is initiated at 100mg BID in patients and increased to 150mg BID after 4 weeks if needed. Titration visits are also minimized due to the low incidence of thrombocytosis (1.4% over 5 years). ITP patients have an increased risk of thrombotic events, which may be due to SYK-dependent platelet activation in patients with ITP.2 In the randomized fostamatinib studies, 87% of patients had at least one risk factor for thrombosis, and 58% had multiple risk factors. Over the 62-month study, one (0.7%) thrombotic event was reported: a patient with pre-existing atherosclerosis had a mild transient ischemic attack, which resolved spontaneously. This rate is lower than seen in long-term ITP clinical trials (2-8 years duration), which ranged from 2.6% to 8.9%. Summary/Conclusion: Fostamatinib is an immunomodulatory treatment that elevates platelet counts and may lower the risk of thrombosis in ITP. There is also a reduced need for office visits due to oral administration, simplified titration, and infrequency of thrombocytosis. Fostamatinib is an appropriate therapeutic option for the treatment of ITP in the COVID-19 era.

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: • Age ≥18;• Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);• failure of ≥1 prior treatment for wAIHA;• Haptoglobin <LLN (lower limit of normal) or total bilirubin >ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;• Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: • Presence of other forms of AIHA;• Uncontrolled or insufficiently controlled hypertension;• Neutrophil count <1,000/µL, • Platelet count <30,000/μL (unless patient has Evans syndrome);• Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy;duration of hemoglobin response;and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patien s have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. [Formula presented] Disclosures: Cooper: Amgen: Honoraria, Speakers Bureau;Novartis: Honoraria, Speakers Bureau. Numerof: Rigel: Current Employment, Current equity holder in publicly-traded company. Tong: Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter: Incyte: Consultancy, Honoraria;Genzyme: Consultancy, Honoraria;Immunovant: Consultancy, Honoraria;Momenta: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Dova: Consultancy, Honoraria;Merck Sharp Dohme: Consultancy, Honoraria;UCB: Consultancy, Honoraria;Up-To-Date: Consultancy, Honoraria, Patents & Royalties;Zafgen: Consultancy, Honoraria;Sanofi (Genzyme): Consultancy, Honoraria;Shionogi: Consultancy, Honoraria;Shire: Consultancy, Honoraria;Principia: Consultancy, Research Funding;Protalix Biotherapeutics: Consultancy;Shionogi: Consultancy;Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Daiichi Sankyo: Consultancy, Honoraria;Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding;Immunovant: Other: Travel Expenses, Research Funding;Caremark: Consultancy, Honoraria;CRICO: Consultancy, Honoraria;Kezar Life Sciences, Inc: Other, Research Funding;Principia Biopharma: Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Other, Research Funding;Rigel: Consultancy, Honoraria, Other, Research Funding;Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding;Protalex: Consultancy, Honoraria, Research Funding;Kyowa-Kirin: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Platelet Disorder Support Association: Consultancy, Honoraria.

ITP World Impact Survey (I-WISh) 2.0: Further Exploration of the Impact of ITP on Patients

