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Gene Colice - One of the best experts on this subject based on the ideXlab platform.

  • application of structured statistical analyses to identify a biomarker predictive of enhanced Tralokinumab efficacy in phase iii clinical trials for severe uncontrolled asthma
    BMC Pulmonary Medicine, 2019
    Co-Authors: Mattis Gottlow, Karin Bowen, Peter Wessman, David Svensson, Ilya Lipkovich, Monika Huhn, Gene Colice
    Abstract:

    Tralokinumab is an anti–interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict Tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2. The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data. FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting Tralokinumab efficacy. A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced Tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population. STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

  • Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma
    Drug Safety, 2019
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice
    Abstract:

    Introduction Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. Objective The objectives of this study were to characterize the potential immunogenic properties of Tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. Methods The oligosaccharide structure of Tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of Tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). Results No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of Tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G_4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no Tralokinumab-related severe hypersensitivity or anaphylaxis reactions. Conclusion Preclinical assessments suggested a low likelihood of immunogenicity for Tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between Tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with Tralokinumab treatment. Together, the results suggest that Tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

  • Tralokinumab did not demonstrate oral corticosteroid sparing effects in severe asthma
    European Respiratory Journal, 2019
    Co-Authors: William W Busse, Millie Wang, Karin Bowen, Guy Brusselle, Stephanie Korn, Piotr Kuna, A Magnan, David Cohen, Teresa Piechowiak, Gene Colice
    Abstract:

    Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects. This 40-week, randomised, double-blind trial evaluated the OCS-sparing potential of Tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting β2-agonists. Overall, 140 patients were randomised to Tralokinumab 300 mg or placebo (n=70 in each group) administered subcutaneously every 2 weeks. The primary end-point was percentage change from baseline in average OCS dose at week 40, while maintaining asthma control. Secondary end-points included proportion of patients with a prescribed maintenance OCS dose of ≤5 mg, those with a ≥50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed. At week 40, the percentage reduction from baseline in the final daily average OCS dose was not significantly different between Tralokinumab and placebo (37.62% versus 29.85%; p=0.271). There were no significant between-treatment differences for any secondary end-point. Overall, reporting of adverse events and serious adverse events were similar for the Tralokinumab and placebo groups. Although a greater proportion of Tralokinumab-treated patients reported upper respiratory tract infections (35.7% versus 14.3%), there were no reported cases of pneumonia. Overall, Tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma.

  • evaluation of antibody properties and clinically relevant immunogenicity anaphylaxis and hypersensitivity reactions in two phase iii trials of Tralokinumab in severe uncontrolled asthma
    Drug Safety, 2019
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice
    Abstract:

    Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. The objectives of this study were to characterize the potential immunogenic properties of Tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. The oligosaccharide structure of Tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of Tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of Tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no Tralokinumab-related severe hypersensitivity or anaphylaxis reactions. Preclinical assessments suggested a low likelihood of immunogenicity for Tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between Tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with Tralokinumab treatment. Together, the results suggest that Tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

  • no clinically relevant hypersensitivity reactions in clinical trials with Tralokinumab in asthma
    European Respiratory Journal, 2018
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Gene Colice
    Abstract:

    Introduction: Anaphylaxis and severe hypersensitivity reactions are a concern for any biologic substance. The anti-IL-13 agent Tralokinumab is produced by a murine cell line and may thus incorporate immunogenic α-Gal epitopes in the Fab domain. Objectives: 1) To identify possible events of anaphylaxis or severe hypersensitivity reactions in pivotal clinical studies of Tralokinumab in severe, uncontrolled asthma. 2) To evaluate development of anti-drug antibodies (ADA) post dosing. 3) To characterize the glycosylation of Tralokinumab and the presence of α-Gal epitopes in the Fab domain and Fc region. Methods: Drug safety was evaluated in the pivotal Phase III clinical studies (NCT02161757 and NCT02194699). Adverse events associated with anaphylaxis/hypersensitivity were captured with MedDRA SMQs: Hypersensitivity, Anaphylactic Reaction and Anaphylactic/Anaphylactoid Shock Conditions. Relevant cases were assessed by an independent expert for anaphylaxis (Sampson criteria). ADA and carbohydrate structure of Tralokinumab were characterized by standard techniques. Results: Data from more than 1200 subjects indicate that there were no cases of anaphylaxis or severe hypersensitivity reactions related to Tralokinumab administration. Less than 1% of the Tralokinumab-treated subjects had ADA formation and no glycoforms with α-Gal epitopes were detected in the Fab region of the antibody. Conclusion: No safety concerns have been identified with respect to anaphylaxis/hypersensitivity and immunogenicity of Tralokinumab in clinical studies. Tralokinumab is not considered to constitute an increased risk for anaphylaxis/hypersensitivity reactions by being manufactured in a murine cell line.

