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Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma.

ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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. DISCUSSION: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. TRIAL REGISTRATION:STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

SUBMITTER: Gottlow M

PROVIDER: S-EPMC6637533 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma.

Gottlow Mattis M Svensson David J DJ Lipkovich Ilya I Huhn Monika M Bowen Karin K Wessman Peter P Colice Gene G

BMC pulmonary medicine 20190717 1

<h4>Background</h4>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.<h4>Methods</h4>The biomarkers ...[more]

PMID: 31315668

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Project description: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-?-1,3-galactose (?-Gal) epitopes were found in the Fab region of tralokinumab and only 4.5% of glycoforms contained ?-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. 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.

Project description:BackgroundTwo phase III trials, ECZTRA 1 and 2, confirmed the efficacy and safety of tralokinumab versus placebo in adults with moderate-to-severe atopic dermatitis (AD). To further explore the long-term efficacy of tralokinumab for AD, a pooled analysis of these trials was conducted.MethodsECZTRA 1 and 2 patients (n = 1596 total) were randomized to tralokinumab 300 mg or placebo every 2 weeks (q2w) over 16 weeks. Patients achieving Investigator's Global Assessment of clear/almost clear skin (IGA 0/1) and/or 75% improvement in the Eczema Area and Severity Index (EASI-75) at Week 16, were re-randomized to tralokinumab q2w, every 4 weeks (q4w), or placebo (tralokinumab withdrawal) for another 36 weeks. Patients not achieving the response criteria at Week 16 received open-label tralokinumab q2w plus optional topical corticosteroids (TCS). A pooled, prespecified analysis assessed the proportions of Week 16 responders that maintained IGA 0/1 and/or EASI-75 at Week 52. Pooled data from all patients initiated with tralokinumab, regardless of the response at Week 16 or dosing regimen received thereafter, were analyzed post hoc.ResultsIn patients who achieved the primary endpoints at Week 16, IGA 0/1 responses were maintained at Week 52 without rescue treatment (including TCS) by 55.9%, 42.4%, and 34.0% of patients re-randomized to tralokinumab q2w, q4w, or placebo (tralokinumab withdrawal), respectively, while EASI-75 responses were maintained by 57.3%, 50.4%, and 26.4%, respectively (prespecified analysis). In a post hoc analysis of all patients initiated with tralokinumab, response rates improved over time with continued tralokinumab treatment beyond Week 16 to Week 52 for EASI-50 (63.1-82.7%), EASI-75 (37.6-61.8%), EASI-90 (20.4-37.3%), and IGA 0/1 (23.0-36.2%).ConclusionsTralokinumab treatment provides progressive and sustained improvement over 1 year in the extent and severity of AD in patients with moderate-to-severe AD.Clinical trial registrationNCT03131648 (ECZTRA 1); study start date: 30 May 2017; primary completion date: 7 August 2018; study completion date: 10 October 2019. NCT03160885 (ECZTRA 2); study start date: 12 June 2017; primary completion date: 4 September 2019; study completion date: 14 August 2019. INFOGRAPHIC.

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Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma.

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Application of structured statistical analyses to identify a biomarker predictive of enhanced tralokinumab efficacy in phase III clinical trials for severe, uncontrolled asthma.

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