For patients with moderate to severe asthma, blockade with itepekimab, a new human IgG4P monoclonal antibody against the upstream alarmin interleukin-33, led to a reduction in events that indicate loss of asthma control. Treatment with itepekimab also led to an improvement in lung function compared with placebo, according to results of a phase 2 trial.
However, findings for a subgroup of patients treated with itepekimab in combination with dupilumab, an anti-interleukin-4 receptor subunit α and -13 monoclonal antibody, were not favorable in comparison with placebo, noted M. E. Wechsler, MD, and colleagues in an article published online in The New England Journal of Medicine.
Despite the demonstrated efficacy of available biologic therapies targeting IgE, interleukin-4, interleukin-13, and interleukin-5 for treating moderate to severe type 2 asthma, many patients with type 2 or non–type 2 asthma continue to have symptoms, exacerbations, and reduced lung function. New therapies targeting alternative pathophysiologic pathways are needed.
Genomewide studies show that type 2 and non–type 2 inflammation that contributes to asthma and chronic obstructive pulmonary disease (COPD) are genetically associated with interleuken-33. This inflammation occurs when interleuken-33 binds to its cognate receptor (ST2) and engages the coreceptor interleukin-1 receptor accessory protein to initiate downstream signaling, activating cells of both the innate and adaptive immune systems.
The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group (four groups), proof-of-concept trial to evaluate the efficacy and safety of the interleuken-33 targeting itepekimab in comparison with placebo for adults with moderate to severe asthma. Dupilumab, which was the active comparator, was administered in combination with itepekimab to evaluate potential additive effects. Dupilumab’s efficacy in this population had been demonstrated previously.
All 296 patients (mean age, 49.1 years; 64% women) were receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs). They were randomly assigned in a 1:1:1:1 ratio to receive subcutaneous itepekimab (300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. LABAs were discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary endpoint was the occurrence of an event indicating the loss of asthma control.
Primary endpoint analysis at 12 weeks revealed a lower rate of asthma-control loss events in the itepekimab and dupilumab monotherapy groups but not in the combination group compared with patients who received placebo. Events occurred in 22% of patients in the itepekimab group, in 27% of those in the combination group, in 19% of the dupilumab group, and in 41% of the placebo group. The odds ratios for comparisons with placebo were 0.42 for the itepekimab group (95% CI, 0.20 – 0.88; P = .02); 0.33 in the dupilumab group (95% CI, 0.15 – .70); and 0.52 in the combination group (95% CI, 0.26 – 1.06; P = .07) .
Following a similar pattern, forced expiratory volume in 1 second before use of a bronchodilator increased with both monotherapies but not with the combination or placebo. Although the trial was not powered to determine differences between itepekimab and dupilumab, the effects of dupilumab therapy were generally greater than those observed with itepekimab, especially for patients with type 2 asthma.
Also, asthma control and quality of life were improved with itepekimab and dupilumab monotherapy in comparison with placebo. There were also greater reductions in the mean blood eosinophil count.
The authors urge further research into the complexities of asthma physiology and encourage researchers to look for predictive biomarkers of anti-interleuken-33 blockade response. They conclude, “In this trial, we found that itepekimab monotherapy led to a lower incidence of events indicating loss of asthma control and to improved lung function, findings that are consistent with a role for interleukin-33 in the pathogenesis of exacerbations and airflow limitation in asthma.”
In an accompanying editorial, Philip G. Bardin, PhD, and Paul S. Foster, DSc, ask why itepekimab and dupilumab, a combination based on a sound scientific rationale, failed. As monotherapies, both itepekimab and dupilumab are roughly similar in reducing asthma events and improving lung function; thus, it is unlikely that inadequate dosing led to the failure of itepekimab.
interleuken-33 is an attractive target because the cells it promotes secrete cytokines that induce asthma’s pathognomonic features, and biologic agents that target those cytokines (interleukin-5/-5R/-4/-13 axes) have been highly effective. They do not, however, prevent exacerbations after treatment.
Alternative pathways within or outside that paradigm are operant, and other epithelial alarmins, such as interleukin-25 and thymic stromal lymphopoietin, promote type 2 inflammation, Bardin and Foster state.
“Combination therapy with itepekimab and dupilumab may have failed because these pathways bypass interleukin-33,” they write. Also, preexisting ILC2 and TH2 cells may have residual capacity to release mediators. The short-term trial design, the editorialists write, may have contributed to the failure of the itepekimab/dupilumab combination; interleukin-33 may be appropriate as a target in a longer-term exacerbation-type trial “in which epithelial infection and other relevant stimuli instigate exacerbated disease. Combination therapy may be capable of lowering exacerbations rather than preventing loss of control in chronic disease.
“Clinical translation of basic science in asthma remains a challenge to be pursued…. It is imperative to harness scientific insights from translational studies that frustrate our hopeful expectations — so that something can also be gained,” they conclude.
The Role of Interleuken-33
“Our study of itepekimab provides valuable insight into pathophysiology of severe asthma,” said Wechsler, professor of medicine at the NJH Cohen Family Asthma Institute, Denver, Colorado, in an interview. “As blocking IL-33 [interleuken-33] reduced asthma worsening and improved lung function compared to placebo, it suggests that IL-33 plays an important role in asthma pathophysiology and may be a valuable target for a subset of patients with severe asthma,” he stated.
“Since the effect of itepekimab is comparable to that of dupilumab, it is suggested that patients may benefit from blockade of this pathway, but what remains to be seen is identifying which patients are more likely to respond better to one therapy vs another. The future of blocking IL-33 remains exciting, and studies are being planned to evaluate its efficacy in airways diseases, including COPD,” he concluded.
Walter Alexander, MS, is a freelance medical journalist.
N Engl J Med. 2021;385:1656-1668.