The median rate of ACS was 0 in each treatment arm, with a total of 18 ACS events in 14 patients treated with crizanlizumab 5 mg/kg and 15 ACS events in 13 patients treated with placebo. Rother:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. n = 31bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. The HU use subgroups were also further categorized by prior VOC events (2‐4 or 5‐10). In total, 82 patients (62.1%) were using concomitant HU at baseline. Clinical trials are underway using different gene transfer vectors and cassettes. SUSTAIN clinical trial data. DKL, RDC, JRF and JMK‐M declared no conflicts of interest. Rollins:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. All data are number of event‐free patients/number of patients in subgroup (%). A blinded, independent committee adjudicated all SCPC events. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. As previously reported in Ataga et al.,17 central randomization was performed using a block design, with stratification according to the number of VOCs in the prior year (2‐4 or 5‐10) and concomitant HU use (yes or no). In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. Uncomplicated VOCs were defined as crises other than ACS, hepatic or splenic sequestration, or priapism. Investigate combination therapies and new drug-delivery models. Upregulation of P-selectin on endothelial cells and platelets also contributes to the cell-cell interactions involved in the pathogenesis of SCPC. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The study enrolled 198 patients with SCD across 60 centers in the United States, Brazil, and Jamaica. The most marked increases observed were in the HbSS genotype subgroup (4.07 months in the crizanlizumab group vs 1.12 months in the placebo group; HR: 0.50; 95% CI 0.31‐0.80) and no concomitant HU use (5.68 vs 2.86 months; HR: 0.39; 95% CI 0.20‐0.76) (Table 2; Figure 2). No treatment‐related AEs led to death. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Wally Smith, MD, Virginia Commonwealth University, Richmond, VA, outlines the findings of a post hoc analysis of length of opioid use in sickle cell disease (SCD) patients enrolled in the SUSTAIN trial (NCT01895361). Primary Purpose: Treatment. Importantly, reductions were seen — including in those treated at the low 2.5 mg/kg dose — regardless of patients’ specific mutations or whether they were also using hydroxyurea at the ti… n = 39bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. 1) and time to second SCPC was increased 2.0-fold (medians of 10.3 vs. 5.1 months, p = 0.022, Fig. The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). Overall, these findings support the initial findings from the SUSTAIN study17 and suggest that crizanlizumab is a potentially disease‐modifying agent that reduces the frequency of, or prevents, VOCs in patients with SCD (of all genotypes). Safety assessments included frequency of treatment‐emergent adverse events (AEs) and treatment‐emergent serious adverse events (SAEs). The frequency of treatment‐emergent AEs and SAEs for crizanlizumab 5 mg/kg and placebo was generally consistent across all the subgroups analyzed. Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time‐to‐first VOC vs placebo in these subgroups. Key inclusion criteria included patients 16 to 65 years of age; diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia); and history of 2 to 10 SCPC in the previous 12 months. This pattern of response was also apparent in patients with 2‐4 VOCs in the previous year, no concomitant HU use, and non‐HbSS genotype. Crizanlizumab also consistently delayed time‐to‐first and time‐to‐second VOC compared with placebo in all subgroups. For all other types of VOC, including ACS, the incidence of events was too low to provide any meaningful subgroup analysis. The results from this analysis will help to determine if the outcomes with crizanlizumab treatment were similar in all subgroups analyzed. Abdullah Kutlar, Sickle Cell Center, Medical College of Georgia, Augusta University, 989 Street Sebastian Way, EF 145C, Augusta, GA 30912. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. Each patient will be asked to participate in a long-term follow-up study. Novartis is committed to sharing with qualified external researchers, access to patient‐level data and supporting clinical documents from eligible studies. Sickle cellrelated pain crises are the primary cause of health care encounters in patients with sickle cell disease.1 These crises result in a decrease in quality of life2 and an increase in the risk of death.3 Crises … The primary efficacy endpoint was the annual rate of SCPC in the 5.0 mg/kg SelG1 group vs. placebo. All data are median (IQR) unless otherwise stated. Kutlar:Novartis Pharmaceuticals: Research Funding. o Data from the Hospital Episode Statistics (HES) database was used to estimate the risk of acute SCD-related complications or death associated with varying frequency of VOC. No hepatic or splenic sequestration events were reported