Depemokimab reduces severe asthma exacerbations by half with twice-yearly treatment
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Key takeaways:
- Depemokimab has high binding affinity and potency for IL-5.
- Eosinophils fell by 83% and 82% with treatment in the two trials.
- The treatment and placebo groups had similar rates and types of adverse events.
Patients with severe eosinophilic asthma who used depemokimab administered every 6 months experienced a 54% reduction in exacerbations over 52 weeks, according to a study presented at the European Respiratory Society International Congress.
The reduction in dosing frequency compared with other biologic therapies may reduce treatment burden and health care use while improving quality of life, David J. Jackson, PhD, MSc, FRCP, professor of respiratory medicine at King’s College London, and colleagues wrote.
The role of IL-5
Manufactured by GSK, depemokimab significantly reduces asthma exacerbations through sustained suppression of type 2 inflammation, which is a key driver of exacerbations, with just two injections a year, a company spokesperson told Healio.
“Extended dosing intervals could also help tackle other barriers to optimal outcomes such as adherence or frequent health care appointments,” the spokesperson continued.
Also, the spokesperson called the biologic the first ultra-long-acting biologic treatment seeking indication for severe asthma and nasal polyps, with a high binding affinity and potency for IL-5, enabling 6-month dosing intervals for patients with severe asthma.
“Our expertise in IL-5 science along with the extensive data we have for IL-5 inhibition has informed the development plan for depemokimab,” the spokesperson said. “This has enabled us to be confident in efficacy depemokimab could deliver in severe asthma.”
Study design, results
At screening, 90% of the 732 patients in the multicenter, randomized, double-blind, placebo-controlled SWIFT-1 (n = 367) and SWIFT-2 (n = 365) trials had blood eosinophil counts of 150 cells/µL or higher.
Patients also were aged 12 years and older and had at least 2 years of physician-diagnosed asthma, along with regular inhaled corticosteroid (ICS) treatment over the previous 12 months and one or more additional controllers over the previous 3 months or more.
Further, patients had experienced two or more exacerbations that required systemic corticosteroids in the previous 12 months.
Treatment included subcutaneous injections of 100 mg of depemokimab (n = 250 in SWIFT-1; n = 252 in SWIFT-2) or placebo (n = 132 in SWIFT-1; n = 128 in SWIFT-2) at weeks 0 and 26 along with standard care including medium- to high-dose ICS and an additional controller in 17 attended visits through 182 days after the final dose.
“There was a 54% reduction in annualized rate of clinically significant exacerbationsacross both SWIFT-1 and SWIFT-2,” the spokesperson said.
At week 52, annualized rates of exacerbations in SWIFT-1 and SWIFT 2 were significantly lower in the treatment vs. placebo groups (SWIFT-1: 0.46 vs. 1.11; rate ratio, 0.42; SWIFT-2: 0.56 vs. 1.08; rate ratio, 0.52). Annualized rates of exacerbations in the pooled analysis were 0.51 vs. 1.11, with a rate ratio of 0.46.
Specifically, reductions in annualized rates of reactions included 58% (95% CI, 41%-70%) in SWIFT-1 and 48% (95% CI, 27%-64%) in SWIFT-2, as well as a 72% reduction in the annualized rate of reactions requiring hospitalizations and/or ED visits in the pooled analysis (rate ratio = 0.28; 95% CI, 0.13-0.61).
Mean changes in St. George’s Respiratory Questionnaire scores from baseline to week 52, with negative scores indicating better quality of life, in SWIFT-1 included –13.03 (95% CI, –15.22 to –10.84) for the treatment group and –9.67 (95% CI, –12.71 to –6.64) in the placebo group.
Similarly, mean changes in these scores from baseline to week 52 in SWIFT-2 included –14.8 (95% CI, –16.85 to –12.75) in the treatment group and –12.49 (95% CI, –15.36 to –9.63) in the placebo group.
In SWIFT-1, 81 patients in the treatment group (32%) experienced 124 exacerbation events, and 61 patients in the placebo group (46%) experienced 151 events. In SWIFT-2, these numbers included 81 patients (32%) with 159 events in the treatment group and 64 patients (50%) with 167 events in the placebo group.