Edward Piper - One of the best experts on this subject based on the ideXlab platform.

  • Tralokinumab for severe uncontrolled asthma stratos 1 and stratos 2 two randomised double blind placebo controlled phase 3 clinical trials
    The Lancet Respiratory Medicine, 2018
    Co-Authors: Gene Colice, Edward Piper, Reynold A Panettieri, Peter Wessman, Ulf Sjobring, Annamaria Peterffy, Kkarin Bowen, Christopher E Brightling
    Abstract:

    Summary Background Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of Tralokinumab in this population. Methods STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12–75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β 2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive Tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive Tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced Tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). Findings STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: Tralokinumab every 2 weeks (n=398), Tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: Tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, Tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI −20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, Tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, Tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI −33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous Tralokinumab trials. Interpretation Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. Funding AstraZeneca.

  • a randomized placebo controlled single ascending dose study to assess the safety tolerability pharmacokinetics and immunogenicity of subcutaneous Tralokinumab in japanese healthy volunteers
    Drug Metabolism and Pharmacokinetics, 2017
    Co-Authors: Paul Baverel, Edward Piper, Raffaella Faggioni, Shinya Ueda, Tomoko Yoshioka, Hakop Gevorkyan
    Abstract:

    Abstract Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous Tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. The frequency and severity of TEAEs was similar across Tralokinumab doses. Cmax, AUC(0–t), and AUC(0–inf) increased in a dose-proportional manner, and mean t1/2 ranged from 20 to 25 days. No anti-drug antibodies were detected. A post-hoc pooled population PK modeling analysis, incorporating PK data from this study, demonstrated that Japanese individuals had greater systemic exposure to Tralokinumab than non-Japanese individuals. This difference was not clinically relevant and was primarily due to differences in body weight, with lower body weight associated with greater PK exposure. Japanese ethnicity was not a significant predictor of Tralokinumab PK. This study indicates that single-dose subcutaneous administration of Tralokinumab 150–600 mg was well tolerated in Japanese healthy volunteers, and supports the 300 mg dose selection for Japanese patients with asthma in ongoing clinical trials.

  • effect of Tralokinumab on gina control in severe uncontrolled asthma
    European Respiratory Journal, 2017
    Co-Authors: Christopher E Brightling, Edward Piper, Peter Wessman, Gene Colice
    Abstract:

    Background: In a Phase 2b trial in patients with severe, uncontrolled asthma, the anti–Il-13 monoclonal antibody Tralokinumab improved lung function and, in patients with increased baseline periostin and DPP-4, reduced asthma exacerbations [Lancet Respir Med 2015]. We retrospectively analyzed this clinical trial to assess the effect of Tralokinumab on asthma control, as per GINA 2016 categorization. Methods: In a 52-week double-blind study (NCT01402986) 452 adults with severe, uncontrolled asthma taking high-dose ICS/LABA were randomized to Tralokinumab 300mg/placebo (PBO) every 2 weeks (Q2W) or Q2W for 12 weeks followed by every 4 weeks (Q4W). Asthma was categorized as partly or well controlled during previous week after 52 weeks’ treatment using established GINA methods. All analyses were descriptive. Results: All patients entering the study had uncontrolled asthma. At week 52, 58% of patients in the Tralokinumab Q2W group were partly or well controlled vs. 48% of PBO recipients. Patients receiving Tralokinumab Q2W with baseline periostin and DPP-4 above the median (‘periostin-high’ and ‘DPP-4-high’) had higher rates of well controlled asthma. Conclusions: Tralokinumab treatment, 300mg Q2W, may provide a better chance for severe, uncontrolled asthma patients to achieve well controlled asthma status using GINA criteria, particularly those with elevated periostin and DPP-4. Supported by AstraZeneca

