Published data on the efficacy of lebrikizumab in the treatment of asthma are relatively limited to date.26
In a randomized controlled trial in 28 patients with allergic asthma, the late asthmatic response after inhaled allergen challenge (primary outcome measure) was reduced by 48% following 3 months of treatment with lebrikizumab compared with placebo (95% confidence interval [CI]: −19%–90%).28
Lebrikizumab had no effect on the early asthmatic response.28
Systemic biomarkers considered to indicate Th2 inflammation (serum IgE, Cys-Cys ligand [CCL]13 chemokine, and CCL17 chemokine), decreased by 20% to 25% after lebrikizumab treatment.28
Participants with peripheral blood eosinophils, serum IgE, or serum periostin levels above the median compared to those below this cutoff were reported to obtain a greater decrease in the late asthmatic response after lebrikizumab, suggesting that systemic biomarkers may help predict the magnitude of clinical response to lebrikizumab treatment.
A Phase II randomized, double-blind, placebo-controlled study of lebrikizumab was performed in 219 adults with asthma that was poorly controlled despite inhaled corticosteroids (mean dose: 580 μg per day) (NCT00930163; MILLY trial).26
Eighty percent of the participants were also taking LABA therapy. Lebrikizumab was administered subcutaneously at a dose of 250 mg monthly for 24 weeks. The primary efficacy outcome measure was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV1
) from baseline to 12 weeks. Secondary end points included rate of asthma exacerbations from baseline to 24 weeks and morning prebronchodilator peak exploratory flow, change in Asthma Control Questionnaire (ACQ) score, asthma symptom score, use of recue medication, and measurement of the fraction of exhaled nitric oxide (FeNO
) from baseline to 12 weeks. Lebrikizumab treatment produced an improvement in mean (95% CI: prebronchodilator FEV1
of 5.5% [0.8 to 10.2]) compared with placebo (P
= 0.02) (). At 20 weeks, the postbronchodilator FEV1
was slightly higher in the lebrikizumab group (3.4%) compared with placebo (−1.5%). Treatment with lebrikizumab had no significant effects on the secondary efficacy end points. Lebrikizumab treatment produced a 19% mean fall in FeNO
at 12 weeks compared with a 10% increase with placebo (P
Figure 2 Effect of lebrikizumab treatment on the change in FEV1 values in adults with asthma. For all patients at week 12 (A), the increase from baseline in mean (±SE) FEV1 was higher in the lebrikizumab group (9.8% ± 1.9%) than in the placebo (more ...)
A preliminary report on a further analysis of this study found that lebrikizumab treatment reduced severe asthma exacerbations over 32 weeks (24 weeks during the randomized controlled trial plus the post-last dose 8-week follow-up period) in adults with inadequately controlled asthma.29
Severe exacerbations were defined as new or worsened asthma symptoms requiring systemic corticosteroid treatment, overnight hospital admission, or institution of high-dose inhaled corticosteroid therapy. In all patients (n = 218), the severe exacerbation rate over the 32-week period was reduced by 50% in the lebrikizumab group (0.17 exacerbations) compared to the placebo group (0.34 exacerbations, P
= 0.03) – a relative absolute reduction in severe exacerbation of 0.17. A trend toward a larger reduction in severe exacerbations rates was found in patients with high periostin levels prior to treatment (61% [−1, 85], P
Prior to randomization, the MILLY trial patients were categorized into high-Th2 or low-Th2 status, based on total IgE level, blood eosinophil count, and serum periostin level. The improvement in mean FEV1 was 8.2% compared with placebo (P = 0.02) in the high-periostin subgroup (P = 0.03), whereas in the low-periostin subgroup, the increase in FEV1 was 1.6% compared with placebo (P = 0.61) (). The fall in FeNO was greater in the high-periostin subgroup compared to the low-periostin subgroup (34.4% vs 4.3%; P < 0.001). At 24 weeks, systemic biomarkers of Th2 inflammation (serum CCL13, CCL17, and total IgE levels) decreased, and peripheral blood eosinophil counts slightly increased in the group treated with lebrikizumab.
A post hoc analysis of the MILLY trial, presented at the American Thoracic Society meeting in 2012, reported that lebrikizumab treatment reduced serum periostin levels in asthma patients with elevated baseline levels of periostin, whereas low-periostin patients exhibited no significant reduction in response to lebrikizumab.30
Placebo-corrected serum periostin levels were reduced by 9.7% (95% CI: 5.5%–14%; P
= 0.001) at 12 weeks in the total study group. In high-periostin patients, the reduction in serum periostin was 14.4% (95% CI: 8.3%–20.5%; P
< 0.001), while in low-periostin patients, it was only 2.9% (95% CI: 2.5%–8.4%; P
These findings suggest that in uncontrolled asthma patients, excess serum periostin is due to the activity of IL-13, and that inhibition of IL-13 with lebrikizumab decreases serum periostin levels. In summary, Phase II randomized controlled clinical trials report that lebrikizumab treatment for 12 weeks reduces late asthmatic responses after allergen challenge and improves lung function, and that this effect occurs in those subjects with a high pretreatment level of serum periostin. A dose-ranging study of lebrikizumab in adult patients who are not taking inhaled corticosteroids has been completed, but the results have not yet been reported (ClinicalTrials.gov Identifier: NCT00971035, MOLLY trial). Two large Phase III randomized controlled trials are underway that will help establish the safety and efficacy of lebrikizumab in the treatment of asthma: these trials will each aim to recruit 1400 patients with uncontrolled asthma who are receiving inhaled corticosteroids and a second controller medication. Treatment with lebrikizumab or placebo will be for 52 weeks, and the primary outcome measure is the asthma exacerbation rate (ClinicalTrials.gov Identifiers: NCT01545440, LUTE trial and NCT01545453, VERSE trial). The estimated study completion date for both trials is 2017.