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Introduction In Phase II trials, lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p

Introduction Patients with COPD and at risk of exacerbations have poor health status (GOLD 2016); exacerbations are associated with worsening health status. The FLAME study compared the efficacy of dual-bronchodilation with IND/GLY (LABA/LAMA) to SFC (LABA/ICS) in patients with moderate-to-very severe COPD with an increased risk of exacerbations. Outcomes compared include the health status of such patients. Methods This multi-centre, double-blind, 52-week (wk) study randomised (1:1) patients (with moderate-to-very severe COPD, history of ≥1 COPD exacerbation in the past 12 months and post-bronchodilator FEV 1 predicted ≥25%− Results Of 3362 patients randomised, 82.2% completed 52 wks of treatment. The treatment difference between regimens in SGRQ-C scores was between −1.2 and −1.8 (all p values ≤0.003) from wk 12 through wk 52 representing better health status in the IND/GLY arm. A higher proportion of patients in the IND/GLY arm (42.2-49.5%) showed a clinically meaningful improvement (≥4units), from wk 12 onwards, vs SFC arm (40.0-43.8%) (all p values ≤0.024). This improvement persisted over the 52-wk period and, altogether, patients receiving IND/GLY were 30% more likely to achieve a clinically meaningful improvement in SGRQ-C scores at wk 52. Conclusions IND/GLY was superior to SFC in improving health status (SGRQ-C) in patients with moderate-to-very severe COPD, suggesting its potential for management of COPD patients at risk of exacerbation.

Introduction Rescue Medication (RM) use is an indirect measure of symptom burden in COPD patients 1 . FLAME study assessed the use of daily RM with IND/GLY vs SFC in moderate-to-very severe COPD patients with ≥1 exacerbation in the previous year. Methods FLAME was a 52-week, multicentre, double-blind study. Patients with moderate-to-very severe COPD were randomised (1:1) to IND/GLY 110/50 µg o.d. or SFC 50/500 µg b.i.d. RM (albuterol/salbutamol) was used on 9as needed9 basis throughout the study and was captured using a daily patient e-diary. Results In total, 3362 patients were randomised. Patients in the IND/GLY treatment arm showed significantly lower mean daily, day-time number of RM puffs used and % days with no RM use vs SFC over the 52 weeks treatment period. Reductions in the night-time number of puffs were comparable between IND/GLY and SFC (table). Conclusion IND/GLY treatment resulted in a significant reduction in mean daily RM use and an increase in days without RM use compared with SFC in patients with moderate-to-very severe COPD during 52 week treatment period. Reference 1. Jenkins CR et al. BMC Pulm Med. 2015; doi: 10.1186/s12890-015-0077-0.

Introduction The FLAME study compared the effect of IND/GLY vs SFC on exacerbations in COPD patients with a risk of exacerbation. Here we present the rate of reduction of moderate or severe exacerbations and lung function changes based on blood eosinophils in moderate-to-very severe COPD patients. Methods This was a 52-week, multicentre study. Patients with moderate-to-very severe COPD, post-bronchodilator FEV1 ≥25% - 300 and ≥300) and percentages ( Results 3362 patients were randomised to IND/GLY (n=1680) or SFC (n=1682). The annualised rate of moderate or severe exacerbations was significantly lower in IND/GLY-treated vs SFC-treated patients9 at all eosinophil counts, although not significant for small number of patients with ≥300 cells/µL. The lung function was significantly improved at all the visits with IND/GLY vs SFC irrespective of eosinophil count (Table 1). Conclusion In patients with high risk of exacerbations, IND/GLY was superior in reducing moderate or severe exacerbations and showed significant improvement in lung function vs SFC independent of blood eosinophil counts.