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder defined by a platelet count < 100 × 109/L without explanation, and an increased risk of bleeding. ITP itself as well as its treatments have multifaceted, often poorly understood impacts on patients’ quality of life (QoL). These effects include impact on activities of daily living, emotional health, energy, ability to think well and clearly, and productivity in the workplace. There are limited data on which individual aspects of ITP are perceived both by patients and physicians as having the greatest impact on QoL. Understanding patients’ perspectives is vital to optimize their QoL by specifying particular areas in need of therapy. I-WISh 1.0 was an exploratory, cross-sectional survey in which 1507 patients with ITP and 472 physicians across 13 countries completed separate, but related, online surveys that included assessments of ITP signs and symptoms, impact of symptoms, and patient-physician relationships. These findings have been presented at previous ASH and EHA congresses, and manuscripts are currently in preparation. However, although I-WISh 1.0 provided considerable insights into unexplored facets of the effects of ITP, an all-too-large number of gaps in understanding still remain. In response to this, I-WISh 2.0 is currently being developed. The objectives of the I-WISh 2.0 patient and physician cross-sectional surveys include: (1) to further explore the burden of fatigue and how it affects patients' lives, including what makes it better or worse;(2) to assess the emotional impact of living with chronic ITP, especially in relation to depression;(3) to assess how treatments for ITP can impact activities of daily living (positively and negatively);(4) to further relate effects of treatment to patients' QoL;and (5) to explore how telemedicine affects healthcare delivery for patients with ITP. Furthermore, data from subsets of patients will address (6) the impact of COVID-19 in patients with ITP;and (7) special issues affecting ITP in pregnancy. A steering committee of ITP expert physicians and patient advocacy group representatives are designing and will endorse the patient and physician surveys now nearing readiness after several meetings to determine the areas of greatest need of assessment. In addition, a control group will be included. Survey launch and data collection are scheduled to commence in early Q4 2020. Patients and physicians will complete similar online surveys. Both patient and physician surveys include a screener and sections of questions related to the specific objectives of I-WISh 2.0. The surveys include updates to key topics in I-WISh 1.0 (impact of fatigue, impact on daily life, treatment of ITP, emotional impact of ITP);validated patient-reported outcome tools to measure fatigue (MFIS-5), presence and severity of depression (PHQ-9), work-related burden (WPAI), and impact on quality of life (ILQI) tools;and questions related to COVID-19, telemedicine (remote patient monitoring), and pregnancy and ITP. Patients will be recruited to I-WISh 2.0 via treating physicians and patient advocacy groups, and will be included if they are ≥ 18 years of age, diagnosed with ITP, and agree to participate. Participating physicians will be required to be actively managing patients with ITP and have a minimum caseload of 3 ITP patients currently under their care;physicians must also have a primary specialty of hematology or hematology-oncology. Approval will be sought from an independent centralized Institutional Review Board. Data analysis will be primarily descriptive and correlative in nature. Breakdown by country and geographic areas will be included. A global sample is planned from 21 countries across 6 continents, with the aim of surveying more than 2000 patients and 600 physicians. I-WISh 2.0 will be the largest observational global survey ever conducted in ITP. If accepted, preliminary data are planned to be presented at the ASH meeting. I-WISh 2.0 will build on the strengths of I-WISh 1.0, which highlighted areas requir ng further assessment and will explore aspects of ITP of great interest that were neither conclusively addressed in the first survey nor well-studied in the past. Disclosures: Ghanima:Bristol Myers Squibb:Research Funding;Principia:Honoraria, Speakers Bureau;Pfizer:Honoraria, Research Funding, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;Novartis:Honoraria, Speakers Bureau;Bayer:Research Funding.Provan:ONO Pharmaceutical:Consultancy;MedImmune:Consultancy;UCB:Consultancy;Amgen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Cooper:Amgen:Honoraria, Speakers Bureau;Novartis:Honoraria, Speakers Bureau.Matzdorff:Roche Pharma AG:Other: Family stockownership;Amgen GmbH:Consultancy, Other: Honoraria paid to institution;Grifols Deutschland GmbH:Consultancy, Other: Honoraria paid to institution;Swedish Orphan Biovitrium GmbH:Consultancy, Other: Honoraria paid to institution;UCB Biopharma SRL:Consultancy, Other: Honoraria paid to institution;Novartis Oncology:Consultancy, Other: Honoraria paid to institution.Santoro:Novartis:Honoraria, Speakers Bureau;Takeda:Honoraria, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;Novo Nordisk:Honoraria, Speakers Bureau;Bayer:Honoraria, Speakers Bureau;CSL Behring:Honoraria, Speakers Bureau;Roche:Honoraria, Speakers Bureau;Sobi:Honoraria, Speakers Bureau.Morgan:Sobi:Other: Consultancy fees paid to the ITP Support Association;UCB:Other: Consultancy fees paid to the ITP Support Association;Novartis:Other: Consultancy fees paid to the ITP Support Association.Kruse:Principia:Other: Grant paid to PDSA;Pfizer:Other: Grant and consultancy fee, all paid to PDSA;Argenx:Other: Grant paid to PDSA;Novartis:Other: PDSA received payment for recruiting patients to I-WISh and for promoting I-WISh on the globalitp.org website. Grant and consultancy fee, all paid to PDSA outside the submitted work;CSL Behring:Other: Grant paid to PDSA;UCB:Other: Grant and consultancy fee, all paid to PDSA;Rigel:Other: Grant paid to PDSA;Amgen:Other: Grant and honorarium, all paid to PDSA.Zaja:Janssen-Cilag:Honoraria, Speakers Bureau;Takeda:Honoraria, Speakers Bureau;Bristol Myers Squibb:Honoraria, Speakers Bureau;Grifols:Honoraria, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;AbbVie:Honoraria, Speakers Bureau;Kyowa Kirin:Honoraria, Speakers Bureau;Mundipharma:Honoraria, Speakers Bureau;Novartis:Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau;Roche:Honoraria, Speakers Bureau.Lahav:Novartis:Other: Consultancy fees paid to the Israeli ITP Support Association.Tomiyama:Novartis:Consultancy, Honoraria;Kyowa Kirin:Honoraria;Sysmex:Consultancy.Winograd:Novartis:Other: Consultancy fees paid to the Israeli ITP Support Association.Lovrencic:UCB:Other: Consultancy fees paid to AIPIT;Novartis:Other: Honorarium paid to AIPIT.Bailey:Adelphi Real World:Current Employment;Novartis:Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis.Haenig:Novartis:Current Employment.Bussel:Novartis:Consultancy;Argenx:Consultancy;UCB:Consultancy;CSL Behring:Consultancy;Shionogi:Consultancy;Regeneron:Consultancy;3SBios:Consultancy;Dova:Consultancy;Principia:Consultancy;Rigel:Consultancy;Momenta:Consultancy;RallyBio:Consultancy;Amgen:Consultancy.

