Patients in Risankizumab Phase 2a Trial Saw Some Asthma Symptoms Increase

A study released Thursday in The New England Journal of Medicine of risankizumab for the treatment of asthma found it did not meet its primary end point in the phase 2a trial and made symptoms worse twice as fast as the placebo group.

Risankizumab, a biologic, is sold under the name Skyrizi for the treatment of psoriasis. It inhibits interleukin-23 (IL-23), which is mediated by type 2 and type 17 cytokines, but it isn't known if targeting IL-23 for asthma improves disease control and reduces airway inflammation, the researchers wrote.

The international study recruited 214 patients into the trial; 105 patients were randomized to a risankizumab injection every 4 weeks over a 24-week period while 109 patients received a placebo.

Time-to-first asthma worsening was determined by deterioration from baseline on 2 or more consecutive days; deterioration was classified as 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 4 additional puffs).

Deterioration also included a severe asthma exacerbation or an increase of 0.75 or more points on the 5-item Asthma Control Questionnaire (ACQ-5).

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 (FEV₁).

Participants were treated with 90 mg of risankizumab or placebo, consistent with the efficacy trial for plaque psoriasis.

Patients treated with risankizumab had an average time-to-first-worsening of 40 days compared with 86 days for the patients given a placebo (hazard ratio [HR], 1.46; 95% CI, 1.05-2.04; P = .03).

The rate ratio for annualized asthma worsening with risankizumab as compared with placebo was 1.49 (95% CI, 1.12-1.99), and the rate ratio for severe exacerbations was 1.13 (95% CI, 0.75-1.70).

No safety concerns were linked with risankizumab therapy.

In addition, the investigators studied gene signatures from immune cells in airway samples. The biologic attenuated the sputum interleukin-23 gene set and gene pathways associated with activation of cytotoxic T cells and natural killer cells and the Th17 transcription factor RORC and the Th1 transcription factor TBX21. Risankizumab appears to have had a biologic effect on airway immunity, which may have contributed to the poor clinical outcome.

"Our findings therefore challenge the current understanding of the role that Th17- and interleukin-23–mediated pathways play in the pathogenesis of asthma," wrote the authors.

The study had a number of limitations, the researchers said. The sample-size calculation for the primary end point was based on a one-sided power calculation with a sample size that was powered for the secondary and exploratory end points. Other aspects of severe asthma, such as airway hyperresponsiveness, airway remodeling, airway microbiome, and autoimmunity, could not be explored. It is also possible that certain subgroups of patients with severe asthma, who were not enrolled in this trial, might have had better outcomes.

Reference

Brightling CE, Nair P, Cousin DJ, Louis R, Singh D. Risankizumab in severe asthma — a phase 2a, placebo-controlled trial. N Engl J Med. 2021;385:1669-1679. doi:10.1056/NEJMoa2030880