scholarly journals 561. Phase 3 Trial of Fostamatinib for the Treatment of COVID-19: Repurposing an Immunomodulatory Drug Previously Approved for Immune Thrombocytopenia

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S382-S383
Author(s):  
Ziad Mallat ◽  
Suzana Margareth Lobo ◽  
Anuj Malik ◽  
Sandra Tong
Keyword(s):  
Immune Thrombocytopenia ◽  
Cell Activation ◽  
Adaptive Design ◽  
Immune Cell ◽  
Clinical Status ◽  
Supplemental Oxygen ◽  
Neutrophil Extracellular Trap ◽  
Ordinal Scale ◽  
Phase 3 ◽  
Status Score

Abstract Background Key pathologies in severe COVID-19 include immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Figure 1). Fostamatinib, an oral SYK inhibitor approved for chronic immune thrombocytopenia, has shown activity in vitro using plasma from patients with severe COVID-19, by abrogating the hyperimmune response triggered by anti-spike IgG; 1 inhibiting hyperactivation in platelets; 2 and blocking NETosis in neutrophils.3 R406, active metabolite of fostamatinib, protected against LPS-induced acute lung injury and thrombosis in mice.4,5 In clinical studies, fostamatinib reduced IL-6 in patients with rheumatoid arthritis.6 Therefore, a phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo plus standard of care (SOC) in 59 hospitalized COVID-19 patients (manuscript pending). We initiated a phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19. Methods A double-blind, randomized, placebo-controlled, adaptive design, multi-center, Phase 3 study (NCT04629703) is underway to evaluate the safety and efficacy of fostamatinib in 308 adult patients with COVID-19 (Figure 2). Hospitalized patients without respiratory failure (with or without supplemental oxygen) were included. Patients with ARDS or using extracorporeal membrane oxygenation (ECMO) were excluded. Patients will receive fostamatinib 150 mg BID or placebo for 14 days; both arms receive SOC. The primary outcome will be progression to severe/critical disease (worsening in clinical status score on the 8-point ordinal scale) within 29 days of the first dose of study drug. Fostamatinib is investigational for COVID-19. Results Blinded update of trial in progress as of 28 April 2021. 12 patients have been randomized in North and South America. The clinical status score at Baseline was 5 (Hospitalized, requiring supplemental oxygen) in all 12 patients. Five patients had 8 adverse events (AE) (Fig 3). One AE (PE) was serious and is resolving. No deaths have been reported. At least two patients have been discharged (Day 5, Day 13) with continued dosing at home. Conclusion Fostamatinib has the potential to provide a treatment option for the hyperimmune complications of COVID-19. Disclosures Ziad Mallat, MD, PhD, Rigel Pharmaceuticals, Inc. (Consultant) Sandra Tong, MD, Rigel Pharmaceuticals, Inc. (Employee, Shareholder)

scholarly journals 311. Impact of Non-alcoholic Fatty Liver Disease on Clinical Outcomes in Patients with COVID-19