A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

Corticosteriods (CSs) remain the standard of care for immune thrombocytopenia (ITP);however, many patients relapse after initial treatment, and long-term CS use is associated with considerable toxicity and tolerability issues (Provan et al. Blood 2010). Clinically, there is a need for a less toxic regimen that will provide sustained response. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) currently approved in the United States for the treatment of ITP in patients who have had an insufficient response to CSs, immunoglobulins, or splenectomy. Limited evidence from retrospective studies and the phase II ESTIT study (NCT02402998) suggests that earlier use of TPO-RAs after ITP diagnosis may allow a larger proportion of patients to achieve sustained responses after tapering off drug (Červinek et al. Int J Hematol 2015;Gonzalez-Lopez et al. Am J Hematol 2015;Newland et al. Br J Haematol 2016;Lucchini, et al. Haematologica 2019). TAPER (NCT03524612) is an ongoing phase II, open-label, prospective, single-arm study assessing sustained response off treatment in adult patients with ITP receiving eltrombopag, who had relapsed or failed to respond to initial CS treatment. Eligible patients are adults (≥ 18 years old) with ITP who are not responsive to or are in relapse after first-line CS therapy ± immunoglobulins used as rescue therapy, with platelet counts < 30×109/L, and assessed as needing treatment. Patients receive a starting dose of 50 mg eltrombopag QD (East/Southeast Asian ancestry: 25 mg QD;Japanese patients treated in Japan: 12.5 mg QD per approved starting dose in the Japanese prescribing information). The primary endpoint is the number (%) of patients with sustained responses off treatment by Month 12. Sustained response is defined as a complete response (platelet count ≥ 100×109/L) with platelet counts ≥ 70×109/L maintained for 2 months, followed by dose reduction and treatment discontinuation while maintaining platelet counts ≥ 30×109/L, without bleeding or rescue therapy, until Month 12. Platelet counts are assessed weekly during the first 8 weeks of treatment, and biweekly thereafter, depending on patient response. Rescue therapy is permitted within the first 14 days of study treatment and does not preclude patients from reaching the primary endpoint criteria, if successful discontinuation of eltrombopag is reached and maintained at Month 12. The proportion of patients who reach the primary endpoint will be summarized with the 95% confidence interval (Clopper-Pearson method). A binomial test for one proportion, H0: P = 0.15 vs. H1: P > 0.15 will be performed to test if the proportion of remission patients is greater than 15%, using a target alpha level of 0.05. Patients who meet the primary endpoint at 12 months will be followed up for an additional 12 months.Patients who relapse between Months 12 and 24 will be offered retreatment with eltrombopag until the end of Month 24. Secondary endpoints will include measures of quality of life, and exploratory endpoints will include biomarker assessments of immunomodulation. Here, we report an update on trial recruitment and patient baseline characteristic data from an early data cut (November 15, 2019). An estimated 101 patients across 50 sites will be enrolled;47 sites are currently active and 3 are pending site initiation visits. As of November 15, 2019, 66 patients had been screened, 53 of whom had been enrolled and had undergone treatment. Of the patients enrolled, 60.4% were female and the mean (± standard deviation) age was 49.4 (± 19.0) years. The majority of patients were White (88.7%). On June 24, 2020, patients from 15 countries worldwide were committed to screening (Figure 1);the number of patients screened had risen to 98, with 82 patients enrolled. The planned study timeline has been disrupted due to the COVID-19 pandemic. Enrollment is expected to complete in November 2020, with final results expected in 2023. Conclusion: The purpose of this trial is to assess sustained response off treatment following eltrombopag therap in patients with ITP who failed to respond to or have relapsed after initial treatment with steroids. The data generated by TAPER will provide insights into whether eltrombopag could be a viable treatment option after first-line steroid treatment. If this were confirmed, the earlier use of eltrombopag could have the potential to reduce the toxicity from repeated steroid exposure in patients with ITP. [Formula presented] Disclosures: Cooper: Novartis: Honoraria, Speakers Bureau;Amgen: Honoraria, Speakers Bureau. Ghanima: Amgen: Honoraria, Speakers Bureau;Bristol Myers Squibb: Research Funding;Bayer: Research Funding;Novartis: Honoraria, Speakers Bureau;Principia: Honoraria, Speakers Bureau;Pfizer: Honoraria, Research Funding, Speakers Bureau. Haenig: Novartis: Current Employment. Lee: Novartis: Current Employment, Other: Novartis AG equity holder. Rahman: Novartis: Other: Full time employee of IQVIA which provides services to Novartis;IQVIA: Current Employment. Zaja: Kyowa Kirin: Honoraria, Speakers Bureau;Mundipharma: Honoraria, Speakers Bureau;Novartis: Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau;Roche: Honoraria, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Amgen: Honoraria, Speakers Bureau;Grifols: Honoraria, Speakers Bureau;Bristol Myers Squibb: Honoraria, Speakers Bureau;Takeda: Honoraria, Speakers Bureau;Janssen-Cilag: Honoraria, Speakers Bureau.

