ABSTRACT
OBJECTIVES: Determine the prevaccination healthcare impact of COVID-19 in patients with systemic lupus erythematosus (SLE) in England. DESIGN: Retrospective cohort study of adult patients with SLE from 1 May to 31 October 2020. SETTING: Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics (HES) databases from general practitioners across England combining primary care and other health-related data. PARTICIPANTS: Overall, 6145 adults with confirmed SLE diagnosis ≥1 year prior to 1 May 2020 were included. Most patients were women (91.0%), white (67.1%), and diagnosed with SLE at age <50 (70.8%). Patients were excluded if they had a COVID-19 diagnosis before 1 May 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics and clinical characteristics were compared. COVID-19 severity was determined by patient care required and procedure/diagnosis codes. COVID-19 cumulative incidence, hospitalisation rates, lengths of stay and mortality rates were determined and stratified by SLE and COVID-19 severity. RESULTS: Of 6145 patients, 3927 had mild, 1288 moderate and 930 severe SLE at baseline. The majority of patients with moderate to severe SLE were on oral corticosteroids and antimalarial treatments. Overall, 54/6145 (0.88%) patients with SLE acquired and were diagnosed with COVID-19, with 45 classified as mild, 6 moderate and 3 severe COVID-19. Cumulative incidence was higher in patients with severe SLE (1.4%) compared with patients classified as mild (0.8%) or moderate (0.8%). Ten COVID-19-specific hospital admissions occurred (n=6 moderate; n=4 severe). Regardless of COVID-19 status, hospital admission rates and length of stay increased with SLE severity. Of 54 patients with SLE diagnosed with COVID-19, 1 (1.9%) COVID-19-related death was recorded in a patient with both severe SLE and severe COVID-19. CONCLUSIONS: SLE severity did not appear to impact COVID-19 outcomes in this study. The COVID-19 pandemic is evolving and follow-up studies are needed to understand the relationship between COVID-19 and SLE.
Subject(s)
COVID-19 , Lupus Erythematosus, Systemic , Adult , Humans , Female , Male , COVID-19/epidemiology , Retrospective Studies , COVID-19 Testing , Pandemics , SARS-CoV-2 , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/epidemiology , VaccinationABSTRACT
OBJECTIVES: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups. METHODS: We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers. RESULTS: In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage (<10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score <10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups. CONCLUSIONS: Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab. TRIAL REGISTRATION NUMBER: NCT02446912, NCT02446899.
Subject(s)
Antibodies, Monoclonal, Humanized , Interferon Type I , Lupus Erythematosus, Systemic , Antibodies, Monoclonal, Humanized/adverse effects , Biomarkers , Double-Blind Method , Female , Glucocorticoids/therapeutic use , Humans , Interferon Type I/adverse effects , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/genetics , Male , Treatment OutcomeABSTRACT
BACKGROUND: Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab's effect on flares, including those arising with glucocorticoid taper. METHODS: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8-40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo. RESULTS: Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60-0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55-0.89), and fewer patients with ≥1 flare (difference -9.3%, 95% CI -16.3 to -2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185). CONCLUSIONS: Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE.ClinicalTrials.gov identifiersTULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912);TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).
