ACOUSTICS data sounds good for adolescent asthma exacerbations

According to the findings from the terminated ACOUSTICS study, lebrikizumab reduced exacerbations in adolescents with uncontrolled asthma in a dose-dependent manner. The effect was greatest in patients with eosinophils ≥300 cells/microliter.

The phase 3, multicentre, randomised, double-blind, placebo-controlled ACOUSTICS study (NCT01875003) aimed to test the efficacy and safety of lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting IL-13, selectively preventing the formation of the IL-13/IL-4 heterodimer receptor signalling complex. The trial was stopped early by the sponsor.

In ACOUSTICS, participants (n=346 adolescents, aged 12 to 17 years) with uncontrolled asthma – despite using inhaled corticosteroids daily in addition to at least 1 other asthma controller medication – were randomised to receive lebrikizumab 125 mg (n=116) or 37.5 mg (n=113), or placebo (n=117) subcutaneously once every 4 weeks. The primary outcome was the asthma exacerbation rate, defined as new or worsened asthma symptoms that led to treatment with systemic corticosteroids of hospital admission. The time to first asthma exacerbation and safety outcomes were also evaluated. Prof. Stanley Szefler (Children’s Hospital Colorado, CO, USA) presented the results from the 224 (65%) adolescents who have completed 52 weeks thus far [1].

Compared with the placebo group, participants assigned lebrikizumab 125 mg had a 51% reduction in exacerbation rates (adjusted RR 0.49; 95% CI 0.28–0.83), and the 37.5 mg arm had a 40% reduction (aRR 0.60; 95% CI 0.35–1.03). Compared with the placebo group, patients in the lebrikizumab arms experienced a longer interval before their first asthma exacerbation for both the 37.5 mg dose (HR 0.40; 95% CI 0.22–0.73) and the 125 mg dose (HR 0.37; 95% CI 0.21–0.66).

The baseline median blood eosinophil count was 295 cells/µL; the researchers accordingly looked at the data using a threshold baseline blood eosinophil count of ≥300 cells/µL. In those with blood eosinophil counts of ≥300 cells/µL, the lebrikizumab 125 mg arm had a reduction of 56% (RR 0.44; 95% CI 0.21–0.89) in asthma exacerbation rates, but that rate was similar in the 37.5 mg arm with a 58% reduction (RR 0.42; 95% CI 0.19–0.93) (see Figure).

Figure: Reduction in asthma exacerbation rates with lebrikizumab versus placebo was greatest in patients with eosinophils ≥300 cells/µL [1]



CI, confidence interval; LEB, lebrikizumab; PBO, placebo; Q4W, every 4 weeks.

Most adverse events that occurred during the study were mild-to-moderate in severity and did not lead to discontinuation of the study drug. Eosinophil-associated, treatment-related adverse events included decreased neutrophil count and eosinophilia; there were no cases of eosinophilic granulomatosis with polyangiitis. “In terms of safety, it was pretty comparable to what was seen in the adult studies to date,” Prof. Szefler said.

Prof. Szefler concluded that there was a greater effect observed with the higher dose in the overall population and that exacerbation rates were trending toward further reduction in patients with baseline eosinophilia. He pointed out that, despite the lack of a consistent dose-response, post-hoc analyses of adult studies (e.g. LAVOLTA I and II, MILLY) showed similar results. This data collectively supports additional research into the optimal use of lebrikizumab with higher and more frequent dosing in patients with type 2 inflammation at risk for exacerbations.

1. Szefler SJ, et al. Efficacy, Safety, and Tolerability of Lebrikizumab in Adolescent Patients with Uncontrolled Asthma (ACOUSTICS): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study. Session B93, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.

 

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Posted on 18 July 202218 July 2022