Fostamatinib treatment of warm antibody autoimmune hemolytic anemia: A global, randomized, double-blind, placebo-controlled, phase 3 study

Content: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can have serious complications. In this disorder, autoantibodies bind to antigens on red blood cells leading to phagocytosis and destruction of the cells. This is mediated by Fcg receptors on macrophages through a spleen tyrosine kinase (SYK)-dependent pathway. Fostamatinib is a potent, oral SYK inhibitor approved for the treatment of chronic immune thrombocytopenia. Fostamatinib prevents platelet destruction by inhibition of platelet phagocytosis mediated through Fcg receptor and SYK in macrophages. Fostamatinib was evaluated for wAIHA in an open-label, multicenter, phase 2 study (NCT02612558). This study demonstrated markedly improved hemoglobin levels in 11 of 25 patients (44%) after fostamatinib treatment. Adverse events (AEs) were consistent with the safety database (>4000 patients across multiple diseases). Based on this phase 2 study, a randomized, double-blind, placebo-controlled, global phase 3 study (NCT03764618) was initiated in wAIHA patients to investigate the safety and efficacy of fostamatinib. The phase 3 study began enrolling patients at 103 sites in 22 countries (North America, Europe and Australia) in 2020 with a goal of enrolling approximately 90 patients. This is the first phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA. Inclusion criteria include: age ?18;documented diagnosis of primary or secondary wAIHA;failure of ?1 prior wAIHA treatment;haptoglobin below normal or total bilirubin above normal or lactate dehydrogenase above normal;and baseline hemoglobin ?9 g/dl or, if hemoglobin >9 g/dl and <10 g/dl, subject must be on permitted wAIHA treatment AND have anemia symptoms. Exclusion criteria include: other forms of AIHA;uncontrolled or poorly controlled hypertension;neutrophil count <1,000/ l;platelet count <30,000/?l (unless patient has Evans syndrome);and transaminase levels >1.5 x normal. Randomization of eligible patients will be 1:1 to fostamatinib or placebo for 24 weeks. Randomized patients will be stratified by concomitant steroid use and baseline anemia severity. Fostamatinib is started at 100 mg BID and increased to 150 mg BID at Week 4, if tolerated. The dose may be reduced for AEs. Patients may continue selected concurrent wAIHA therapies (maximum of 2) throughout the study. A steroid taper will be allowed in patients with a hemoglobin response. Rescue therapy will also be allowed. Patients who complete the study can rollover to an open-label extension. Efficacy endpoints will include hemoglobin response, ( ?10 g/dl with a ?2 g/dl increase from baseline without rescue therapy);duration of hemoglobin response;and the need for rescue therapy. Safety endpoints will be the recording of AEs. Patients will be evaluated in the clinic at two-week intervals. Using the Cochran Mantel Haenszel test at a two-sided significance level of 0.05, to detect a difference in response between the active and placebo groups with 80% power would require 90 subjects randomized 1:1. The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. As of 11 January 2021, 62 sites are open to screening (subject to local COVID-19 regulations), and 64 patients have been randomized.