Subject(s)
Lupus Erythematosus, Systemic , Antibodies, Monoclonal, Humanized , Glucocorticoids , Humans , Lupus Erythematosus, Systemic/drug therapy , Prednisone/therapeutic useABSTRACT
OBJECTIVE: In phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs). METHODS: Data were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest. RESULTS: During treatment, 86.9% of patients receiving anifrolumab 300 mg (n=459) experienced AEs (≥1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (≥1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95% CI) -7.2 (-12.5 to -1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively. CONCLUSIONS: In this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300 mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Lupus Erythematosus, Systemic , Humans , Lupus Erythematosus, Systemic/drug therapy , Respiratory Tract InfectionsABSTRACT
BACKGROUND: Quadrivalent live attenuated influenza vaccine (LAIV4) showed reduced effectiveness against the A/H1N1 component in the 2013-2014 and 2015-2016 influenza seasons. The most likely cause of reduced LAIV effectiveness against A(H1N1)pdm09 strains was poor intranasal replication. OBJECTIVES: To compare the immunogenicity and shedding of a new A/H1N1 strain (A/Slovenia), to a A/H1N1 strain known to have reduced effectiveness (A/Bolivia). PATIENTS/METHODS: This was a randomized, double-blind, multicenter study. Children aged 24-<48 months of age were randomized 1:1:1 to receive two doses of LAIV4 2017-2018 (LAIV4A/Slovenia), or LAIV4 2015-2016 or trivalent LAIV (LAIV3) 2015-2016 formulations (LAIV4A/Bolivia or LAIV3A/Bolivia, respectively) on days 1 and 28. The primary endpoint was strain-specific hemagglutination inhibition (HAI) antibody seroresponse at 28 days post each dose, and secondary endpoints included immunogenicity, shedding, and safety. Solicited symptoms, adverse events (AEs), and serious AEs (SAEs) were recorded. Pre-specified statistical testing was limited to the primary endpoint of HAI antibody responses. RESULTS: A total of 200 children were randomized (median age 35.3 months; 53% male; 57% had previously received influenza vaccine). Significantly higher HAI antibody responses for the A/Slovenia strain were observed after Dose 1 and Dose 2. Neutralizing antibodies and nasal immunoglobulin A antibody responses were higher for A/Slovenia versus A/Bolivia. More children shed the A/Slovenia vaccine strain than the A/Bolivia strain on Days 4-7 after Dose 1. No deaths, SAEs, or discontinuations from vaccine occurred. CONCLUSIONS: The new A(H1N1)pdm09 A/Slovenia LAIV strain demonstrated improved immunogenicity compared with a previous strain with reduced effectiveness and induced immune responses comparable to a highly efficacious pre-pandemic H1N1 LAIV strain. These results support the use of LAIV4 containing A/Slovenia as a vaccine option in clinical practice.
Subject(s)
Immunogenicity, Vaccine , Influenza Vaccines/administration & dosage , Influenza, Human , Virus Shedding , Antibodies, Viral/blood , Child, Preschool , Double-Blind Method , Female , Hemagglutination Inhibition Tests , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/prevention & control , Male , Vaccines, Attenuated/administration & dosageABSTRACT
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Subject(s)
Ligands , Receptor, Melanocortin, Type 4/agonists , Animals , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.
Subject(s)
Alkanes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Alkanes/chemical synthesis , Alkanes/chemistry , Amides/chemistry , Humans , Molecular Structure , Nitriles/chemistry , Piperidines/chemical synthesis , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Design and synthesis of potent MC4 selective agonists based on cyclohexylpiperidine derived cyclic urea, oxazolidinones, and sulfonamide based privileged structures are disclosed.
Subject(s)
Drug Design , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Humans , Ligands , Molecular Structure , Sensitivity and Specificity , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
Subject(s)
Drug Design , Pyridazines/chemistry , Pyridazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyridazines/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Subject(s)
Appetite Depressants/administration & dosage , Appetite Depressants/chemical synthesis , Eating/drug effects , Oligopeptides/administration & dosage , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Animals , Appetite Depressants/metabolism , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Eating/physiology , Humans , Male , Models, Molecular , Oligopeptides/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The discovery of 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid analogs as potent human melanocortin-4 selective agonists is described.
Subject(s)
Carboxylic Acids/pharmacology , Receptor, Melanocortin, Type 4/agonists , Tetrahydroisoquinolines/chemistry , Tetrahydronaphthalenes/pharmacology , Humans , Molecular Conformation , Molecular Mimicry , Protein Binding/drug effects , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
Subject(s)
Aza Compounds/pharmacology , Eating/drug effects , Penile Erection/drug effects , Piperazines/pharmacology , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Aza Compounds/chemical synthesis , Humans , Male , Microsomes, Liver/metabolism , Piperazines/chemistry , Piperidines/chemical synthesis , Protein Binding , Quinuclidines/chemistry , Rats , Rats, Sprague-Dawley , Rodentia , Structure-Activity Relationship , Time FactorsABSTRACT
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.
Subject(s)
Piperazines/pharmacology , Piperidines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Dogs , Erectile Dysfunction/drug therapy , Haplorhini , Male , Mice , Obesity/drug therapy , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/therapeutic use , RatsABSTRACT
The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed.
Subject(s)
Pyridazines/chemical synthesis , Pyridazines/pharmacology , Receptor, Melanocortin, Type 4/agonists , Animals , Binding Sites , Humans , Indicators and Reagents , Kinetics , Mice , Molecular Conformation , Pyridazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.