Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies

Abstract

IntroductionIn a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity.MethodsLUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.ResultsThe median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.ConclusionsThese data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.Trial registration numbersThe LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

Improving the diagnosis of eosinophilic asthma

“…This difference in thresholds might be explained by the relatively large proportion of patients who were on systemic corticosteroid treatment in the mepolizumab studies. Yet another value for blood eosinophils (0.3 × 10 9 /L was found to be optimal for the selection of patients likely to respond to lebrikizumab, the monoclonal antibody against IL-4R-alpha (dupilumab),and IL-5R-alpha (benralizumab) [53,58,65]. Taken together, the threshold for blood eosinophils to be used for treatment with Type 2 biologicals is variable and depends on medication used and the biological of choice.…”

“…The cutoff values for blood eosinophils differ between 0.22 and 0.32 × 10 9 /L, for FeNO levels between 10 and 41 ppb, and for IgE 72 and 900 IU/mL [23]. For periostin, a value of 25-50 ng/mL or the median of the study population is mostly used [35,42,58]. These cutoff values are based on the optimal combination of sensitivity and specificity.…”

Severe Asthma: Moving from Phenotype to Endotype Classification with Updates on Treatment

“…Patients on lebrikizumab at a dose of 250 mg/month for 6 months had a higher increase in FEV1 versus at baseline. Hanania et al provided more evidence in support of lebrikizumab efficacy through two randomized, double-blind, placebocontrolled studies; they found that treatment with lebrikizumab reduced asthma exacerbations, in particular in periostin-high patients, with a significant 60% reduction, versus the subgroup of periostin-low patients [65]. However, the same group could not replicate these results in phase 3 trials and lebrikizumab did not consistently show significant reduction in asthma exacerbations in periostin-high patients [66].…”

Emerging Biological Therapies in Severe Eosinophilic Asthma

“…One of the mechanisms by which IL-13 induces airway fibrosis and remodeling is by upregulating the secretion of periostin [64], which has been linked as a systemic biomarker specific for airway eosinophilia [65]. Lebrikizumab is a humanized monoclonal antibody that binds to IL-13, which is under investigation for the treatment of uncontrolled asthma [66,67].…”