among patients in either the crizanlizumab 5 mg/kg or placebo arms. Raffaella Colombatt Future studies of crizanlizumab include an ongoing phase 2 pharmacokinetic/pharmacodynamic (PK/PD) study (NCT03264989), through which the safety of a higher dose of crizanlizumab (7.5 mg/kg) is being explored, and a planned dose confirmation and safety study in pediatric patients with SCD (NCT03474965). The current standard‐of‐care for frequent pain episodes is HU, which was the first drug therapy approved by the US Food and Drug Administration for SCD.20 HU improves RBC rheology,21 has proven clinical efficacy, and reduces the frequency of VOCs by approximately 50%, but patients who receive this treatment still experience recurrent crises.22, 23 Furthermore, patient concerns regarding the HU safety profile and the monitoring that is required to determine a well‐tolerated, effective dose have led to low prescription rates and poor patient adherence.18, 23-25 A new therapeutic option is L‐glutamine. The efficacy of ADAKVEO ® (crizanlizumab-tmca) was evaluated based on the annual rate of VOCs in patients (16 to 63 years of age) with SCD in a pivotal, phase 2, 52-week, randomized, multicenter, placebo-controlled, double-blind study. In almost all the subgroups evaluated, crizanlizumab increased the time‐to‐first VOC vs placebo. Blood 2016; 128 (22): 1. doi: https://doi.org/10.1182/blood.V128.22.1.1. The safety profile of crizanlizumab 5 mg/kg vs placebo in the SUSTAIN study has previously been discussed17 and this analysis did not identify any new safety concerns for crizanlizumab 5 mg/kg. The SelG1 drug effect was dose-dependent as the annual rate of SCPC at 2.5 mg/kg vs. placebo was reduced 33% (medians of 2.0 vs. 3.0, p = 0.180). A hierarchical testing procedure was employed (α = 0.05 for high dose vs. placebo, and if significant, low dose vs. placebo). The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. The annual rate of days hospitalized at 5.0 mg/kg vs. placebo showed a non-significant, 42% reduction (medians of 4.0 vs. 6.9, p = 0.450). Descriptive statistics were used to summarize the number of VOC event‐free patients and types of VOC in the following subgroups: prior VOC events (2‐4 or 5‐10), genotype (HbSS or non‐HbSS), and concomitant HU use (yes or no). Results from the Phase 2 SUSTAIN clinical trial demonstrated that crizanlizumab (SEG101, Selexys Pharmaceuticals, Novartis), an anti-P-selectin antibody, reduced by 45.3% the median annual rate of sickle cell-related pain crises (SCPC), compared to placebo in patients with or without hydroxyurea therapy, a drug used to reduce the rate of painful attacks in sickle-cell disease (SCD). The funder had no role in the design or conduct of the SUSTAIN study or in data collection. Kenneth I. Ataga, Abdullah Kutlar, Julie Kanter, Darla Liles, Rodolfo Cancado, João Friedrisch, Troy H. Guthrie, Jennifer Knight-Madden, Ofelia A. Alvarez, Victor R. Gordeuk, Sandra Gualandro, Marina Pereira Collela, Wally R. Smith, Scott A. Rollins, Jonathan W. Stocker, Russell P. Rother; SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises. It is a key molecule in the initiation of leukocyte rolling on the vessel wall that leads to firm attachment and extravasation to underlying tissues during inflammation. The analysis focused on patient characteristics of interest, including those specified as stratification criteria in the original study protocol (number of VOC events in the year prior to study entry, and concomitant HU use) and genotype. Antiplatelet agents. ACS events were rare in this study. OAA has participated in advisory boards for Novartis Pharmaceuticals Corporation. Efficacy endpoints evaluated were the proportion of VOC event‐free patients, time‐to‐first VOC, time‐to‐second VOC, and types of VOC including uncomplicated crises and acute chest syndrome (ACS). This article reviews the evidence pertaining to crizanlizumab in SCD by searching records in Medline, Embase, and International Pharmaceutical Abstracts. Key inclusion criteria were patients aged 16‐65 years with SCD of any genotype, who had experienced 2‐10 VOCs in the previous 12 months. There were no apparent increases in infections with SelG1 treatment. The randomization was stratified by historical SCPC in the prior year (2-4 or 5-10) and concomitant HU use (yes or no). Adverse events that occurred in 5% or more of patients in an active dose group and were elevated over placebo by at least 2-fold were arthralgia, pruritus, vomiting, chest pain, diarrhea, road traffic accident, fatigue, myalgia, musculoskeletal chest pain, abdominal pain, influenza and oropharyngeal pain. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. There is a high degree of phenotypic variability within each SCD genotype, and all can experience frequent VOCs.5, 6, Polymerization of deoxygenated HbS distorts the shape of erythrocytes, and leads to the “sickle” appearance associated with SCD.7 Erythrocytes containing HbS can adhere to vascular endothelial cells, which become activated by circulating free heme and inflammatory stimuli inherent to the pathophysiology of SCD,8 and promote further inflammation and leukocyte adherence to the endothelium.9 Activated platelets can also adhere to leukocytes and sickled erythrocytes, forming aggregates.10, 11 These interactions with the endothelium lead to altered hemodynamics, vascular obstruction, acute vaso‐occlusion, and tissue ischemia, causing VOCs.9 The initiation of a VOC is a complex event involving a multitude of molecules.9 One of the molecules involved is P‐selectin, a cell adherence molecule that is rapidly and chronically expressed on the surface of endothelial cells and platelets when activated.12, 13 Leukocytes are initially captured on the endothelium via P‐selectin and its ligand P‐selectin glycoprotein ligand 1 (PSGL‐1).14 The expression of PSGL‐1 by leukocytes also causes activated platelets to adhere to the leukocyte, leading to aggregate formation. The FDA’s approval decision was based on data from the randomized, double-blind, and placebo-controlled Phase 2 SUSTAIN (NCT01895361) trial in 198 SCD patients with a history of frequent VOCs (two to 10 episodes the year prior to enrolling in the study). An SCPC was defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. David Gray (DG): Managing Editor of Advances in Therapy. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, Time‐to‐first on‐treatment VOC by prior VOC events, SCD genotype, and HU use Abbreviations: HbSS, hemoglobin S; HU, hydroxyurea; SCD, sickle cell disease; VOC, vaso‐occlusive crisis, I have read and accept the Wiley Online Library Terms and Conditions of Use, The pain experience of patients with sickle cell anemia, Essential of sickle cell disease management, Recent Advances in Pediatric Medicine; Synopsis of Current General Pediatrics Practice, Minireview: genetic basis of heterogeneity and severity in sickle cell disease, The effect of deoxygenation on whole‐cell conductance of red blood cells from healthy individuals and patients with sickle cell disease, Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology, Vaso‐occlusion in sickle cell disease: pathophysiology and novel targeted therapies, Platelet activation and platelet‐erythrocyte aggregates in patients with sickle cell anemia, Platelet‐neutrophil‐interactions: linking hemostasis and inflammation, Inhibition of cell adhesion by anti‐P‐selectin aptamer: a new potential therapeutic agent for sickle cell disease, P‐selectin mediates the adhesion of sickle erythrocytes to the endothelium, Heparin inhibits the flow adhesion of sickle red blood cells to P‐selectin, Crizanlizumab for the prevention of pain crises in sickle cell disease, Hydroxyurea for the treatment of sickle cell anemia, How I use hydroxyurea to treat young patients with sickle cell anemia, The FDA encourages new treatments for sickle cell disease, Hydroxyurea treatment does not increase blood viscosity and improves red blood cell rheology in sickle cell anemia. clinicaltrials.gov: NCT01895361. Asterisk with author names denotes non-ASH members. We thank Andrew Jones, from Mudskipper Business Limited, for medical editorial assistance. The primary endpoint, the annual rate of SCPC in the ITT population at 5.0 mg/kg vs. placebo, was reduced 47% (medians of 1.6 vs. 3.0, p = 0.010, Table 1). Platelets contribute to SCD pathology through multiple mechanism including formation of intravascular aggregates, release of pro-inflammatory cytokines and activation of coagulation. Five deaths occurred during the study, 2 at 5.0 mg/kg, 1 at 2.5 mg/kg and 2 in placebo; no deaths were deemed related to study drug. In these two trial arms, 62.9% had two to four VOC crises in the year before the study’s start, and 37.1% between five and 10. Use the link below to share a full-text version of this article with your friends and colleagues. For time‐to‐first and time‐to‐second VOC, hazard ratios (HRs) were calculated for crizanlizumab vs placebo based on Cox regression analysis, with treatment as a covariate; data are presented as Kaplan‐Meier plots. A subgroup analysis of the primary endpoint (annual rate of VOCs) highlighted that a lower frequency of crises was observed with crizanlizumab 5 mg/kg vs placebo regardless of the number of prior VOC events, concomitant hydroxyurea (HU) use or SCD genotype.17 We therefore conducted a post hoc analysis to further evaluate different endpoints in these same subgroups, including the proportion of patients who did not experience a VOC during the study, additional secondary efficacy endpoints and the safety of crizanlizumab 5 mg/kg compared with placebo. and you may need to create a new Wiley Online Library account. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. These subgroup analyses also indicate that the efficacy observed in the overall study population was likely not driven by a single subgroup or set of subgroups. 