Introduction LABA/ICS combination and/or LAMA have been the first choice of treatment for COPD patients with high risk of exacerbation. FLAME is the first study which compared rate and risk of exacerbations with IND/GLY to SFC in patients with at least one exacerbation in the previous year. Methods Patients with post-bronchodilator FEV 1 ≥25%- Results In total, 3362 patients were randomised. The rate of all exacerbations was lower with IND/GLY compared with SFC (Figure 1A) in subgroups defined by age, smoking status, exacerbation history, and disease severity. IND/GLY also reduced rate of moderate or severe exacerbations in all subgroups except for

Introduction As per GOLD strategy, ICS combined with a LABA and/or a LAMA is a first line choice to treat COPD patients (pts) at a high risk of exacerbations. However, there is widespread use of ICS in COPD pts who do not meet the GOLD criteria for its use. ICS use has been associated with systemic side effects such as suppression of hypothalamic pituitary-adrenal (HPA) axis function (decreased production of endogenous glucocorticosteriods). This reflects the systemic burden of ICS which can be associated with long-term consequences. Here, we present results for indacaterol/glycopyrronium (IND/GLY; LABA/LAMA) vs. salmeterol/fluticasone (SFC; LABA/ICS) in terms of HPA-axis function from the FLAME study. Methods FLAME was a 52-week, multicentre, double-blind study that randomised (1:1) moderate-to-very severe COPD pts (postbronchodilator FEV 1 ≥25 and Results Of 3362 randomised pts, 535 were included in the urine cortisol set. Median urine cortisol level decreased by 8.67% with SFC treatment, while the level increased by 1.42% with IND/GLY treatment from baseline at Week 52. Consistently, median cortisol/creatinine ratio reduced with SFC (by 10.39%) and increased with IND/GLY (by 5.62%) from baseline following 52-week treatment. Conclusion SFC but not IND/GLY treatment was associated with suppression of HPA-axis function in moderate-to-very severe COPD patients, confirming systemic effects of SFC.

Background The RAPID trial showed that infusion of alpha 1 -proteinase inhibitor (A 1 -PI; 60mg/kg/week) slows lung density decline in A 1 -PI-deficient patients (Chapman et al., Lancet, In Press). Aim To assess the safety of bi-weekly infusion of 120mg/kg A 1 -PI (Zemaira ® , CSL Behring) given to cover 2-week periods when patients were unable to receive weekly dosing. Methods Subjects were monitored for 7 days post biweekly 120mg/kg A 1 -PI infusion and the profile of adverse events (AEs) compared with placebo. Results In total, 75 of 93 subjects (80.6%) received 333 bi-weekly infusion of 120mg/kg A 1 -PI (3.9% of 8,538 total infusions), and 70 of 87 subjects (80.5%) received 374 bi-weekly placebo infusions (5.2% of 7,192 total infusions). Predicted C max was 45.1µM after 120mg/kg and 28.5µM after 60mg/kg. The number of AEs after 120mg/kg A 1 -PI was comparable to placebo. Three serious AEs (bladder cancer; transurethral prostatectomy; chest pain) occurred with 120mg/kg A 1 -PI and none with placebo. None were considered related to treatment. Conclusions Bi-weekly 120mg/kg A 1 -PI infusion was well tolerated, with an AE profile comparable to placebo. This short-term option enhances convenience for patients in the future.

Background: Zemaira (A 1 -PI; CSL Behring) is a preparation of human alpha-1 proteinase inhibitor used for augmentation therapy in individuals with A 1 -PI deficiency (AATD) and clinical evidence of emphysema. RAPID (NCT00261833) compared the efficacy and safety of weekly 60 mg/kg of A 1 -PI with placebo. Aim: To characterize the relationship between dose and A 1 -PI concentration, and the exposure-response relationship between A 1 -PI concentration and lung density decline. Methods: The relationship between dose and A 1 -PI concentration was modeled using a linear model with weight, age and baseline A 1 -PI as covariates. The exposure-response relationship between A 1 -PI concentration and lung density at total lung capacity was assessed using a disease progression model with baseline A 1 -PI, FEV 1 , age and BMI as covariates. Disease progression rates were quantified as a function of A 1 -PI concentration using linear and multiple nonlinear models. Results: The relationship between dose and A 1 -PI concentration was linear and demonstrated consistent levels across the range of weights observed in RAPID. The relationship between A 1 -PI concentration and lung density suggested a continuously increasing exposure-response relationship across the exposure levels following 60 mg/kg weekly doses. The mean model predicted a beneficial effect of Zemaira on the rate of lung density decline (0.88 g/L/yr versus 2.17 g/L/yr for placebo patients). Conclusions: Weight-based dosing resulted in achieving consistent exposure levels. 60mg/kg dose was an effective dose. Higher levels of A 1 -PI may result in improved efficacy in some patients.

