麻豆传媒

Adding a novel, ultra-long-acting biologic to standard care for patients with severe asthma and type 2 inflammation significantly reduced exacerbations, a pair of phase IIIA trials showed.

Across the duplicate SWIFT-1 and SWIFT-2 studies, twice-yearly treatment with investigational depemokimab atop medium- or high-dose inhaled glucocorticoids reduced the annualized rate of exacerbations by 58% (rate ratio [RR] 0.42, 95% CI 0.30-0.59) and 48% (RR 0.52, 95% CI 0.36-0.73) compared with placebo over 52 weeks (P<0.001 for both), reported David Jackson, PhD, of Guy's and St. Thomas' NHS Foundation Trust in London.

The treatment effect with the subcutaneous anti-interleukin (IL)-5 biologic was generally consistent across subgroups and there was "no suggestion that there's a waning effect" approaching the time of subsequent dosing, he said at the annual European Respiratory Society (ERS) congress in Vienna.

Adverse event (AE) rates were similar between groups, with no serious AEs considered related to treatment, according to findings published simultaneously in the .

Type 2 inflammation -- measured by blood eosinophil counts -- underpins severe asthma, explained Jackson, and it's a risk factor for severe exacerbations, airway remodeling, and decline in lung function.

"It's there nearly all the time, and when you don't see it, it's normally because of confounding by steroids that the patients are on," he said. "And we know IL-5 is the most important cytokine for eosinophils."

Depemokimab, an anti-IL-5 neutralizing antibody, was engineered to have enhanced IL-5 binding affinity and potency, potentially enabling every 6-month dosing.

Multiple biologics are already available for treating severe asthma, noted ERS-designated discussant Arnaud Bourdin, MD, PhD, of Arnaud-De-Villeneuve Hospital in Montpellier, France. Currently approved IL-5 monoclonal antibodies include mepolizumab (Nucala) and benralizumab (Fasenra), with dosing every 4 and 8 weeks, respectively.

"Adherence to biologics is actually poorly known, but there are some preliminary results suggesting it's not 100%," said Bourdin, adding that "long-lasting monoclonal antibodies have demonstrated benefits in other areas."

Asked by Bourdin whether clinicians would feel comfortable starting a biologic-naive patient on the ultra-long-acting drug, Jackson noted that "very rarely do we switch the biologic before 6 months, so the idea that you're not going to give depemokimab first because you don't want it in the system for 6 months is unrealistic, because virtually all of us only start switching at 6 months anyway."

Jackson added that while there might be some anxiety about side effects, the data showed no increase in AEs with depemokimab. "And when we do see side effects with biologics, it doesn't last the extent of the dosing interval," he said.

In , depemokimab's developer GSK said it plans to submit the results to regulatory bodies worldwide.

The phase IIIA trials randomized 792 patients ages 12 and older with severe asthma in a 2:1 ratio to depemokimab (100 mg subcutaneously) or placebo at weeks 0 and 26 on top of standard care -- 762 were included in the primary analysis.

Eligibility criteria included an asthma diagnosis 2 years or more prior to enrollment; two or more exacerbations requiring systemic corticosteroids in the past year; a blood eosinophil count of at least 300 cells/μL in the past year, or 150 cells/μL at screening; regular treatment with medium- or high-dose inhaled glucocorticoids; and current treatment with at least one additional controller medication for 3 months or more.

Patients were in their early 50s on average (pediatric patients made up 4%), a majority were female, and more than three-fourths were white. Most participants were on high-dose inhaled glucocorticoids, 20% had three or more exacerbations in the past year requiring oral or systemic corticosteroids, and the average asthma duration was 20 years or more across the four study arms.

More than 90% had a blood eosinophil count of at least 150 cells/μl; Asthma Control Questionnaire-5 (ACQ-5) scores ranged from 2.13 to 2.34, and patients had a pre-bronchodilator forced expiratory volume in 1 second (FEV₁) of about 60% overall, said Jackson.

"They had severe lung function impairment," he said. "This was sort of a damaged group of patients."

For the primary analysis in SWIFT-1, the annualized rate of exacerbations over 52 weeks was 0.46 with depemokimab and 1.11 with placebo. In SWIFT-2, these rates were 0.56 and 1.08, respectively.

Pooled analysis of this endpoint showed that treatment with the anti-IL-5 biologic was generally consistent across subgroups, including patients in the U.S. (RR 0.45, 95% CI 0.27-0.76), those on medium-dose (RR 0.39, 95% CI 0.26-0.58) or high-dose (RR 0.51, 95% CI 0.38-0.70) inhaled glucocorticoids, and by blood eosinophil counts at baseline:

• <150 cells/μl: RR 0.52 (95% CI 0.25-1.09)
• 150 to <300 cells/μl: RR 0.54 (95% CI 0.35-0.84)
• ≥300 cells/μl: RR 0.43 (95% CI 0.31-0.59)

Secondary endpoints included changes from baseline on the St. George's Respiratory Questionnaire (SGRQ) total scores, FEV₁, and ACQ-5 scores, as well as the annualized rate of exacerbations resulting in hospitalization at 52 weeks.

At 52 weeks, mean change on the SGRQ (a 0-100 scale where higher scores indicate worse quality of life) was -13.03 and -14.80 with depemokimab versus -9.67 and -12.49 with placebo in the SWIFT-1 and SWIFT-2 trials, respectively, with neither difference reaching statistical significance. Due to the statistical design of the trials, this prevented testing of further secondary endpoints.

However, treatment with depemokimab showed a numerical improvement in the annualized rate of exacerbations resulting in hospitalization (0.02 vs 0.09 with placebo; RR 0.28, 95% CI 0.13-0.61).

For safety, AEs occurred in 72-73% of patients in the depemokimab groups versus 73-78% in the placebo group, with AEs considered related to treatment occurring in 3-4% and 1-4%, respectively. A handful of patients on depemokimab met stopping criteria due to liver measurements, but none were deemed related to treatment and all resolved or were resolving at follow-up.

Treatment discontinuation or withdrawal due to AEs occurred in 1% of the depemokimab groups and 1-2% of placebo groups. No fatal AEs occurred in any of the study arms.

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