  • pharmacokinetics of Tralokinumab in adolescents with asthma implications for future dosing
    British Journal of Clinical Pharmacology, 2015
    Co-Authors: Paul Baverel, Balaji Agoram, Edward Piper, Meena Jain, Iwona Stelmach, Sara Sandbach, Piotr Kuna
    Abstract:

    Aims Tralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin-13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single Tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents. Methods Adolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of Tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57-day follow-up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents. Results Twenty adolescents (12–17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of Tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day–1]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight-based (4 mg kg–1) and fixed (300 mg) fortnightly subcutaneous doses of Tralokinumab. Conclusion Single-dose administration of Tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.

  • Effect of anti-IL-13 treatment on airway dimensions in severe asthma: Subgroup analysis
    European Respiratory Journal, 2015
    Co-Authors: Christopher E Brightling, Gene Colice, Edward Piper, Martin Braddock, Lars H. Nordenmark, Meena Jain, Göran Tornling
    Abstract:

    Introduction: The effects of the anti-IL-13 monoclonal antibody Tralokinumab (tralo) (CAT-354) on airway dimensions were assessed in a subgroup of subjects from a Phase 2b study. Methods: In a 52-week double-blind study (NCT01402986) adults with severe asthma (history of airway reversibility, ≥2 exacerbations in previous year and FEV1 40–80% predicted or ACQ-6 score ≥1.5 at baseline) taking ICS/LABA were randomized to tralo 300 mg/placebo (PBO) every 2 weeks (Q2W), or Q2W for 12 weeks followed by every 4 weeks (Q4W).Quantitative computed tomography (CT) imaging of the upper lung was performed in 26 subjects at baseline and end of treatment. An exploratory post-hoc analysis estimated changes in airway lumen/wall parameters in specific airway segments using VIDA Apollo software. Subjects were combined in two groups: total PBO n=12 (n=6 [Q2W] + 6 [Q4W]) and total tralo n=14 (n=6 [Q2W] + 8 [Q4W]). Results: Sub-segmental lumen area increased by 16.8% (tralo) and 0.3% (PBO) (mean difference: 16.5%; 95% CI: 2.7−30.2%; p Conclusions: CT imaging detected significant improvements in airway lumen parameters with tralo compared with PBO added to ICS-LABA and may provide further mechanistic insights into the effects of IL-13 blockade.

Christopher E Brightling - One of the best experts on this subject based on the ideXlab platform.

  • Tralokinumab for severe uncontrolled asthma stratos 1 and stratos 2 two randomised double blind placebo controlled phase 3 clinical trials
    The Lancet Respiratory Medicine, 2018
    Co-Authors: Gene Colice, Edward Piper, Reynold A Panettieri, Peter Wessman, Ulf Sjobring, Annamaria Peterffy, Kkarin Bowen, Christopher E Brightling
    Abstract:

    Summary Background Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of Tralokinumab in this population. Methods STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12–75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β 2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive Tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive Tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced Tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). Findings STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: Tralokinumab every 2 weeks (n=398), Tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: Tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, Tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI −20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, Tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, Tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI −33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous Tralokinumab trials. Interpretation Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. Funding AstraZeneca.