33 The SUSTAIN trial, a multicenter randomized double blind study, showed that crizanlizumab decreased the incidence of VOC by 45% in patients with or without HU. It is notable that crizanlizumab increased the likelihood of being VOC event‐free and delayed time‐to‐first and time‐to‐second VOC compared with placebo in patients who had experienced 2‐10 VOCs in the year prior to study entry despite receiving concomitant HU. n = 11bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. The rates of treatment‐related (according to investigator judgment) AEs and SAEs were higher in patients treated with crizanlizumab than with placebo, across all subgroups, although the incidence of AEs leading to discontinuation was generally low in both dose groups (0%‐8.0% in the crizanlizumab arm vs 0%‐8.7% in the placebo arm across all subgroups). Sickle cell disease (SCD) is a genetic disorder that predominantly affects individuals of African descent.1 It is characterized by the presence of sickle hemoglobin (HbS), which polymerizes upon deoxygenation, damaging erythrocytes and potentially leading to vaso‐occlusion, multi‐organ damage, and early death.2 Painful vaso‐occlusive crises (VOCs), also known as sickle cell pain crises, are the hallmark of SCD and are the primary cause of hospitalization in SCD.3 VOCs cause pain in the extremities, back, abdomen or chest, and can vary in intensity from mild to excruciating.4 Patients with SCD and frequent VOCs may experience problems with low self‐esteem, anxiety, depression, dissatisfaction with body image, poor school performance, social isolation, decreased participation in normal daily activities, and poor peer and family relationships.4, The most common SCD genotype is homozygous hemoglobin S (HbSS) which, along with sickle β0‐thalassemia (HbSβ0), is generally considered to be the most clinically severe. n = 23bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. Further analysis of annualized days of hospitalization by subgroup was not feasible due to the sample size of the study, given that the overall analysis did not demonstrate statistically significant differences. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC. Patients were excluded if they were undergoing long‐term, RBC transfusion therapy. The observed reductions in VOCs suggest that P‐selectin inhibition can provide an additional treatment effect and, therefore, meets an existing unmet need based on the currently available treatment options. These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with HU for the prevention of VOCs. About the Subgroup Analysis and the SUSTAIN trial The heterogeneity in severity of sickle cell disease and various other factors make it important to understand differences in response of various subgroups of patients in order to increase understanding of crizanlizumab and the role of P-selectin in SCD. Data from SUSTAIN (NCT01895361) showed that in patients treated at the high 5 mg/kg dose, Adakveo significantly reduced the frequency of annual VOCsby a mean of 45.3% compared to those given placebo. Patients using concomitant HU were included if they had been receiving HU treatment for ≥6 months and at a stable dose for at least the previous 3 months; these patients were not allowed to have HU dose adjustments during the study, except for safety reasons (eg, dose interruption/reduction because a patient was not tolerating HU therapy). Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1; patients received their initial dose, a dose 14 days later, and then every 4 weeks through week 50 for a total of 14 doses. AK has received research funding from Novartis Pharmaceuticals Corporation and from Reprixys Pharmaceuticals Corporation (which was acquired by Novartis Pharmaceuticals Corporation on November 18, 2016), is a member of a data monitoring committee for BlueBird Bio, and Chair of a Data and Safety Monitoring Board for Sancilio & Co. JK has received research support from Reprixys Pharmaceuticals Corporation, has participated in advisory boards and other activities for Novartis Pharmaceuticals Corporation, has participated in advisory boards for BlueBird Bio and Prolong Pharmaceuticals, and has acted as a consultant for AstraZeneca. Patients with SCD engrafted, had sustained production of the transgene and a decreased number of vaso-occlusive crises. Most participants (91.9%) were Black or African American. Demographic parameters were evenly distributed in the treatment groups. n = 18bb Number of patients included in the subgroup who experienced any VOC during the SUSTAIN study. Thus, HU primarily targets RBCs, whereas crizanlizumab is targeting the vasculature. Division of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, Division of Hematology–Oncology, East Carolina University, Greenville, North Carolina, Division of Pediatric Hematology, University of Miami, Miami, Florida, Department of Hematology–Oncology, Santa Casa Medical School of São Paulo, São Paulo, Brazil, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, Sickle Cell Unit, Caribbean Institute for Health Research, University of the West Indies, Kingston, Jamaica, Novartis Pharmaceuticals, East