Risankizumab in Severe Asthma - A Phase 2a, Placebo-Controlled Trial

BACKGROUNDInterleukin-23 has been implicated in airway inflammation that is mediated by type 2 and type 17 cytokines. Whether targeting interleukin-23 in the treatment of asthma improves disease control and reduces airway inflammation is unclear.METHODSWe conducted a phase 2a, multicenter, randomized, double-blind, placebo-controlled, 24-week, parallel-group trial to assess the efficacy and safety of risankizumab, an anti–interleukin-23p19 monoclonal antibody, in adults with severe asthma. Patients were assigned to receive 90 mg of risankizumab or placebo, administered subcutaneously once every 4 weeks. The primary end point was the time to the first asthma worsening. Asthma worsening was defined as deterioration from baseline on 2 or more consecutive days; deterioration was considered to be a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in the number of puffs of rescue medication in a 24-hour period (equating to at least four additional puffs), a severe asthma exacerbation, or an increase of 0.75 or more points on the 5-item Asthma Control Questionnaire (ACQ-5; scores range from 0 to 6, with higher scores indicating less control). Secondary end points were the annualized rate of asthma worsening, the annualized rate of severe exacerbations, the ACQ-5 score, and the forced expiratory volume in 1 second. Exploratory end points were assessed with the use of sputum cytologic analysis and gene expression analysis, and safety was assessed.RESULTSA total of 105 patients received risankizumab and 109 received placebo. The clinical characteristics of the patients were similar in the two groups. The time to the first asthma worsening was shorter with risankizumab than with placebo (median, 40 days vs. 86 days; hazard ratio, 1.46; 95% confidence interval [CI], 1.05 to 2.04; P=0.03). The rate ratio for annualized asthma worsening with risankizumab as compared with placebo was 1.49 (95% CI, 1.12 to 1.99), and the rate ratio for severe exacerbations was 1.13 (95% CI, 0.75 to 1.70). Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of the type 1 helper T and type 17 helper T transcription factors were down-regulated by risankizumab. No safety concerns were associated with risankizumab therapy.CONCLUSIONSRisankizumab treatment was not beneficial in severe asthma. The time to the first asthma worsening was shorter and the annualized rate of asthma worsening was higher with risankizumab than with placebo. (Funded by AbbVie and Boehringer Ingelheim; ClinicalTrials.gov number, NCT02443298. opens in new tab.)</div

Cytokine levels in “IgE high” and “IgE low” asthmatics.

<p>Cytokine levels in “IgE high” and “IgE low” asthmatics.</p

Correlation between sputum total IgE and serum total IgE in asthmatics.

<p>Correlation between sputum total IgE and serum total IgE in asthmatics.</p

Demographic, functional and airway inflammatory characteristics according to disease severity.

<p>Age, BMI and lung function are expressed as mean ± SD, PC20M as geometric mean and other paramaters as median (range) * p<0.05, ** p<0.01, *** p<0.001 vs healthy subjects; † p<0.05, †† p<0.01, ††† p<0.001 vs mild-to-moderate untreated; ‡ p<0.05, ‡‡ p<0.01, ‡‡‡ p<0.001 vs mild-to-moderate treated. ND = not defined.</p

Additional file 1: Table S1. of Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory?

Sputum and blood cell counts of eosinophilic phenotypes classified by ICS treatment and healthy subjects. (DOCX 29.3 kb

Total sputum and serum IgE and sputum cytokine levels in “IgE high” vs “IgE low” asthmatics.

*<p>p<0.05, ** p<0.01, **** p<0.0001 vs IgE low asthmatics. ND =  not done, spec = specific. Results are expressed as median (range) except as otherwise stated.</p

Demographic, functional, airway inflammatory and treatment characteristics in “IgE high” vs “IgE low” asthmatics.

*<p>p<0.05, ** p<0.01, ***p<0.001 vs IgE low asthmatics. Age, BMI, lung function, hospi/patient/year and exacerbation/patient/year are expressed as mean ± SD, PC20M as geometric mean and other parameters as median (range).</p

IL-5 and IL-13 levels in asthmatics according sputum cellular profile.

<p>IL-5 and IL-13 levels in asthmatics according sputum cellular profile.</p

Demographic, functional, airway inflammatory and treatment characteristics according to sputum cellular profile.

<p>Age, BMI, lung function, hospi/patient/year and exacerbation/patient/year are expressed as mean ± SD, PC20M as geometric mean and other parameters as median (range), becl = beclomethasone, * p<0.05, ** p<0.01, *** p<0.001 vs healthy subjects; † p<0.05, †† p<0.01, ††† p<0.001 vs eosinophilic; ‡ p<0.05, ‡‡ p<0.01, ‡‡‡ p<0.001 vs neutrophilic. ND = not defined.</p

Total sputum and serum IgE, serum specific IgE and sputum cytokine levels according to sputum cellular phenotype.

<p>*p<0.05, **p<0.01, *** p<0.001 vs healthy subjects, † p<0.05, †† p<0.01, ††† p<0.001 vs eosinophilic asthmatics, ND =  not done, spec = specific. Results are expressed as median (range) except as otherwise stated.</p