  • effect of Tralokinumab on gina control in severe uncontrolled asthma
    European Respiratory Journal, 2017
    Co-Authors: Christopher E Brightling, Edward Piper, Peter Wessman, Gene Colice
    Abstract:

    Background: In a Phase 2b trial in patients with severe, uncontrolled asthma, the anti–Il-13 monoclonal antibody Tralokinumab improved lung function and, in patients with increased baseline periostin and DPP-4, reduced asthma exacerbations [Lancet Respir Med 2015]. We retrospectively analyzed this clinical trial to assess the effect of Tralokinumab on asthma control, as per GINA 2016 categorization. Methods: In a 52-week double-blind study (NCT01402986) 452 adults with severe, uncontrolled asthma taking high-dose ICS/LABA were randomized to Tralokinumab 300mg/placebo (PBO) every 2 weeks (Q2W) or Q2W for 12 weeks followed by every 4 weeks (Q4W). Asthma was categorized as partly or well controlled during previous week after 52 weeks’ treatment using established GINA methods. All analyses were descriptive. Results: All patients entering the study had uncontrolled asthma. At week 52, 58% of patients in the Tralokinumab Q2W group were partly or well controlled vs. 48% of PBO recipients. Patients receiving Tralokinumab Q2W with baseline periostin and DPP-4 above the median (‘periostin-high’ and ‘DPP-4-high’) had higher rates of well controlled asthma. Conclusions: Tralokinumab treatment, 300mg Q2W, may provide a better chance for severe, uncontrolled asthma patients to achieve well controlled asthma status using GINA criteria, particularly those with elevated periostin and DPP-4. Supported by AstraZeneca

  • Effect of anti-IL-13 treatment on airway dimensions in severe asthma: Subgroup analysis
    European Respiratory Journal, 2015
    Co-Authors: Christopher E Brightling, Gene Colice, Edward Piper, Martin Braddock, Lars H. Nordenmark, Meena Jain, Göran Tornling
    Abstract:

    Introduction: The effects of the anti-IL-13 monoclonal antibody Tralokinumab (tralo) (CAT-354) on airway dimensions were assessed in a subgroup of subjects from a Phase 2b study. Methods: In a 52-week double-blind study (NCT01402986) adults with severe asthma (history of airway reversibility, ≥2 exacerbations in previous year and FEV1 40–80% predicted or ACQ-6 score ≥1.5 at baseline) taking ICS/LABA were randomized to tralo 300 mg/placebo (PBO) every 2 weeks (Q2W), or Q2W for 12 weeks followed by every 4 weeks (Q4W).Quantitative computed tomography (CT) imaging of the upper lung was performed in 26 subjects at baseline and end of treatment. An exploratory post-hoc analysis estimated changes in airway lumen/wall parameters in specific airway segments using VIDA Apollo software. Subjects were combined in two groups: total PBO n=12 (n=6 [Q2W] + 6 [Q4W]) and total tralo n=14 (n=6 [Q2W] + 8 [Q4W]). Results: Sub-segmental lumen area increased by 16.8% (tralo) and 0.3% (PBO) (mean difference: 16.5%; 95% CI: 2.7−30.2%; p Conclusions: CT imaging detected significant improvements in airway lumen parameters with tralo compared with PBO added to ICS-LABA and may provide further mechanistic insights into the effects of IL-13 blockade.

  • MESOS: considerations in designing a mechanistic study for a biologic used to treat asthma
    Clinical investigation, 2015
    Co-Authors: Christopher E Brightling, Martin Braddock, Millie Wang, Lars H. Nordenmark, Mattis Gottlow, Gene Colice
    Abstract:

    Eosinophils are key effector cells in asthma-associated airway inflammation and remodeling; IL-13 is involved in regulating eosinophil activity. Tralokinumab, currently in Phase III clinical development for patients with severe uncontrolled asthma, is an investigational fully human monoclonal antibody designed to inhibit IL-13. In Phase II studies, Tralokinumab improved lung function and had other clinical benefits in those patients with asthma who had an upregulated IL-13 axis. In a subgroup of patients that underwent quantitative computed tomography, there were improvements in airway morphometry, suggestive of a possible effect upon remodeling. The Phase II MESOS study (NCT02449473) aims to better understand the mechanism of action of Tralokinumab in improving asthma control, by investigating Tralokinumab effects on eosinophil-driven inflammation and airway remodeling.

