Rationale:Interleukin-33 (IL-33) is a key orchestrator of broad-spectrum downstream host-response mechanisms, including inflammation, tissue homeostasis, and repair. Dysregulation of IL-33 signaling is associated with several pathological conditions. The FRONTIER program comprised four phase 2 signal-finding studies of tozorakimab, an anti-IL-33 human immunoglobulin G1 monoclonal antibody, in diabetic kidney disease (FRONTIER-1), moderate-to-severe atopic dermatitis (FRONTIER-2), moderate-to-severe asthma (FRONTIER-3), and moderate-to-severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER-4). This analysis assessed the safety data from these clinical studies. Methods:FRONTIER-1-4 were randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of tozorakimab in adults. Participants received subcutaneous tozorakimab (FRONTIER-1, 30-300 mg; FRONTIER-2, 60-600 mg; FRONTIER-3, 300-600 mg; FRONTIER-4, 600 mg) or placebo every 4 weeks for 4-7 doses, with follow-up periods ranging from 24-36 weeks from the first dose. Safety (adverse events [AEs], serious AEs, and AEs of special interest) and immunogenicity endpoints from the FRONTIER studies were summarized. Results:In total, 1076 patients were included in this analysis (tozorakimab, n=738; placebo, n=338). Deaths occurred only in FRONTIER-1, in similar proportions between treatment groups (tozorakimab, 0.9%; placebo, 0.8%), and were unrelated to tozorakimab. The proportion of participants experiencing at least one treatment-emergent AE (TEAE) or serious TEAEs was generally similar between tozorakimab and placebo groups. The proportion of participants experiencing AEs of special interest, including events of progression of heart failure, was low (tozorakimab, 0.0-1.5%; placebo, 0.0-0.8%), with no meaningful differences between groups; the frequency of injection-site reactions was however higher in tozorakimab than in placebo recipients (tozorakimab, 1.2-20.9%; placebo, 0.0-4.9%). No clinically significant trends were observed in laboratory or vital-sign parameters, and immunogenicity was low. Conclusion:Tozorakimab was well tolerated across a range of inflammatory diseases, with no safety concerns identified.

Background:Interleukin (IL)-33 is implicated in the initiation and progression of asthma. FRONTIER-3 (NCT04570657) was a phase 2a study to investigate tozorakimab, an anti-IL-33 monoclonal antibody, in adults with moderate-to-severe early-onset asthma receiving standard of care. Methods:Patients were randomised 1:1:1 to tozorakimab 600 mg, tozorakimab 300 mg or placebo, once every 4 weeks subcutaneously. The primary end-point was change from baseline to week 16 in pre-bronchodilator (pre-BD) forced expiratory volume in 1 s (FEV1) measured in clinic. Secondary and exploratory end-points included home pre-BD FEV1, home peak expiratory flow (PEF), rescue medication use, CompEx, pharmacokinetics, immunogenicity and safety. Results:The intent-to-treat (ITT) population included 235 patients with a median disease duration of >30 years; a majority had a baseline blood eosinophil count (BEC) <300 cells·μL-1. At week 16, tozorakimab did not show a statistically significant improvement in change from baseline in clinic pre-BD FEV1 versus placebo (least-squares mean difference (LSMD) (80% CI), 600 mg: 4 mL (-71-79), p=0.473; 300 mg: 36 mL (-38-111), p=0.267). Compared with the ITT population, a pre-specified subgroup of patients with ≥2 prior exacerbations showed greater improvements in clinic pre-BD FEV1 at week 16 with tozorakimab versus placebo (LSMD (80% CI), 600 mg: 212 mL (102-322), p=0.007; 300 mg: 77 mL (-34-187), p=0.186). Tozorakimab also showed greater improvements in home FEV1 and home PEF versus placebo at week 16 in patients with ≥2 prior exacerbations than in the ITT population. Tozorakimab was well tolerated. Conclusions:Although FRONTIER-3 did not meet the primary study end-point, tozorakimab treatment showed encouraging efficacy signals in patients with early-onset asthma and a history of exacerbations.

Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-IL-33 monoclonal antibody) in moderate-to-severe COPD patients with chronic bronchitis receiving dual or triple inhaled therapy. FRONTIER-4 was a phase 2a, randomized, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary endpoint was change in pre-bronchodilator (BD) FEV1 from baseline to week 12. Secondary outcomes included post-BD FEV1, time-to-first COPDCompEx event and safety. The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase from baseline in pre-BD FEV1 (least-squares mean [LSM]: 24 mL [80% confidence interval (CI): -15,63]; p=0.216) that was not statistically significant, and in post-BD FEV1 (LSM: 67 mL [80% CI: 17,116]; p=0.044), when compared with placebo. Tozorakimab showed improvements versus placebo (LSM [80% CI]) in change from baseline in pre-BD FEV1 (69 mL [9,130]; p=0.072) and post-BD FEV1 (124 mL [47,201]; p=0.020) at week 12 in a pre-specified subgroup of patients with ≥2 prior exacerbations. Tozorakimab did not significantly reduce the risk of COPDCompEx events (HR: 0.79 [80% CI: 0.57,1.11]; p=0.186) in the intent-to-treat population, although there were greater effects in patients with ≥2 prior exacerbations (hazard ratio: 0.61 [80% CI: 0.37,1.00]). Results were similar in former and current smokers. Tozorakimab was well tolerated. Although the primary endpoint was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.

BACKGROUND:Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy. METHODS:FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV1, time-to-first COPD composite exacerbation event and safety. RESULTS:The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV1 (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV1 (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements versus placebo in change from baseline in pre-bronchodilator FEV1 (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV1 (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated. CONCLUSION:Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.

Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24 kg/m 2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300 mg [2 mL] or 600 mg [4 mL]) or matching placebo (2 or 4 mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7 μg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

AimsThis study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data.MethodsThe analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach.ResultsThe final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg.ConclusionsThe PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24 kg/m2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300 mg [2 mL] or 600 mg [4 mL]) or matching placebo (2 or 4 mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7 μg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

Background: Increased serum levels of the alarmin cytokine Interleukin (IL)-33 are associated with poor outcomes in hospitalised COVID-19 patients. Tozorakimab is an IL-33 neutralising monoclonal antibody. Aim: To evaluate efficacy and safety of tozorakimab in the Phase 2a ACCORD-2 COVID-19 study (EudraCT:2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2 adaptive study in adults hospitalised with COVID-19 (WHO Ordinal Scale score of 3–5), randomised 1:1 to tozorakimab 300mg+standard of care [SoC] or SoC alone. Recruitment occurred in two time periods; in period 2, dexamethasone was the SoC. Primary endpoint was time to sustained 2-point clinical improvement or hospital discharge, with other endpoints including death or respiratory failure, mortality, ICU admissions and safety. Results: Of 97 patients eligible for efficacy analyses, 53 received tozorakimab+SoC and 44 received SoC alone. Whilst median time to response was similar in both arms, tozorakimab numerically reduced the risk of death or respiratory failure, mortality, and ICU admissions vs SoC (Table), and was well-tolerated. Subgroup analyses suggest that high baseline serum levels of IL-33/sST2 complex may be a predictor of tozorakimab response (Table). Conclusion: ACCORD-2 analyses suggest that tozorakimab may be a novel therapy improving outcomes in patients hospitalised with COVID-19.

Background Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70–1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27–1.12; p=0.26), while the OR was 0.31 (80% CI 0.09–1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

Introduction: Interleukin (IL)-33 is released from the airway epithelium and can sense the proteolytic and oxidative environment (Cohen, E.S. et al. Nat Comms 2015; 6:8327; Scott, I.C. et al. Sci Rep 2018; 8:3363). IL-33 amplifies inflammation via its receptor ST2 and is associated with type 2 immunity. IL-33 exists in reduced and oxidized forms of IL-33 but can be sequestered by soluble ST2 (sST2), however, there are no assays that distinguish forms. Inconsistencies with IL-33 detection with commercial assays might be due to the differential detection of these antigenically distinct forms. Here we describe new assays for IL-33 forms and measurements in patient samples. Methods: anti-IL-33 mAb were paired in S-plex assays (MSD) with lower limit of detection (LLOD): reduced IL-33 (~16 fg/ml), oxidized (ox) (~100 fg/ml) or IL-33/sST2 complexes (~100 fg/ml). Assays were evaluated in serum from healthy (n=20), asthmatics (n=14) and COPD patients (n=16) or nasal mucosal lining fluid (MLF) from atopics (n=6) following allergen challenge (NAC, 0-24h). Results: We detected comparable levels of IL-33/sST2 complex (~1-5 pg/ml) in serum from healthy individuals and patients. Total sST2 in serum was similar between patients but at high levels (~10-100 ng/ml). Reduced and oxIL-33 were undetected in serum. In contrast, we detected reduced and oxIL-33 in MLF from atopics with levels increased post-NAC that peaked after 1 h (20-1000 pg/ml). In comparison, PGD2 (1-3 ng/ml) peaked after 15 min and IL-5 (~25-300 pg/ml) after 3-10 h. IL-33/sST2 complexes were low in MLF. Conclusions: We have generated novel assays for detection of IL-33 forms that will provide insights into mechanisms regulating IL-33 activity.

Rationale: IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. Objectives: Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF. Methods: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. Measurements and Main Results: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC-greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively. Conclusions: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints.

Background: IL-13 has an important role in atopic dermatitis (AD) pathogenesis. Tralokinumab is a fully human mAb that potently and specifically neutralizes IL-13. Objective: We sought to evaluate the efficacy and safety of tralokinumab in adults with moderate-to-severe AD. Methods: In this phase 2b study (NCT02347176), 204 adults were randomized 1: 1: 1: 1 to receive 45, 150, or 300 mg of subcutaneous tralokinumab, or placebo, every 2 weeks for 12 weeks with concomitant topical glucocorticoids. Coprimary end points were change from baseline in Eczema Area Severity Index score and percentage of participants with an Investigator's Global Assessment response (0/1 score and reduction of >= 2 grades from baseline) at week 12. Results: At week 12, 300 mg of tralokinumab significantly improved change from baseline in Eczema Area Severity Index score versus placebo (adjusted mean difference, -4.94; 95% CI, -8.76 to -1.13; P =.01), and a greater percentage of participants achieved an Investigator's Global Assessment response (26.7% vs 11.8%). Greater responses were found in participants with greater concentrations of biomarkers of increased IL-13 activity. Participants treated with 300 mg of tralokinumab demonstrated improvements in SCORAD, Dermatology Life Quality Index, and pruritus numeric rating scale (7-day mean) scores versus placebo. Upper respiratory tract infection was the most frequent treatment-emergent adverse event reported as related to study drug in the placebo (3.9%) and pooled tralokinumab (3.9%) groups. Conclusions: Tralokinumab treatment was associated with early and sustained improvements in AD symptoms and an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with AD.

Abstract not available. Disclosures: Study sponsored by LEO Pharma Copyright 2018 SKIN

INTRODUCTION:The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥ 30 IU/mL.METHODS:Subjects with atopy and/or baseline IgE ≥ 30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made.RESULTS:MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events.CONCLUSIONS:The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab.FUNDING:MedImmune.TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT01544348.

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue β(2)-agonist use and safety. Numerical end-points are reported as mean±sd. At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV(1)) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. β(2)-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV(1) following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab. No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.