Nearly 300 million people suffer from asthma worldwide and treatment with high doses of inhaled glucocorticoids is ineffective in providing relief to patients with severe symptoms and frequent asthma attacks.
Since the proinflammatory cytokine interleukin-23 (IL-23) is known to play a role in the pathogenesis of asthma, researchers explored whether a licensed drug approved for psoriasis treatment that targets IL-23 could also be used to treat severe asthma.
However, a randomized, Phase IIa, double-blind, placebo-controlled clinical trial that assessed the efficacy and safety of this drug—a monoclonal antibody against IL-23—has found that the drug exacerbates symptoms in adults with severe and persistent asthma.
The findings are reported in an article in the New England Journal of Medicine titled, “Risankizumab in Severe Asthma — A Phase IIa, Placebo-Controlled Trial.” The study was led by researchers at the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC)—a partnership between Leicester’s Hospitals, the University of Leicester, and Loughborough University.
“It is always disappointing when a potential treatment is shown to be ineffective at treating a disease, more so when it makes symptoms worse,” said Chris Brightling, MD, PhD, senior investigator at the NIHR Leicester BRC and study lead. “We think risankizumab reduces the presence of substances in the airways that are important factors in preventing infections, which probably makes the patients’ symptoms worse. This theory is backed by molecular profiling, which shows reduced levels of these substances in samples taken from patients on the trial.”
The drug, risankizumab, is a humanized, monoclonal antibody that targets a subunit (p19) of the cytokine IL-23. Inhibition of IL-23 has been effective in psoriasis and Crohn’s disease.
Earlier studies have shown patients with asthma have elevated levels of IL-23 in their serum and that this is associated with worse lung function.
Studies have also shown that suppressing IL-23 decreases airway inflammation. In addition, IL-23, through parallel mechanisms that involve the increase of Th17 immune cells and the release of IL-17, increases the production of structural airway cells such as fibroblasts and smooth muscle cells that are likely to contribute to the remodeling of air passages.
However, whether inhibiting IL-23 in asthma reduces airway inflammation and helps control disease symptoms has not been explored until now.
Through a collaborative international study that included scientists from Manchester, Belgium, and Canada, the trial recruited 214 patients with severe persistent asthma. The researchers randomized 105 patients to a subcutaneous injection of 90 mg risankizumab every four weeks over a 24-week period. The remaining patients (109) received a placebo.
The primary endpoint of the study was the time to first asthma worsening, determined by increasing symptoms compared to baseline, deterioration in breathing tests, increased use of inhalers, and need for steroid tablets.
The study found that patients treated with risankizumab reached the primary endpoint at an average of 40 days, compared to 86 days for the patients given the placebo. The study also reported that the annualized rate of asthma worsening was higher with risankizumab than with placebo.
Transcriptome analysis of sputum samples from patients showed risankizumab decreased the expression of genes that activate immune cells such as natural killer cells and subsets of T cells. The downregulation of genes that are important in protecting against infection could explain the poor efficacy of the drug in controlling asthma symptoms.
The authors concluded risankizumab does not benefit severe asthma. No safety concerns were associated with the risankizumab treatment.
The clinical trial (NCT02443298) was sponsored by AbbVie and Boehringer Ingelheim, and was funded in part by 3TR-Innovative Medicines Initiative.