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S261-S262
Author(s):  
Nina Vrsaljko ◽  
Lara Samadan ◽  
Jelena Budimir ◽  
Mirjana Balen Topic ◽  
Ivan Kurelac ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Clinical Status ◽  
Supplemental Oxygen ◽  
High Flow ◽  
Adverse Outcomes ◽  
Ordinal Scale ◽  
Alcoholic Fatty Liver ◽  
High Flow Oxygen ◽  
Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with a prevalence up to 30%. NAFLD is strongly associated with components of metabolic syndrome, already recognized as risk factors for worse outcomes in COVID-19. However, the impact of NAFLD on COVID-19 is not well characterized. The aim of this study was to investigate a possible association between NAFLD and COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients with severe COVID-19 at the University Hospital for Infectious Diseases in Zagreb, Croatia between March and June 2021. On admission patients were screened for fatty liver by the ultrasound and subsequently diagnosed with NAFLD according to current guidelines. Demographic, clinical and laboratory data was collected and correlated to clinical outcomes. Results Of the 112 patients included in the study, 77 (68.7%) had NAFLD (59.7% males; median age of 62, IQR 54-66 years). Except for higher prevalence of obesity in NAFLD group (61.0% vs 17.1%) there were no differences in other comorbidities. NAFLD group had higher inflammatory markers CRP (96, IQR 51-138 vs 59, IQR 29-99mg/L) and IL-6 (129, IQR 44-169 vs 25, IQR 8-56pg/mL). Steatosis stage showed positive correlation with BMI, waist/hip ratio, CRP, PCT, IL-6, AST, ALT, LDH and fibrinogen. Steatosis stage correlated with clinical status at the 7-category scale on admission and at days 7, 14 and 28. Patients with NAFLD had longer duration of hospitalization (9, IQR 6-15 vs 6, IQR 5-11 days, p=0.024), more frequently required noninvasive ventilation or high-flow oxygen (24.7% vs 5.7%, p=0.018) and had higher rate of pulmonary embolism (22.1% vs 5.7%, p=0.024). There was no difference in mortality. The median value for clinical status on the ordinal scale at day 7 was significantly higher in NAFLD group at days 7 and 14, as presented in Fig. 1. Multivariable analysis identified age > 65 (OR 3.6, 95%CI 1.3-10.9), LDH > 350 (OR 8.1, 95%CI 2.7-29.4), NAFLD (OR 3.9, 1.1-20.5) and pulmonary embolism (OR 10.4, 2.7-48.3) associated with adverse outcomes at day 28. The figure shows the patients’ clinical status as assessed on the seven-category ordinal scale on admission and at day 7, 14 and 28, according to the presence of NAFLD. Categories on the ordinal scale were as follows: 1, discharged or ready for discharge; 2, hospitalization in a non–intensive care unit (ICU) without supplemental oxygen; 3, non–ICU hospitalization with supplemental oxygen; 4, ICU or non–ICU hospitalization with noninvasive ventilation or high-flow oxygen; 5, ICU hospitalization with mechanical ventilation; 6, ICU hospitalization with extracorporeal membrane oxygenation or mechanical ventilation and additional organ support; and 7, death. Conclusion Our data suggests that NAFLD is associated with COVID-19 severity and might be linked to adverse outcomes in hospitalized patients. Disclosures All Authors: No reported disclosures

scholarly journals Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care

2020 ◽  
Author(s):  
Susan A Olender ◽  
Katherine K Perez ◽  
Alan S Go ◽  
Bindu Balani ◽  
Eboni G Price-Haywood ◽  
...  
Keyword(s):  
Retrospective Cohort ◽  
Clinical Status ◽  
Antiviral Agent ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Open Label ◽  
Phase 3 ◽  
Inverse Probability ◽  
Care Treatment ◽  
Standard Of Care Treatment

Abstract Background We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. Methods GS-US-540–5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540–5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. Results After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34–3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22–.68, P = .001). Conclusions In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. Clinical Trials Registration NCT04292899 and EUPAS34303.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

2013 ◽  
Vol 20 (37) ◽  
pp. 4806-4814 ◽  
Author(s):  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
Rita Businaro ◽  
Luciano Saso ◽  
Raffaele Capoano ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cell Activation ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Immune Cell Activation ◽  
Novel Therapeutic

scholarly journals Neuronal guidance proteins in cardiovascular inflammation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Marius Keller ◽  
Valbona Mirakaj ◽  
Michael Koeppen ◽  
Peter Rosenberger
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Therapeutic Approaches ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
The Future ◽  
Cardiovascular Pathologies ◽  
Neuronal Guidance

AbstractCardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

scholarly journals OP0286 PROTEOMICS AND RNA SEQUENCING APPROACHES HIGHLIGHT THE ROLE OF ENDOTHELIAL CELL DYSREGULATION IN IL-1 AND IFN MEDIATED AUTOINFLAMMATORY DISEASES, NOMID AND CANDLE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 178-179
Author(s):  
S. Alehashemi ◽  
M. Garg ◽  
B. Sellers ◽  
A. De Jesus ◽  
A. Biancotto ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Whole Blood ◽  
Cell Activation ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Neutrophilic Dermatosis ◽  
Healthy Controls ◽  
Differentially Expressed Proteins ◽  
Rna Seq ◽  
Before And After