Introduction: RAPID (NCT00261833), the largest (N=180) randomized placebo-controlled trial assessing emphysema progression in alpha-1 antitrypsin deficiency (AATD) completed to date, was followed by the open-label RAPID Extension trial (NCT00670007). Methods: Subjects in RAPID received alpha-1 proteinase inhibitor (A 1 -PI, Zemaira; CSL Behring) or placebo for 2 yrs. Eligible subjects (N=140) continued in Extension to receive A 1 -PI for another 2 yrs. The Early-Start (N=75) and Delayed-Start (n=64) cohorts were defined by their treatment with A 1 -PI and placebo in RAPID, respectively. Computed tomography (CT) lung density decline rate was measured annually and forced expiratory volume in 1 sec (FEV 1 ) was measured quarterly. Results: Annual CT lung density decline rate in the first 2 yrs was less by 0.75 g/L/yr in the Early-Start cohort (-1.51 g/L/yr vs -2.26 g/L/yr, p=0.021 one sided). In the Delayed-Start cohort, lung density decline was reduced to -1.26 g/L/yr after switching to A 1 -PI. Changes in FEV 1 over 4 yrs correlated significantly with changes in CT lung density. Conclusions: In RAPID, A 1 -PI therapy reduced the rate of lung density decline compared to placebo. Over 48 months, the Delayed-Start cohort showed a greater loss of lung density. These data demonstrate a disease-modifying effect of A 1 -PI therapy, suggesting that early treatment may reduce emphysema progression in AATD patients.

Background: Alpha 1 proteinase inhibitor (A 1 -PI; Zemaira, CSL Behring) is used for augmentation therapy in patients with A 1 -PI deficiency (AATD). RAPID, a randomized, double-blind, placebo-controlled study, demonstrated a lower rate of lung density decline in patients treated with 60mg/kg/week A 1 -PI compared to placebo. Serum A 1 -PI levels (normal range 20–53µM) were measured every 3 months over 2 years. Aim: Characterize pharmacokinetics (PK) of A 1 -PI in deficient patients enrolled in RAPID. Methods: A one-compartmental model was developed using nonlinear mixed effects modeling. Residual variability was estimated separately for samples collected 6-8 days post-dose (trough) and samples collected outside this time window. A full covariate model was used to test covariates (weight, sex, age, baseline A 1 -PI and genotype) on PK parameters. Simulation of 1,000 patients after 3 months of A 1 -PI dosing at 60mg/kg/week was used to calculate C avg , C max and C trough concentrations at steady-state (ss). Results: A 1 -PI PK was well described using a one-compartment model with parameter estimates (inter-individual variability) of 45.2mL/day (28.7%) for clearance, 10.0L (61.2%) for volume of distribution. The half-life estimate (t 1/2 ) of A 1 -PI=6.8 days and residual error for C trough was estimated to be 21.4%. No relationship could be defined between any of the covariates tested and variability in the PK parameters. The mean (90% CI) model predicted ss C avg =20.9µM (14.8–26.7), C max =28.5µM (13.3–44.7) and C trough =16.2µM (11.1–22.6). Conclusions: Weekly infusion of 60mg/kg A 1 -PI provides patients with average A 1 -PI serum concentrations well above the accepted therapeutic threshold of 11µM and at the lower end of normal.