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Background Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. Methods and results Patient-level, pooled analysis of ORION-9, −10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]. Conclusion This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Purpose Patients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD. Methods In this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients’ PVD status. Safety was assessed over 540 days. Results Of 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran. Conclusion Twice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status.

Introduction: Excessive bodyweight, often associated with dyslipidemia, may affect the pharmacology of drugs. Inclisiran, a small interfering RNA targeting PCSK9 hepatic mRNA, is an effective LDL-C lowering agent with twice-yearly subcutaneous dosing (after the initial and 3-month doses). Aim: To analyze the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent across body mass index (BMI) strata. Methods: In this post hoc analysis from ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800), eligible patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, Day 90 and 6-monthly thereafter. Analyses were stratified by baseline BMI: 2 . Percentage change in atherogenic lipids from baseline at Day 510 was evaluated. Safety was assessed over 540 days. Results: Baseline demographic and clinical characteristics including atherogenic lipid levels were mostly balanced between the treatment arms and across the BMI strata ( Table ). Percentage change in atherogenic lipids from baseline at Day 510 was significantly greater with inclisiran vs placebo within each BMI stratum ( Table ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms and were reported more frequently with increasing BMI strata (data not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs placebo similarly across strata, but all were mild or moderate. Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained lipid lowering in patients, irrespective of their baseline BMI, and was generally well tolerated.

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.

Introduction: Smoking in asthma patients is an important factor contributing to worsened control of asthma. Despite increased awareness of the harmful effects of smoking in patients with asthma, a significant proportion of asthmatics remain smokers. Here, we present findings from the Still Fighting for Breath global survey regarding the prevalence of smoking in patients with severe asthma, impact of smoking on asthma control and correlation of smoking with different aspects of quality of life in patients with severe persistent asthma.

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C–lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was −50.7% (95% confidence interval: −52.9% to −48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was −50.5% (95% confidence interval: −52.1% to −48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Aim: Prior studies have confirmed the fast and sustained bronchodilation with IND and GLY1, and improved lung function with MF2. Here we evaluated the effect of IND/GLY/MF fixed-dose combination via Breezhaler® vs Sal/Flu+Tio on symptoms and rescue medication use in uncontrolled asthma patients. Methods: ARGON(NCT03158311) was a 24 wk, Phase 3b, multicentre, randomised, partially-blinded, non-inferiority, active-controlled study in symptomatic (ACQ-7 ≥1.5) patients (≥18 yrs). This exploratory analysis evaluated the effect of IND/GLY/MF medium-dose (150/50/80µg) o.d. vs combination of Sal/Flu high-dose (50/500µg) b.i.d. + Tio 5µg o.d. on symptom scores and rescue medication use at Wk 24. Results: Reduction in total daily symptom scores (LSM treatment difference [Δ]: −0.103, p=0.119), percentage of nights without awakenings (Δ: 0.864, p=0.608) and reduction in rescue medication use (Δ: −0.134, p=0.081) with IND/GLY/MF medium-dose were comparable with Sal/Flu+Tio. Patients receiving IND/GLY/MF medium-dose had a higher percentage of days with no day-time symptoms (Δ: 4.453, p=0.016) and mornings with no symptoms (Δ: 4.976, p=0.012) vs Sal/Flu+Tio. Conclusion: IND/GLY/MF medium-dose o.d. delivered via a single inhaler was comparable in terms of symptom scores and rescue medication use, while resulting in better improvements in day-time symptoms and morning symptoms vs Sal/Flu high-dose b.i.d. + Tio o.d. delivered via two inhalers, at a reduced ICS dose. References:1.Rossi A. et al. Int J Chron Obstruct Pulmon Dis 2015;10:1383-92; 2.Kemp JP. et al. J Allergy Clin Immunol 2000;106:485-92

Background The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. Methods Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting β2-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 μg) or medium-dose (150/50/80 μg) o.d. or SAL/FLU high-dose (50/500 μg) b.i.d.+Tio 5 μg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. Results IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and −0.038, respectively; both p Conclusions IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