  • STRATOS 1 and 2: considerations in clinical trial design for a fully human monoclonal antibody in severe asthma
    Clinical investigation, 2015
    Co-Authors: Reynold A Panettieri, Christopher E Brightling, Koustubh Ranade, Ulf Sjobring, Annamaria Peterffy, Göran Tornling, Sami Z Daoud, Sally Hollis, Gene Colice
    Abstract:

    New therapies are being developed to target proinflammatory mediators thought to be involved in the pathophysiology of severe asthma. Tralokinumab is an investigational fully human monoclonal antibody that specifically blocks binding of IL-13 to its receptors. Here, we describe the background leading to the design of two Phase III trials, STRATOS 1 and 2 (NCT02161757 and NCT02194699), which aim to provide confirmatory evidence of the efficacy and safety of Tralokinumab in patients with asthma that is uncontrolled despite treatment with inhaled corticosteroids and long-acting β2-agonists. These trials will also confirm the validity of periostin and DPP-4, identified in a prior Phase IIb study (NCT01402986), as predictors of an enhanced response to Tralokinumab.

Balaji Agoram - One of the best experts on this subject based on the ideXlab platform.

  • dose exposure response relationship of the investigational anti interleukin 13 monoclonal antibody Tralokinumab in patients with severe uncontrolled asthma
    Clinical Pharmacology & Therapeutics, 2018
    Co-Authors: Paul Baverel, Nicholas White, Paolo Vicini, Mats O Karlsson, Balaji Agoram
    Abstract:

    : Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G4 monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which Tralokinumab was administered subcutaneously. This investigation aimed to characterize Tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1 )) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of Tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for Tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.

  • Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates
    Principles and Practice of Constraint Programming, 2017
    Co-Authors: Meena Jain, Balaji Agoram, Nicholas White, Diane V Doughty, Corbin Clawson, Xiaobai Li, Rene Van Der Merwe
    Abstract:

    Objective Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of Tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. Methods This phase I study randomized 60 healthy adults to receive 300 mg Tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). Results No differences in the PK profile of Tralokinumab were observed between cohorts. Immediately following injection, injection-site pain intensity (mean (SD)) was lowest following 0.167 mL/min injection (5.1 mm (8.0) via visual analog scale (VAS)) and greatest following 12 mL/min injection (41 mm (27.7) via VAS); with mean injection-site pruritus intensity low for all participants. Two types of local injection-site reactions were observed: erythema (58.3%) and hematoma/bleeding (18.3%). All treatment-emergent adverse events were mild. Conclusions Tralokinumab 300 mg is well tolerated, with comparable PK, when administered by a single 2-mL injection at different rates of subcutaneous injection vs. two 1-mL injections. .

  • Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates .
    International journal of clinical pharmacology and therapeutics, 2017
    Co-Authors: Meena Jain, Balaji Agoram, Nicholas White, Diane V Doughty, Corbin Clawson, Xiaobai Li, Rene Van Der Merwe
    Abstract:

    OBJECTIVE: Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of Tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. METHODS: This phase I study randomized 60 healthy adults to receive 300 mg Tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). RESULTS: No differences in the PK profile of Tralokinumab were observed between cohorts. Immediately following injection, injection-site pain intensity (mean (SD)) was lowest following 0.167 mL/min injection (5.1 mm (8.0) via visual analog scale (VAS)) and greatest following 12 mL/min injection (41 mm (27.7) via VAS); with mean injection-site pruritus intensity low for all participants. Two types of local injection-site reactions were observed: erythema (58.3%) and hematoma/bleeding (18.3%). All treatment-emergent adverse events were mild. CONCLUSIONS: Tralokinumab 300 mg is well tolerated, with comparable PK, when administered by a single 2-mL injection at different rates of subcutaneous injection vs. two 1-mL injections.
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  • A Mathematical Modeling Approach to Understanding the Effect of Anti‐Interleukin Therapy on Eosinophils
    CPT: pharmacometrics & systems pharmacology, 2016
    Co-Authors: Tatiana Karelina, Oleg Demin, Veronika Voronova, Gene Colice, Balaji Agoram
    Abstract:

