Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B-C). METHODS: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B-C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. FINDINGS: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B-C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B-C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was -95·9% (95% CI -96·9 to -94·9) in the weekly dupilumab/weekly dupilumab group, -84·2% (-98·3 to -70·2) in the placebo/weekly dupilumab group, -84·8% (-94·3 to -75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -91·2% (-95·9 to -86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was -1·0 point (95% CI -1·1 to -0·9) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was -0·9 points (-1·0 to -0·8) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was -30·3 points (95% CI -34·5 to -26·1) in the weekly dupilumab/weekly dupilumab group, -27·3 points (-32·1 to -22·4) in the placebo/weekly dupilumab group, -20·9% (-25·4 to -16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -23·7% (-29·1 to -18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was -5·4 points (95% CI -6·1 to -4·6) in the weekly dupilumab/weekly dupilumab group, -6·1 points (-7·3 to -4·9) in the placebo/weekly dupilumab group, -5·2% (-6·0 to -4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -4·3% (-5·4 to -3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B-C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). INTERPRETATION: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Effect of Dupilumab on Type 2 Biomarkers in Chronic Rhinosinusitis With Nasal Polyps: SINUS-52 Study Results.

OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab's effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study. METHODS: Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks. RESULTS: Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings. CONCLUSION: Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab's therapeutic effects. CLINICAL TRIAL REGISTRY NAME: SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454. CLINICALTRIALS.GOV IDENTIFIER: NCT02898454.

Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.

BACKGROUND: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials. OBJECTIVE: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis. METHODS: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/µL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented. RESULTS: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/µL; week 4: 515-578 cells/µL), CRSwNP (baseline: 440-448 cells/µL; week 16: 595 cells/µL), and atopic dermatitis (baseline: 434-600 cells/µL; week 4: 410-710 cells/µL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/µL; week 4: 230 cells/µL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy. CONCLUSIONS: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.

Dupilumab Demonstrates Rapid Onset of Response Across Three Type 2 Inflammatory Diseases.

BACKGROUND: Type 2 inflammatory diseases often coexist in patients. Dupilumab targets type 2 inflammation and has demonstrated treatment benefits in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) with an acceptable safety profile. OBJECTIVE: This post hoc analysis across five phase 3 studies in patients with moderate to severe AD or asthma, or severe CRSwNP, evaluated time of onset and duration of the treatment response. METHODS: Patients received subcutaneous dupilumab 200/300 mg or placebo. Assessments included the Eczema Area and Severity Index, Peak Pruritus Numerical Rating Scale, and Dermatology Life Quality Index in AD; pre-bronchodilator FEV1, daily morning peak expiratory flow, and symptom scores in asthma; and University of Pennsylvania Smell Identification Test, daily nasal congestion, and loss of smell scores in CRSwNP. RESULTS: At week 2 after the initiation of dupilumab versus placebo, 67.8% versus 36.5% of AD patients achieved a clinically meaningful benefit (Eczema Area and Severity Index: 50% or greater improvement; Peak Pruritus Numerical Rating Scale: 3 point or greater improvement; or Dermatology Life Quality Index: 4 point or greater improvement) (P < .001). Moreover, 61.6% versus 39.9% of asthma patients achieved improvements in pre-bronchodilator FEV1 of 100 mL or greater and 48.8% versus 26.3% achieved 200 mL or greater improvement (both P < .001); 33.2% versus 5.6% of CRSwNP patients regained a sense of smell (P < .001). Treatment effects further improved or were sustained to the end of treatment. CONCLUSIONS: Clinically meaningful responses were achieved rapidly after the first dupilumab dose in AD, asthma, or CRSwNP and were sustained throughout treatment (see Video in this article's Online Repository at www.jaci-inpractice.org).

Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials.

BACKGROUND: About one-tenth of patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, is an approved add-on treatment in severe CRSwNP. This post hoc analysis evaluated dupilumab efficacy and safety in patients with CRSwNP with/without NSAID-ERD. METHODS: Data were pooled from the phase 3 SINUS-24 and SINUS-52 studies in adults with uncontrolled severe CRSwNP who received dupilumab 300 mg or placebo every 2 weeks. CRSwNP, nasal airflow, lung function, and asthma control outcomes at Week 24 were evaluated, and treatment-subgroup interactions were assessed for patients with and without NSAID-ERD. RESULTS: Of 724 patients, 204 (28.2%) had a diagnosis of NSAID-ERD. At Week 24, least squares mean treatment differences demonstrated significant improvements in nasal polyp score, nasal congestion (NC), Lund-Mackay computed tomography, 22-item Sinonasal Outcome Test (SNOT-22), Total Symptom Score (TSS), rhinosinusitis severity visual analog scale, peak nasal inspiratory flow (PNIF), six-item Asthma Control Questionnaire score, and improvement in smell with dupilumab versus placebo (all p < .0001) in patients with NSAID-ERD. Treatment comparisons demonstrated significantly greater improvements with dupilumab in patients with versus without NSAID-ERD for NC (p = .0044), SNOT-22 (p = .0313), TSS (p = .0425), and PNIF (p = .0123). CONCLUSIONS: In patients with uncontrolled severe CRSwNP, dupilumab significantly improved objective measures and patient-reported symptoms to a greater extent in the presence of comorbid NSAID-ERD than without. Dupilumab was well tolerated in patients with/without NSAID-ERD.

Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy.

BACKGROUND: People with HIV (PWH) on antiretroviral therapy (ART) still experience an increased risk of morbidity and mortality, presumably driven by chronic inflammation, yet predictors of discrete or combinatorial outcomes remain unclear. Galectin-9 (Gal-9), a driver of both inflammatory and immunosuppressive responses, has been associated with HIV disease progression and multimorbidity. OBJECTIVE: To determine whether plasma Gal-9 levels are associated with the occurrence of specific non-AIDS events (NAEs) in PWH initiating ART. DESIGN: We performed a nested case-control study of PWH enrolled from 2001 to 2009 and evaluated pre-ART (66 cases, 97 controls), a year post-ART (112 cases, 211 controls), and immediately preceding an event (89 cases, 162 controls). Events included myocardial infarction/stroke, malignancy, serious bacterial infection, or death. METHODS: Plasma Gal-9 levels were assessed by ELISA. Conditional logistic regression assessed associations with NAEs and Spearman's correlations compared Gal-9 with other previously assessed biomarkers. RESULTS: NAEs occurred at a median of 2.8 years (1.7-4.6) after ART initiation. Higher Gal-9 levels were associated with increased risk of NAEs at year 1 and preevent [odds ratio (OR) per 1 interquartile range = 1.4-1.6; all P < 0.05], specifically myocardial infarction/stroke at year 1 (OR = 1.9; P = 0.029). Gal-9 also correlated with multiple inflammatory and immune activation predictors of NAEs (all timepoints). CONCLUSION: Elevated Gal-9 levels are predictive of deleterious NAEs, particularly cardiovascular complications. Whether the Gal-9 pathway, potentially binding to its putative ligands, is active in the pathogenesis of these outcomes warrants further investigation to determine if targeting Gal-9 may slow or reverse the risk of NAEs.

Increased Monocyte Inflammatory Responses to Oxidized LDL Are Associated with Insulin Resistance in HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1ß, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1ß and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1ß and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.

Mycobacterium avium Subspecies paratuberculosis Recombinant Proteins Modulate Antimycobacterial Functions of Bovine Macrophages.

It has been shown that Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) activates the Mitogen Activated Protein Kinase (MAPK) p38 pathway, yet it is unclear which components of M. paratuberculosis are involved in the process. Therefore, a set of 42 M. paratuberculosis recombinant proteins expressed from coding sequences annotated as lipoproteins were screened for their ability to induce IL-10 expression, an indicator of MAPKp38 activation, in bovine monocyte-derived macrophages. A recombinant lipoprotein, designated as MAP3837c, was among a group of 6 proteins that strongly induced IL-10 gene transcription in bovine macrophages, averaging a 3.1-fold increase compared to non-stimulated macrophages. However, a parallel increase in expression of IL-12 and TNF-α was only observed in macrophages exposed to a subset of these 6 proteins. Selected recombinant proteins were further analyzed for their ability to enhance survival of M. avium within bovine macrophages as measured by recovered viable bacteria and nitrite production. All 6 IL-10 inducing MAP recombinant proteins along with M. paratuberculosis cells significantly enhanced phosphorylation of MAPK-p38 in bovine macrophages. Although these proteins are likely not post translationally lipidated in E. coli and thus is a limitation in this study, these results form the foundation of how the protein component of the lipoprotein interacts with the immune system. Collectively, these data reveal M. paratuberculosis proteins that might play a role in MAPK-p38 pathway activation and hence in survival of this organism within bovine macrophages.

Contributions of herpes simplex virus 1 envelope proteins to entry by endocytosis.

Herpes simplex virus (HSV) proteins specifically required for endocytic entry but not direct penetration have not been identified. HSVs deleted of gE, gG, gI, gJ, gM, UL45, or Us9 entered cells via either pH-dependent or pH-independent endocytosis and were inactivated by mildly acidic pH. Thus, the required HSV glycoproteins, gB, gD, and gH-gL, may be sufficient for entry regardless of entry route taken. This may be distinct from entry mechanisms employed by other human herpesviruses.