Background:Systemic Autoinflammatory diseases present with sterile inflammation. NOMID (Neonatal-Onset Multisystem Inflammatory Disease) is caused by gain-of-function mutations inNLRP3and excess IL-1 production, presents with fever, neutrophilic dermatosis, aseptic meningitis, hearing loss and eye inflammation; CANDLE (Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy and Elevated Temperature) is caused by loss-of-function mutations in proteasome genes that lead to type-1 interferon signaling, characterized by fever, panniculitis, lipodystrophy, cytopenia, systemic and pulmonary hypertension and basal ganglia calcification. IL-1 blockers are approved for NOMID and JAK-inhibitors show efficacy in CANDLE treatment.Objectives:We used proteomic analysis to compare differentially expressed proteins in active NOMID and CANDLE compared to healthy controls before and after treatment, and whole blood bulk RNA seq to identify the immune cell signatures.Methods:Serum samples from active NOMID (n=12) and CANDLE (n=7) before and after treatment (table 1) and age matched healthy controls (HC) (n=7) were profiled using the SomaLogic platform (n=1125 proteins). Differentially expressed proteins in NOMID and CANDLE were ranked after non-parametric tests for unpaired (NOMIDp<0.05, CANDLE,p<0.1) and paired (p<0.05) analysis and assessed by enriched Gene Ontology pathways and network visualization. Whole blood RNA seq was performed (NOMID=7, CANDLE=7, Controls =5) and RPKM values were used to assess immune cells signatures.Table 1.Patient’s characteristicsNOMIDN=12, Male =6CANDLEN=7, Male =6AgeMedian (range)12 (2, 28)16 (3, 20)Ethnicity%White (Hispanic)80 (20)100 (30)GeneticsNLRP3mutation(2 Somatic, 10 Germline)mutations in proteasome component genes(1 digenic, 6 Homozygous/compound Heterozygous)Before treatmentAfter treatmentBefore treatmentAfter treatmentCRPMedian (range) mg/L52 (16-110)5 (0-23)5 (0-101)1 (0-4)IFN scoremedian (range)0NA328 (211-1135)3 (0-548)Results:Compared to control, 205 proteins (127 upregulated, 78 downregulated) were significantly different at baseline in NOMID, compared to 163 proteins (101 upregulated, and 62 downregulated) in CANDLE. 134 dysregulated proteins (85 upregulated, 49 downregulated) overlapped in NOMID and CANDLE (Figure 1). Pathway analysis identified neutrophil and monocyte chemotaxis signature in both NOMID and CANDLE. NOMID patients had neutrophilia and active neutrophils. CANDLE patients exhibited active neutrophils in whole blood RNA. Endothelial cell activation was the most prominent non-hematopoietic signature and suggest distinct endothelial cell dysregulation in NOMID and CANDLE. In NOMID, the signature included neutrophil transmigration (SELE) endothelial cell motility in response to angiogenesis (HGF, VEGF), while in CANDLE the endothelial signatures included extracellular matrix protein deposition (COL8A) suggesting increased vascular stiffness. CANDLE patients had higher expression of Renin, 4 out of 7 had hypertension, NOMID patients did not have hypertension. Treatment with anakinra and baricitinib normalized 143 and 142 of dysregulated proteins in NOMID and CANDLE respectively.Conclusion:Differentially expressed proteins in NOMID and CANDLE are consistent with innate immune cell activation. Distinct endothelial cell signatures in NOMID and CANDLE may provide mechanistic insight into differences in vascular phenotypes. Treatment with anakinra and Baricitinib in NOMID and CANDLE leaves 30% and 13% of the dysregulated proteins unchanged.Acknowledgments:This work was supported by Intramural Research atNational Institute of Allergy Immunology and Infectious Diseases of National Institutes of Health, Bethesda, Maryland, the Center of Human Immunology and was approved by the IRB.Disclosure of Interests:None declared

scholarly journals Oxidative stress and immune cell activation quantification in sepsis and non-sepsis critical care patients by neopterin/7,8-dihydroneopterin analysis

Pteridines ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 68-82
Author(s):  
Gregory Baxter-Parker ◽  
Ravinder Reddy Gaddam ◽  
Elena Moltchanova ◽  
Anitra Carr ◽  
Geoff Shaw ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Function ◽  
Cell Activation ◽  
Immune Cell ◽  
Intensive Care Patients ◽  
Immune Cell Activation ◽  
Immune System Activation ◽  
System Activation ◽  
Urinary Neopterin ◽  
Critical Care Patients

AbstractIntroduction: Neopterin and 7,8-dihydroneopterin are used as biomarkers of oxidative stress and inflammation, but the effect of kidney function on these measurements has not been extensively explored. We examine the levels of oxidative stress, inflammation and kidney function in intensive patients and compare them to equivalent patients without sepsis.Methods: 34 Intensive care patients were selected for the study, 14 without sepsis and 20 with. Both groups had equivalent levels of trauma, assessed by SAPS II, SOFA, and APACHE II and III scores. Plasma and urinary neopterin and total neopterin (neopterin + 7,8-dihydroneopterin) values were measured.Results: Neopterin and total neopterin were significantly elevated in urine and plasma for multiple days in sepsis versus non-sepsis patients. Plasma neopterin and total neopterin have decreasing relationships with increased eGFR (p<0.008 and p<0.001, respectively). Plasma/urinary neopterin and total neopterin ratios demonstrate that total neopterin flux is more influenced by eGFR than neopterin, with significantce of p<0.02 and p<0.0002 respectively.Conclusion: Sepsis patients present with greater levels of oxidative stress and immune system activation than non-sepsis patients of equal levels of trauma, as measured by neopterin and total neopterin. eGFR may need to be taken into account when accessing the level of inflammation from urinary neopterin measurements.

Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature

Lupus ◽  
2021 ◽  
pp. 096120332199010
Author(s):  
Vineeta Shobha ◽  
Anu Mohan ◽  
AV Malini ◽  
Puneet Chopra ◽  
Preethi Karunanithi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Time Course ◽  
Cell Activation ◽  
Immune Cell ◽  
Gene Signature ◽  
Systemic Lupus ◽  
Auto Antibody ◽  
Activation Status

Objective Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. Methods We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. Results Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. Conclusions Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

scholarly journals RhoA Signaling in Immune Cell Response and Cardiac Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1681
Author(s):  
Lucia Sophie Kilian ◽  
Derk Frank ◽  
Ashraf Yusuf Rangrez
Keyword(s):  
Cardiac Disease ◽  
Cell Response ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Small Gtpase ◽  
Cardiac Inflammation ◽  
Immune Cell Activation ◽  
Immune Cell Response

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

scholarly journals 551. Convalescent plasma early in disease course improves survival in COVID-19

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S341-S342
Author(s):  
Varidhi Nauriyal ◽  
Anita Shallal ◽  
Amit T Vahia ◽  
Linoj Samuel ◽  
Robert Tibbetts ◽  
...  
Keyword(s):  
Scale Score ◽  
Medical Records ◽  
Clinical Status ◽  
Ordinal Scale ◽  
Optimal Timing ◽  
Care Hospital ◽  
Future Studies ◽  
Patient Gender ◽  
Significant Difference ◽  
Pcr Test

Abstract Background Convalescent plasma (CP) has been described as a potential therapy for coronavirus disease 2019 (COVID-19). Given paucity of data, we sought to describe characteristics of CP recipients in survivors and non-survivors. Methods We conducted retrospective review of electronic medical records which included any patient with a positive SARS-CoV-2 PCR test who received CP at an 890-bed quaternary care hospital in Southeast Michigan between March-May 2020. Data collected included: demographics, co-morbidities, mSOFA score on admission, laboratory values, and treatment. Outcomes assessed included inflammatory markers and clinical status based on an 8-point ordinal scalea. These values were recorded on admission, the date of CP (day 1), day 3, 7, and day 30 post-CP. Patient outcomes were stratified by ordinal scale score and compared using Mann-Whitney U tests to examine differences in clinical characteristics: scale of 1–4 (“meaningful survivor”), 5–7 (“survivor”), and 8 (“non-survivor”). Results Results of our study are summarized in Table 1 and 2. Non-survivors were older than survivors (62 vs 71 years; p=0.026). There was no statistically significant difference between patient gender, race, number of days from positive PCR test to CP, treatments, and co-morbidities. There was a trend toward higher mSOFA score on admission in non-survivors (p=0.056). A lower ordinal scale score on the date of receiving CP was significantly associated with meaningful survivorship (6 vs 7, p=0.005). Comparisons of Characteristics Based on Ordinal Scale at Day 30 Comparisons of Outcomes Based on Ordinal Scale at Day 30 Conclusion Patients who have a lower ordinal scale score on the date of CP administration are most likely to have meaningful survivorship at day 30. Future studies should evaluate optimal timing and outcomes for CP therapy in COVID-19. Disclosures All Authors: No reported disclosures

scholarly journals LB0001 MAVRILIMUMAB IMPROVES OUTCOMES IN PHASE 2 TRIAL IN NON-MECHANICALLY-VENTILATED PATIENTS WITH SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPERINFLAMMATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 198.2-199
Author(s):  
L. Pupim ◽  
T. S. Wang ◽  
K. Hudock ◽  
J. Denson ◽  
N. Fourie ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Oxygen Therapy ◽  
Supplemental Oxygen ◽  
Ordinal Scale ◽  
Phase 2 ◽  
Double Blind ◽  
Gm Csf ◽  
Risk Of Death ◽  
Percentage Points ◽  
Supplemental Oxygen Therapy