Background Omalizumab improves clinical outcomes in patients with asthma. Several studies have shown lung function improvements with omalizumab; however, this has not been examined exclusively in adolescents. Objective To assess the effect of omalizumab on lung function and eosinophil counts in adolescents with uncontrolled moderate-to-severe allergic asthma. Methods In this post hoc analysis, data from adolescents aged 12 to 17 years from 8 randomized trials of omalizumab were pooled (studies 008, 009, and 011, and SOLAR, INNOVATE, ALTO, ETOPA, and EXTRA). Changes from baseline to end of study in forced expiratory volume in 1 second (FEV1), percent predicted FEV1 (ppFEV1), forced vital capacity (FVC), and blood eosinophil counts were assessed by fitting an analysis of covariance model and calculating least squares mean (LSM) difference for omalizumab vs placebo. Results A total of 340 adolescents were identified (omalizumab, n = 203 [59.7%]; placebo, n = 137 [40.3%]). Omalizumab increased all baseline lung function variables more than placebo by end of study: LSM treatment differences (95% confidence interval) were 3.0% (0.2%-5.7%; P = .035), 120.9 mL (30.6-211.2 mL; P = .009), and 101.5 mL (8.3-194.6 mL; P = .033) for ppFEV1, absolute FEV1, and FVC, respectively. The LSM difference demonstrated a greater reduction in eosinophil counts for omalizumab vs placebo: −85.9 cells/μL (−137.1 to −34.6 cells/μL; P = .001). Conclusion Omalizumab was associated with lung function improvements and circulating eosinophil counts reductions in adolescents with moderate-to-severe uncontrolled asthma. Findings emphasize the effect of omalizumab in young patients and the need to optimize treatment early in the disease course. https://clinicaltrials.gov/: NCT00314574, NCT00046748, NCT00401596

We conducted a large global survey, Still Fighting for Breath, in patients with severe persistent asthma, 10 years after the Fighting for Breath survey to assess the impact of disease on patients' lives and to determine if control and management have changed in recent years. Data were collected from 1333 adults (aged >18 years) and caregivers of children (aged 6–17 years) with severe persistent asthma from nine countries through an online survey conducted in 2016 by GfK. A decade after the first survey, our results showed that the impact of severe asthma has not changed significantly and a high proportion of patients with severe asthma remain inadequately controlled. A large discrepancy was observed between the proportion of patients who perceived their asthma to be well controlled (42%) and the proportion of patients who reported to be well controlled as per the Global Initiative for Asthma (GINA) assessment (6%). Although most patients perceived their asthma to be controlled, many experienced frequent symptoms that affected their daily lives. Thus, there is a need for improved management (support and strategies) of patients with severe persistent asthma and improved coordination of efforts that would enable these patients to achieve better disease control., There is a need for improved management of patients with severe persistent asthma to achieve better disease control http://ow.ly/rv5K30mQdGG

Objective: To assess the impact of severe asthma on daily life (asthma control, activity, psychological aspects, treatment). Methods: Data were collected from 1333 adults and children (through caregivers) with severe persistent asthma in 9 countries through an online survey done by GfK on behalf of Novartis in 2016 (Table 1a). Results: Severe asthmatics were diagnosed by respiratory physicians (42%), general practitioners (30%), allergists (21%) and paediatricians (6%). On average, adults were diagnosed 15 years ago, adolescents 7 years and pediatrics 3 years ago. As per patients’ knowledge, 47% were non-allergic. A large discrepancy was seen between real-life control according to GINA guidelines (6%) and self-estimated control (42%). In the previous year, 73% of patients experienced exacerbations that required treatment from a healthcare professional (emergency room, ambulance, physician at home); 34% had ≥2 exacerbations (13%, three; 7%, four; 3%, five; 11%, more than 5). On an average, 20 days of OCS use was reported in the last 6 months. The impact on psychology and activities is shown in Table 1b. Conclusions: Although asthma control is GINA’s main goal, severe asthmatics are uncontrolled with poor quality of life as reflected in their psychological profile and everyday activities. There is a strong disconnect between perceived and actual asthma control. More action is needed to help severe asthmatics achieve control and live normal unrestricted lives.

Introduction: Asthma control assessment is important in patients (pts) with severe asthma, where OCS use, exacerbations and mortality risk are high. We compared the actual (as per GINA) and perceived control (PC) in pts with severe asthma. Methods: Data were collected in 1333 pts [adult (>18yrs) and caregivers of minor pts (6–17yrs)] with severe persistent asthma from 9 countries via a global 20-minute online survey conducted by GfK for Novartis during 2016. Results: A discrepancy was seen between real-life asthma control as per GINA guidelines (6%) and PC (42%). A decision tree analysis showed that higher WHO-5 score (Figure 1a) was a predictor of positive subjective perception of asthma control by pts with uncontrolled asthma based on GINA (disconnect between objective and subjective disease control; Figure 1b ). More days on oral corticosteroids and bad sleep quality were predictors of negative objective asthma control (based on GINA) for pts who subjectively perceive their asthma as well controlled. These analysis fall short in explaining what drives the discrepancy between objective and subjective control of asthma in general due to small sample sizes in particular subgroups. Conclusion: A discrepancy exists in ‘asthma control’ as per GINA and as perceived by patients. We identified the predictors of perceived and actual control (GINA); however, the reason for disconnect between these measures still remains unknown.