Risankizumab fails to outperform placebo in severe asthma treatment
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Risankizumab appeared to worsen severe asthma symptoms compared with placebo, according to results of a randomized phase 2a study published in The New England Journal of Medicine.
Risankizumab (Skyrizi; Boehringer Ingelheim, AbbVie) is a humanized, monoclonal antibody directed against the subunit p19 of interleukin-23 (IL-23) that is used as a treatment against psoriasis and Crohn’s disease. IL-23 is a heterodimeric cytokine that has been implicated in asthma’s pathogenesis, the researchers wrote, although it had been unclear if targeting it in asthma could improve disease control or reduce airway inflammation.
“We know the mediator IL-23 is important in several diseases, especially psoriasis and inflammatory bowel disease,” study author Christopher E. Brightling, PhD, MRCP, FRCP, AFHEA, FMedSci, professor and honorary consultant in the department of respiratory sciences at University of Leicester in England, told Healio. “In some people with asthma, this molecule and downstream pathways are activated. We therefore considered that blocking this mediator might improve asthma.”
The multicenter, double-blind, placebo-controlled, parallel-group study involved 214 patients with severe persistent asthma aged 18 to 75 years. Researchers randomly assigned patients to 90 mg risankizumab (n = 105; mean age, 54 years ± 11 years; 65.7% women; 84% white) or placebo (n = 109; mean age, 52 years ± 13 years; 58.7% women; 88% white), with doses administered subcutaneously once every 4 weeks during a 24-week treatment period followed by a 16-week observation period.
Using an electronic diary, patients answered questions about their use of rescue and asthma controller medication, measured their peak expiratory flow and completed the five-item Asthma Control Questionnaire (ACQ-5) once a week.
Plus, the researchers performed spirometry before and after bronchodilator use, measured fractions of exhaled nitric oxide and obtained sputum and venous blood samples during scheduled clinic visits.
The time to the first asthma worsening during the 24-week treatment period — considered deterioration from baseline on 2 or more consecutive days — served as the study’s primary endpoint. Researchers defined deterioration as a decrease of at least 30% in the morning peak expiratory flow, at least a 50% increase from baseline in the number of puffs of rescue medication needed over 24 hours, a severe asthma exacerbation, or an increase of 0.75 points or more on the ACQ-5.
Results showed time to first asthma worsening was 40 days in the risankizumab group and 86 days in the placebo group (HR = 1.46; 95% CI, 1.05-2.04). The rate ratio for annualized asthma worsening, which served as a secondary endpoint, was 1.49 (95% CI, 1.12-1.99) for risankizumab compared with placebo, with a rate ratio for annualized severe exacerbation of 1.13 (95% CI, 0.75-1.7).
At week 24, the two groups had an adjusted mean difference in ACQ-5 scores of 0.15 ± 0.11 points.
Patients assigned risankizumab compared with placebo had a worse adjusted mean change in forced expiratory volume in 1 second (FEV1) from baseline to week 24 (0.05 ± 0.04 L vs. 0.01 ± 0.03 L; mean difference in change, 0.04 ± 0.51 L), as well as a worse adjusted mean change in FEV1 after bronchodilator use (0.1 ± 0.03 L vs. 0.03 ± 0.03 L; adjusted mean difference in change, 0.07 ± 0.04 L).
Weekly use of rescue medication in a 24-hour period had an adjusted mean change from baseline to week 24 of 0.08 ± 0.31 puffs in the risankizumab group and 0.55 ± 0.31 puffs in the placebo group (mean difference in change, 0.47 ± 0.36 puffs).
Although risankizumab therapy did not affect sputum cell counts, the researchers wrote, it attenuated the sputum IL-23 gene set and gene pathways associated with activation of cytotoxic T cells and natural killer cells as well as with type 1 helper T and type 17 helper T transcription factors.
“We explored the gene signatures in sputum samples from the study participants and found that molecules involved in protecting us from infection were suppressed in those receiving risankizumab,” Brightling said. “This suggests that poorer outcomes in those treated with risankizumab might have been due to reducing the immune response to infection.”
Additionally, patients with a higher blood eosinophil count ( 200 vs. < 200 cells/mm3) and with a lower BMI (< 30 vs. 30) had poorer outcomes with risankizumab.
There were no safety concerns during the study, and both groups had similar incidences of adverse events and serious adverse events.
Overall, the researchers concluded, their findings undermine the role of IL-23 and the Th17 axis as asthma treatment targets.
“We found that in those treated with the anti-IL-23 drug risankizumab, their asthma symptoms and control were worse than those given placebo,” Brightling said.
“This study helps to explain why some treatments work very well in some diseases and not others. When people have multiple conditions, care must be taken to balance the benefit achieved for one condition while possibly worsening another,” said Brightling, adding that the study also helps direct which aspects of asthma biology should and should not be targeted for treatments.
For more information:
Christopher E. Brightling, PhD, MRCP, FRCP, AFHEA, FMedSci, can be reached at ceb17@le.ac.uk.