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BackgroundLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.MethodsWe sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol.ResultsIn the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%.ConclusionsGenetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

Introduction/Background Patients with atopic dermatitis (AD) have greater risk of conjunctivitis and other ocular surface disorders than the general population. In clinical trials of dupilumab in adult patients with moderate-to-severe AD, conjunctivitis and other ocular surface adverse events (AEs) were reported more frequently in patients who received dupilumab than in those who received placebo. Clinical features of ocular AEs in dupilumab-treated patients with AD are not well characterized, and there is a need for consensus on management approaches. Objectives To assess treatment and outcomes for conjunctivitis associated with dupilumab treatment for AD. Methods Treatment patterns and outcomes were assessed during a prospective observational study evaluating conjunctivitis in dupilumab-treated patients with AD (group 1) and a dupilumab-treated reference group of patients with AD without ocular symptoms (group 2). Patients were initially prescribed dupilumab by a dermatologist for treatment of AD. After at least 8 weeks, a patient was eligible to be referred to an ophthalmologist, who then determined final eligibility for the study. Dupilumab-treated patients with AD and conjunctivitis that had newly developed or significantly worsened (group 1) were followed for at least 24 weeks. A reference group of dupilumab-treated patients with AD without ocular symptoms (group 2) was evaluated at baseline visit with the ophthalmologist and Week 4. All ophthalmological treatments were at the discretion of the ophthalmologist, who also assessed conjunctivitis treatment effectiveness. Results A total of 49 patients were enrolled: 35 patients in Group 1 and 14 patients in Group 2. 3 patients in Group 2 who presented with active ocular inflammation at the initial visit were excluded from further analysis. 16 Group 1 patients (46%) and 7 Group 2 patients (64%) had a history of an ocular disorder prior to enrollment. Group 1 patients were diagnosed with AD at a younger age compared with group 2, with longer AD duration. More patients in group 1 reported history of facial AD lesions, including eyelid involvement, and history of AD facial lesions during flares. The most frequent ophthalmological diagnoses in Group 1 were non-infective conjunctivitis (46%), allergic conjunctivitis (26%) and keratoconjunctivitis (14%). The most prominent symptom was itching, followed by redness, grittiness/sandiness, swelling, tearing, burning, stinging, and light sensitivity. Corticosteroid (eye drops) were the most frequently prescribed treatment (n = 46) and their effectiveness was assessed by the ophthalmologist as excellent in 39.1% of uses and very good in 39.1%. Topical calcineurin inhibitors (either tacrolimus ointment or cyclosporin eye drops) were the next most frequently prescribed treatment (n = 31) and their effectiveness assessed as excellent in 45.2% of uses and very good in 12.9%. In participants who completed at least 24 weeks of observation, most events recovered/resolved (21/25 [84.0%]) or were resolving/recovering (3/25 [12.0%]); 1/25 [4.0%] participant had an event that was not recovered/resolved. No participants discontinued treatment with dupilumab. Conclusions Patients with AD treated with dupilumab with prolonged history of AD and facial and/or eyelid lesions may be more prone to developing ocular events. Both topical corticosteroids (eyedrops) and topical calcineurin inhibitors (eyedrops or ointment) resulted in resolution of ocular signs and symptoms and recovery in most patients, without dupilumab discontinuation. [ABSTRACT FROM AUTHOR]