    Emerging T-helper type 2 (Th2) cytokine-based asthma therapies, such as Tralokinumab, lebrikizumab (anti-interleukin (IL)-13), and mepolizumab (anti-IL-5), have shown differences in their blood eosinophil (EOS) response. To better understand these effects, we developed a mathematical model of EOS dynamics. For the anti-IL-13 therapies, lebrikizumab and Tralokinumab, the model predicted an increase of 30% and 10% in total and activated EOS in the blood, respectively, and a decrease in the total and activated EOS in the airways. The model predicted a rapid decrease in total and activated EOS levels in blood and airways for the anti-IL-5 therapy mepolizumab. All model-based predictions were consistent with published clinical observations. The modeling approach provided insights into EOS response after treatment with Th2-targeted therapies, and supports the hypothesis that an increase in blood EOS after anti-IL-13 therapy is part of the pharmacological action of these therapies.

  • A Mathematical Modeling Approach to Understanding the Effect of Anti-Interleukin Therapy on Eosinophils
    CPT: pharmacometrics & systems pharmacology, 2016
    Co-Authors: Tatiana Karelina, Oleg Demin, Veronika Voronova, Gene Colice, Balaji Agoram
    Abstract:

    Emerging T-helper type 2 (Th2) cytokine-based asthma therapies, such as Tralokinumab, lebrikizumab (anti-interleukin (IL)-13), and mepolizumab (anti-IL-5), have shown differences in their blood eosinophil (EOS) response. To better understand these effects, we developed a mathematical model of EOS dynamics. For the anti-IL-13 therapies, lebrikizumab and Tralokinumab, the model predicted an increase of 30% and 10% in total and activated EOS in the blood, respectively, and a decrease in the total and activated EOS in the airways. The model predicted a rapid decrease in total and activated EOS levels in blood and airways for the anti-IL-5 therapy mepolizumab. All model-based predictions were consistent with published clinical observations. The modeling approach provided insights into EOS response after treatment with Th2-targeted therapies, and supports the hypothesis that an increase in blood EOS after anti-IL-13 therapy is part of the pharmacological action of these therapies.

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  • Evaluation of Antibody Properties and Clinically Relevant Immunogenicity, Anaphylaxis, and Hypersensitivity Reactions in Two Phase III Trials of Tralokinumab in Severe, Uncontrolled Asthma
    Drug Safety, 2019
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice
    Abstract:

    Introduction Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. Objective The objectives of this study were to characterize the potential immunogenic properties of Tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. Methods The oligosaccharide structure of Tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of Tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). Results No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of Tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G_4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no Tralokinumab-related severe hypersensitivity or anaphylaxis reactions. Conclusion Preclinical assessments suggested a low likelihood of immunogenicity for Tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between Tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with Tralokinumab treatment. Together, the results suggest that Tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

  • evaluation of antibody properties and clinically relevant immunogenicity anaphylaxis and hypersensitivity reactions in two phase iii trials of Tralokinumab in severe uncontrolled asthma
    Drug Safety, 2019
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Nicholas White, Ayman Megally, Gillian Hunter, Gene Colice
    Abstract:

    Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. The objectives of this study were to characterize the potential immunogenic properties of Tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. The oligosaccharide structure of Tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of Tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of Tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no Tralokinumab-related severe hypersensitivity or anaphylaxis reactions. Preclinical assessments suggested a low likelihood of immunogenicity for Tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between Tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with Tralokinumab treatment. Together, the results suggest that Tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions.

  • no clinically relevant hypersensitivity reactions in clinical trials with Tralokinumab in asthma
    European Respiratory Journal, 2018
    Co-Authors: Mats Carlsson, Martin Braddock, Yuling Li, Jihong Wang, Weichen Xu, Gene Colice
    Abstract:

