麻豆传媒

Two monoclonal antibodies directed toward different interleukin (IL) targets produced wildly different results in randomized phase II trials involving asthma.

On the plus side, an IL-33 inhibitor called itepekimab appeared to help patients keep their asthma under control better than placebo, reported Michael Wechsler, MD, of National Jewish Health in Denver, and colleagues.

While on the minus side, risankizumab (Skyrizi) -- an IL-23 blocker currently approved for psoriasis -- not only failed to show a benefit, but asthma patients receiving it actually fared worse than a placebo group, according to researchers led by Christopher Brightling, FMedSci, of the University of Leicester in England.

Both trials were published in the New England Journal of Medicine (NEJM).

The were especially surprising, given that the drug has had good results in trials involving other inflammatory conditions -- not just psoriasis, but also inflammatory bowel disease.

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

In particular, it appears that IL-23 is not a villain in asthma, but at worst a neutral bystander, as an by two Australian researchers suggested.

"[B]ecause interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred a predisposition in patients to more severe or more frequent virus-induced exacerbations," wrote Philip Bardin, PhD, of Monash University and Hospital in Melbourne, and Paul Foster, DSc, of the University of Newcastle.

And while the results were positive, it, too, raised questions about the role of interleukins and other inflammatory/immune mediators in asthma.

That study included four treatment arms: itepekimab as monotherapy and in combination with the IL-4 blocker dupilumab (Dupixent), dupilumab alone, and placebo. Surprisingly, outcomes in the combination arm were no better, and possibly worse, than in patients receiving either drug alone.

The investigators declined to speculate on the reasons; Bardin and Foster argued that the inflammatory processes in asthma may be too complex for biologic drugs to fully suppress, even in combination.

"In this context, other epithelial alarmins such as interleukin-25 and thymic stromal lymphopoietin, operating independently of interleukin-33, promote type 2 inflammation," they wrote. "Combination therapy with itepekimab and dupilumab may have failed because these pathways bypass interleukin-33."

Risankizumab Study

Designated as phase IIa, randomized 214 adult patients with severe asthma to either risankizumab or placebo, given by subcutaneous injection every 4 weeks for 6 months. All patients had experienced at least one severe exacerbation in the past year (but not in the 6 weeks prior to screening) and were taking inhaled corticosteroids and at least one additional asthma control drug.

The primary outcome measure was time to first asthma worsening, defined as any of several indicators of increased airway constriction such as decreases in peak expiratory flow or increased medication use.

Patients receiving risankizumab demonstrated worsening much sooner than those on placebo: median 40 days versus 86 days, for a hazard ratio of 1.46 (95% CI 1.05-2.04). Already by week 4, nearly 40% of the risankizumab group had worsened asthma, compared with about 25% of the placebo group. The difference was even greater in patients with eosinophil counts of 200/mm³ or more. The rate ratio for severe exacerbations for risankizumab versus placebo during the trial was 1.13, but this was not statistically significant.

One explanation for risankizumab's unexpectedly negative performance lay in biomarker data, indicating that the drug downregulated Th17 and type 1 helper T transcription, along with cytotoxic T cells and natural killer cells in sputum samples. "These findings support the view that risankizumab exerted a biologic effect on airway immunity, which may have contributed to the poor clinical outcome," Wechsler and colleagues wrote.

Other than diminishing asthma symptom control, however, no safety problems with risankizumab were seen in the study, with adverse event rates similar to those in the placebo group.

Itepekimab Study

This randomized 296 adult patients (mean age about 50) with moderate-to-severe asthma in equal numbers to the aforementioned four treatment arms. Drugs and placebo were given by injection every 2 weeks. The primary outcome was "an event indicating loss of asthma control," definitions of which closely paralleled those for asthma worsening in the risankizumab study.

This outcome was met by 41% of the placebo group during the 12-week study, compared with 22% on itepekimab monotherapy, 19% on dupilumab monotherapy, and 27% of the combination arm. While the two drugs as monotherapies both showed statistically significant superiority to placebo, the combination did not (OR 0.52, 95% CI 0.26-1.06).

Moreover, the combination group did not show significant improvement relative to placebo in 1-second forced expiratory volume (0.10 L, 95% CI -0.03 to 0.23), while each drug alone did (0.14-0.16 L, both P<0.05). A similar pattern was seen for other secondary endpoints such as quality-of-life scores.

While the findings bode well for itepekimab as an asthma therapy, its commercial future for that indication is murky. The drug's developers, Sanofi and Regeneron, are also targeting chronic obstructive pulmonary disease, with . The companies' published plans for itepekimab with no mention of asthma, and no phase III trial in asthma is listed on ClinicalTrials.gov.

Sanofi and Regeneron also sell dupilumab, which has been a big money-maker. It appears that the companies were banking on itepekimab as a dupilumab add-on, and see no profit in it as a stand-alone product.