Hanover, New Jersey, The University of Tennessee Health Science Center, Memphis, Tennessee. Descriptive statistics were used to summarize patient demographics and baseline characteristics in the ITT population, and frequency of AEs and SAEs in the safety population, which included all randomized patients who received at least 1 dose of either crizanlizumab 5 mg/kg or placebo. Kanter:Novartis: Consultancy. Patients were randomly assigned to receive 5 mg/kg or 2.5 mg/kg of SelG1 or a placebo intravenously once a month, after an initial loading dose. Enrolled patients, ages 16 and older, were randomly assigned either to an intravenous infusion of Adakveo at one of two doses (2.5 mg/kg … All efficacy analyses were conducted using the intention‐to‐treat (ITT) population, which included all patients randomized to crizanlizumab 5 mg/kg or placebo. Chronic inhibition of P-selectin with once a month IV dosing of SelG1 represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with SCD. The SUSTAIN study will form the basis of health authority submissions, although crizanlizumab in the treatment of patients with SCD will continue to be explored in additional studies. The efficacy and safety of crizanlizumab was studied in a 52-week, randomized, multicenter, placebo-controlled, double-blind, Phase II, clinical trial SUSTAIN (NCT01895361). Within each subgroup, patients were evenly distributed between the crizanlizumab and placebo arms (see Supporting Information Table S1, for an expanded list of patient characteristics). ZZ performed the analyses and contributed to the interpretation of the findings presented. Both the U.S. approval and the new CHMP opinion were based on the results of the SUSTAIN Phase 2 clinical trial (NCT01895361). This article reviews the evidence pertaining to crizanlizumab in SCD by searching records in Medline, Embase, and International Pharmaceutical Abstracts. The full text of this article hosted at iucr.org is unavailable due to technical difficulties. Hydroxyurea in sickle cell disease: drug review, Hydroxyurea use in sickle cell disease: the battle with low prescription rates, poor patient compliance and fears of toxicities, Adherence to hydroxyurea, health‐related quality of life domains, and patients' perceptions of sickle cell disease and hydroxyurea: a cross‐sectional study in adolescents and young adults, A phase 3 trial of L‐glutamine in sickle cell disease, Allogeneic hematopoietic stem‐cell transplantation for sickle cell disease, The role of blood transfusion in sickle cell disease, Paucity of HLA‐identical unrelated donors for African‐Americans with hematologic malignancies: the need for new donor options, https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm418232.htm, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208587s000lbl.pdf, HU use/VOC events in the year prior to study. Before enrollment, all patients provided written informed consent. Study Start Date : In the Phase II SUSTAIN study, crizanlizumab 5.0 mg/kg significantly reduced the median annual rate of VOCs compared with placebo (P=0.010). Patients were randomized by an interactive voice or web response system to receive crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo. Methods: We conducted a randomized, double-blind, placebo-controlled, multinational study. Crizanlizumab, a P-selectin inhibitor, mitigates the microvascular vaso-occlusion in SCD. The drug was approved in the USA26 based on results from a phase 3 study that have recently been published.27 At the time of writing, no additional real‐world experiences are available for this new treatment option. Adakveo, a man-made antibody, works to block the activity of P-selectin, an adhesion protein that makes sickled blood cells more sticky and more likely to clog blood vessels, causing inflammation and pain crises. All authors had access to analyzed data, contributed to the writing and reviewing of the report, and had final responsibility for the decision to submit for publication. No evaluation of crizanlizumab 2.5 mg/kg was included in this analysis because the primary endpoint of the study was only met with the 5 mg/kg dose and therefore this is the dose for which further clinical development is planned. AB, MS and ZZ are employees of Novartis Pharmaceuticals Corporation. Please check your email for instructions on resetting your password. Some patients in the trial were also receiving hydroxyurea. One priapism event was reported in the placebo arm and none was reported in the crizanlizumab 5 mg/kg arm. Gene therapies are being developed, and several are now in various stages of early-phase human clinical trials. AK, JK, DKL, OAA, RDC, JRF, JMK‐M and KIA were investigators of the SUSTAIN study and contributed to the acquisition of data, design of the analyses, and interpretation of the findings presented. Primary results were published in The New … More patients were VOC event‐free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%).
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