    Introduction: Anaphylaxis and severe hypersensitivity reactions are a concern for any biologic substance. The anti-IL-13 agent Tralokinumab is produced by a murine cell line and may thus incorporate immunogenic α-Gal epitopes in the Fab domain. Objectives: 1) To identify possible events of anaphylaxis or severe hypersensitivity reactions in pivotal clinical studies of Tralokinumab in severe, uncontrolled asthma. 2) To evaluate development of anti-drug antibodies (ADA) post dosing. 3) To characterize the glycosylation of Tralokinumab and the presence of α-Gal epitopes in the Fab domain and Fc region. Methods: Drug safety was evaluated in the pivotal Phase III clinical studies (NCT02161757 and NCT02194699). Adverse events associated with anaphylaxis/hypersensitivity were captured with MedDRA SMQs: Hypersensitivity, Anaphylactic Reaction and Anaphylactic/Anaphylactoid Shock Conditions. Relevant cases were assessed by an independent expert for anaphylaxis (Sampson criteria). ADA and carbohydrate structure of Tralokinumab were characterized by standard techniques. Results: Data from more than 1200 subjects indicate that there were no cases of anaphylaxis or severe hypersensitivity reactions related to Tralokinumab administration. Less than 1% of the Tralokinumab-treated subjects had ADA formation and no glycoforms with α-Gal epitopes were detected in the Fab region of the antibody. Conclusion: No safety concerns have been identified with respect to anaphylaxis/hypersensitivity and immunogenicity of Tralokinumab in clinical studies. Tralokinumab is not considered to constitute an increased risk for anaphylaxis/hypersensitivity reactions by being manufactured in a murine cell line.

  • Tralokinumab for the treatment of severe uncontrolled asthma the atmosphere clinical development program
    Immunotherapy, 2018
    Co-Authors: Reynold A Panettieri, Martin Braddock, Millie Wang, Karin Bowen, Gene Colice
    Abstract:

    : Tralokinumab, a fully human IgG4 monoclonal antibody, specifically neutralizes IL-13. The ATMOSPHERE clinical development program comprised four randomized, placebo-controlled clinical trials and an open-label study that aimed to assess the efficacy and safety of Tralokinumab for the treatment of severe, uncontrolled asthma. The two pivotal trials (STRATOS 1 and STRATOS 2; NCT02161757 and NCT02194699) evaluated the efficacy and safety of Tralokinumab, with STRATOS 1 identifying a subgroup most likely to demonstrate enhanced response to treatment. Further trials have assessed the ability of Tralokinumab to reduce oral corticosteroid use (TROPOS; NCT02281357) and determined its mechanistic effects (MESOS; NCT02449473). An open-label study in Japanese individuals (NCT02902809) assessed the long-term safety and tolerability of Tralokinumab in this population.

  • Effect of anti-IL-13 treatment on airway dimensions in severe asthma: Subgroup analysis
    European Respiratory Journal, 2015
    Co-Authors: Christopher E Brightling, Gene Colice, Edward Piper, Martin Braddock, Lars H. Nordenmark, Meena Jain, Göran Tornling
    Abstract:

    Introduction: The effects of the anti-IL-13 monoclonal antibody Tralokinumab (tralo) (CAT-354) on airway dimensions were assessed in a subgroup of subjects from a Phase 2b study. Methods: In a 52-week double-blind study (NCT01402986) adults with severe asthma (history of airway reversibility, ≥2 exacerbations in previous year and FEV1 40–80% predicted or ACQ-6 score ≥1.5 at baseline) taking ICS/LABA were randomized to tralo 300 mg/placebo (PBO) every 2 weeks (Q2W), or Q2W for 12 weeks followed by every 4 weeks (Q4W).Quantitative computed tomography (CT) imaging of the upper lung was performed in 26 subjects at baseline and end of treatment. An exploratory post-hoc analysis estimated changes in airway lumen/wall parameters in specific airway segments using VIDA Apollo software. Subjects were combined in two groups: total PBO n=12 (n=6 [Q2W] + 6 [Q4W]) and total tralo n=14 (n=6 [Q2W] + 8 [Q4W]). Results: Sub-segmental lumen area increased by 16.8% (tralo) and 0.3% (PBO) (mean difference: 16.5%; 95% CI: 2.7−30.2%; p Conclusions: CT imaging detected significant improvements in airway lumen parameters with tralo compared with PBO added to ICS-LABA and may provide further mechanistic insights into the effects of IL-13 blockade.