Introduction/Background The monoclonal antibodies dupilumab (fully human) and lebrikizumab (humanized) have both demonstrated efficacy and safety in clinical trials of atopic dermatitis (AD). In the absence of direct head-to-head comparisons between dupilumab and lebrikizumab, Bucher indirect treatment comparisons (ITCs), in which treatment effects are anchored to a common comparator (e.g. placebo), provide a robust and widely accepted method of evaluating the relative efficacy of drugs, and can offer a useful framework for decision-making. Objectives To report the results of a placebo-adjusted Bucher ITC comparing maintenance of efficacy outcomes between dupilumab and lebrikizumab monotherapy at Week 52 in patients with moderate-to-severe AD who had achieved ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75), or Investigator's Global Assessment (IGA) score 0/1 (clear/almost clear) at Week 16. Methods Placebo-adjusted Bucher ITC utilized phase 3 trial data from SOLO-CONTINUE (dupilumab; NCT02395133) and ADVOCATE 1 and 2 (lebrikizumab; NCT04146363 and NCT04178967) maintenance phase were used. Data at Week 52 was used with the following doses: 300mg dupilumab every 2 weeks (q2w) or placebo, and 250mg lebrikizumab q2w or every 4 weeks (q4w) or placebo. No adjustments were made for baseline characteristics, and missing data were imputed using non-responder imputation (NRI), excluding patients who had received topical corticosteroids during the maintenance phase of ADVOCATE 1 and 2. Outcomes included proportion of patients maintaining IGA 0/1, EASI-75, EASI-90, and 4-point improvement in peak pruritus Numerical Rating Scale score (PP-NRS ≥4) at Week 52 from SOLO-CONTINUE and ADVOCATE 1 and 2 maintenance phase baseline (Week 16). Odds ratio (OR) with 95% confidence interval (CI) are reported. Results Comparison of baseline disease characteristics indicated that the patient populations enrolled in ADVOCATE 1 and 2 maintenance phase baseline presented with lower disease severity compared with SOLO-CONTINUE, based on percentage body surface area affected. However, mean EASI and pruritus NRS baseline scores were similar in the compared trials. This analysis favored dupilumab for all outcomes evaluated at Week 52. Comparing q2w dosing, dupilumab had significantly higher ORs for EASI-75 (OR=4.15, 95%CI 1.41–12.18); EASI-90 (OR=3.72, 95%CI 1.09–12.76); IGA 0/1 (OR=4.62, 95%CI 1.02–20.92); PP-NRS ≥4 (OR=11.96, 95%CI 1.24–115.34). Compared with lebrikizumab q4w, dupilumab q2w maintained significantly higher EASI-75 OR (OR=3.53, 95%CI 1.18–10.53), while OR for the other 3 outcomes favored dupilumab, but did not reach statistical significance: EASI-90 (OR=3.31, 95%CI 0.97–11.33), IGA 0/1 (OR=3.31, 95%CI 0.73–15.08), and PP-NRS ≥4 (OR=8.79, 95%CI 0.91–84.81). Conclusions Based on a Bucher ITC utilizing data from trials with similar designs, patients treated with dupilumab q2w demonstrated higher likelihood of maintaining improvements in signs and symptoms at Week 52 compared with patients treated with lebrikizumab q2w or q4w. [ABSTRACT FROM AUTHOR]

Introduction/Background Dupilumab and lebrikizumab are both monoclonal antibodies that have demonstrated efficacy and safety in clinical trials of patients with moderate-to-severe atopic dermatitis (AD). Dupilumab targets both interleukin (IL)-4 and IL-13, and is fully human, whereas lebrikizumab selectively targets IL-13 and is humanized. However, no direct head-to-head clinical trials have been performed to compare efficacy of dupilumab vs lebrikizumab in combination with topical corticosteroids (TCS). Bucher indirect treatment comparisons (ITCs), in which treatment effects are anchored to a common comparator (e.g. placebo), provide a robust and widely accepted method of evaluating the relative efficacy of drugs in the absence of direct comparisons. Objective To report the results of a placebo-adjusted Bucher ITC of 16-week therapy for moderate-to-severe AD, comparing the efficacy of dupilumab every 2 weeks (q2w) (LIBERTY AD CHRONOS) vs lebrikizumab q2w (ADhere), in combination with TCS. Methods Placebo-adjusted Bucher ITC was conducted using published phase 3 trial data from LIBERTY AD CHRONOS (NCT02260986) and ADhere (NCT04250337). For both studies, data from the 16-week period were used, employing non-responder imputation, with the following doses: 300mg dupilumab + TCS q2w, or placebo + TCS, and 250mg lebrikizumab q2w + TCS, or placebo + TCS. No adjustments were made for baseline characteristics. Outcomes included proportion of patients achieving ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75), Investigator's Global Assessment score 0/1 (IGA-0/1; clear/almost clear), 4-point improvement from baseline in peak pruritus Numerical Rating Scale score (PP-NRS ≥4), and ≥4-point improvement from baseline in Dermatology Life Quality Index (DLQI ≥4). Odds ratio (OR) with 95% confidence interval (CI) are reported. Results Examination of baseline disease characteristics indicated that the patient populations enrolled in ADhere presented with lower disease severity compared with LIBERTY AD CHRONOS, based on IGA; however, PP-NRS, EASI, and DLQI scores were similar between both trials. This placebo-adjusted Bucher ITC favored dupilumab vs lebrikizumab with TCS combination treatment for all outcomes evaluated. Patients treated with dupilumab + TCS had a significantly higher likelihood of achieving EASI-75 (OR=2.39, 95%CI 1.10–5.19) and PP-NRS ≥4 (OR=2.63, 95%CI 1.17–5.95) at Week 16 vs those treated with lebrikizumab + TCS. OR for the endpoints IGA 0/1 and DLQI ≥4 favored dupilumab, but did not reach statistical significance: IGA 0/1 (OR=1.90, 95%CI 0.81–4.42), DLQI ≥4 (OR=2.35, 95%CI 0.94–5.87). Conclusion A placebo-anchored Bucher ITC approach showed that the likelihood of achieving improvements in signs, symptoms, and quality of life is higher for patients treated with dupilumab + TCS vs lebrikizumab + TCS. [ABSTRACT FROM AUTHOR]