Background:Granulocyte/macrophage-colony stimulating factor (GM-CSF) is a cytokine both vital to lung homeostasis and important in regulating inflammation and autoimmunity1,2,3 that has been implicated in the pathogenesis of respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.4-6 Mavrilimumab is a human anti GM-CSF receptor α monoclonal antibody capable of blocking GM-CSF signaling and downregulating the inflammatory process.Objectives:To evaluate the effect of mavrilimumab on clinical outcomes in patients hospitalized with severe COVID-19 pneumonia and systemic hyperinflammation.Methods:This on-going, global, randomized, double-blind, placebo-controlled seamless transition Phase 2/3 trial was designed to evaluate the efficacy and safety of mavrilimumab in adults hospitalized with severe COVID-19 pneumonia and hyperinflammation. The Phase 2 portion comprised two groups: Cohort 1 patients requiring supplemental oxygen therapy without mechanical ventilation (to maintain SpO2 ≥92%) and Cohort 2 patients requiring mechanical ventilation, initiated ≤48 hours before randomization. Here, we report results for Phase 2, Cohort 1: 116 patients with severe COVID- 19 pneumonia and hyperinflammation from USA, Brazil, Chile, Peru, and South Africa; randomized 1:1:1 to receive a single intravenous administration of mavrilimumab (10 or 6 mg/kg) or placebo. The primary efficacy endpoint was proportion of patients alive and free of mechanical ventilation at Day 29. Secondary endpoints included [1] time to 2-point clinical improvement (National Institute of Allergy and Infectious Diseases COVID-19 ordinal scale), [2] time to return to room air, and [3] mortality, all measured through Day 29. The prespecified evidentiary standard was a 2-sided α of 0.2 (not adjusted for multiplicity).Results:Baseline demographics were balanced among the intervention groups; patients were racially diverse (43% non-white), had a mean age of 57 years, and 49% were obese (BMI ≥ 30). All patients received the local standard of care: 96% received corticosteroids (including dexamethasone) and 29% received remdesivir. No differences in outcomes were observed between the 10 mg/kg and 6 mg/kg mavrilimumab arms. Results for these groups are presented together. Mavrilimumab recipients had a reduced requirement for mechanical ventilation and improved survival: at day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher with mavrilimumab (86.7% of patients) than placebo (74.4% of patients) (Primary endpoint; p=0.1224). Mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35; p=0.0175). Day 29 mortality was 12.5 percentage points lower in mavrilimumab recipients (8%) compared to placebo (20.5%) (p=0.0718). Mavrilimumab recipients had a 61% reduction in the risk of death through Day 29 (HR= 0.39; p=0.0726). Adverse events occurred less frequently in mavrilimumab recipients compared to placebo, including secondary infections and thrombotic events (known complications of COVID-19). Thrombotic events occurred only in the placebo arm (5/40 [12.5%]).Conclusion:In a global, diverse population of patients with severe COVID-19 pneumonia and hyperinflammation receiving supplemental oxygen therapy, corticosteroids, and remdesivir, a single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival. Results indicate mavrilimumab, a potent inhibitor of GM-CSF signaling, may have added clinical benefit on top of the current standard therapy for COVID-19. Of potential importance is that this treatment strategy is mechanistically independent of the specific virus or viral variant.References:[1]Trapnell, Nat Rev Dis Pri, 2019[2]Wicks, Nat Rev Immunology, 2015[3]Hamilton, Exp Rev Clin Immunol, 2015[4]De Luca, Lancet Rheumatol, 2020[5]Cremer, Lancet Rheumatol, 2021[6]Zhou, Nature, 2020Disclosure of Interests:Lara Pupim Employee of: Kiniksa, Shareholder of: Kiniksa, Tisha S. Wang Consultant of: Partner Therapeutics; steering committee for Kinevant BREATHE clinical trial, Kristin Hudock: None declared, Joshua Denson: None declared, Nyda Fourie: None declared, Luis Hercilla Vasquez: None declared, Kleber Luz: None declared, Mohammad Madjid Grant/research support from: Kiniksa, Kirsten McHarry: None declared, José Francisco Saraiva: None declared, Eduardo Tobar: None declared, Teresa Zhou Employee of: Kiniksa, Shareholder of: Kiniksa, Manoj Samant Employee of: Kiniksa, Shareholder of: Kiniksa, Joseph Pirrello Employee of: Kiniksa, Shareholder of: Kiniksa, Fang Fang Employee of: Kiniksa, Shareholder of: Kiniksa, John F. Paolini Employee of: Kiniksa, Shareholder of: Kiniksa, Arian Pano Employee of: Kiniksa, Shareholder of: Kiniksa, Bruce C. Trapnell: None declared

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