Probabilities that patients using depemokimab would experience an exacerbation event through week 52 included 32% (95% CI, 27%38%) in SWIFT-1, 33% (95% CI, 27%-39%) in SWIFT-2 and 32% (95% CI, 28%-37%) in the pooled analysis.
Among patients on placebo, probabilities for an exacerbation event included 47% (95% CI, 39%-56%) in SWIFT-1, 51% (95% CI, 42%-60%) in SWIFT-2 and 49% (95% CI, 43%-55%) in the pooled analysis.
Hazard ratios for an exacerbation event among patients on placebo included 0.56 (95% CI, 0.4-0.79) in SWIFT-1, 0.53 (95% CI, 0.38-0.74) in SWIFT-2 and 0.54 (95% CI, 0.43-0.69) in the pooled analysis.
Among patients with baseline blood eosinophils of less than 150 cells/µL, annualized exacerbation rates included 0.35 (95% CI, 0.23-0.54) for patients on depemokimab and 0.67 (95% CI, 0.37-1.19) on placebo for a rate ratio of 0.53 (95% CI, 0.25-1.09).
Patients with baseline blood eosinophils of 150 cells/µL to 300 cells/µL had annualized exacerbation rates including 0.58 (95% CI, 0.43-0.78) for the depemokimab group and 1.06 (95% CI, 0.77-1.46) for the placebo group for a rate ratio of 0.54 (95% CI, 0.35-0.84).
Annualized exacerbation rates included 0.66 (95% CI, 0.49-0.89) for patients who were on depemokimab and 0.74 (95% CI, 0.49-1.12) for those on placebo with a rate ratio of 0.89 (95% CI, 0.53-1.49) among patients with baseline blood eosinophil counts between 300 cells/µL and 500 cells/µL.
Among patients with baseline blood eosinophil counts above 500 cells/µL, annualized exacerbation rates included 0.45 (95% CI, 0.33-0.59) for those on depemokimab and 1.57 (95% CI, 1.17-2.12) for those on placebo, with a rate ratio of 0.28 (95% CI, 0.19-0.42).
Proportions of patients with adverse events included 73% for both the treatment and placebo groups in SWIFT-1 and 72% for the treatment group and 78% for the placebo group in SWIFT-2.
There were no deaths, and the researchers did not consider any of the adverse events to be related to the study. In SWIFT-1, 12% of the treatment group and 19% of the placebo group had nasopharyngitis. In SWIFT-2, these numbers included 13% of the treatment group and 21% of the placebo group.
The researchers also noted rapid and sustained reductions in blood eosinophil count from baseline through week 52 among the patients in the treatment groups, including 83% in SWIFT-1 and 82% in SWIFT-2.
Also, 12% of the treatment group in SWIFT-1 and 5% of those patients in the treatment group in SWIFT-2 developed antibodies to depemokimab, including two patients in SWIFT-2 testing positive for neutralizing antibodies against the drug.
Conclusions, next steps
These findings indicate sustained and significant reductions in annual exacerbation rates with the administration of depemokimab every 6 months for 52 weeks among patients with an eosinophilic endotype of severe asthma, the researchers concluded.
“For patients with severe asthma, these results are important,” the spokesperson said. “More than 80% of patients with severe asthma exhibit markers of type 2 inflammation, a key driver of exacerbations. Biologic therapies available involve 12 to 24 injections a year.”
However, depemokimab significantly reduces asthma exacerbations through sustained suppression of type 2 inflammation with just two injections a year, the spokesperson continued.
“Extended dosing intervals could also help tackle other barriers to optimal outcomes such as adherence or frequent health care appointments,” the spokesperson said.
More than 262 million people have asthma, approximately 10% of whom have severe asthma and are at high risk for exacerbations, the spokesperson added.
“The possibility of a treatment option that can inhibit exacerbation and reduce treatment burden that patients face is an exciting possibility,” the spokesperson said. “Research shows that both health care providers and patients would welcome a treatment with a 6-month dosing schedule.”
GSK will provide updates on depemokimab’s path toward approval at appropriate times, the spokesperson said.
“However, we anticipate potential launches in several indications between 2026 and 2027,” the spokesperson added.
The company is now evaluating depemokimab in phase 3 programs across a range of IL-5 mediated diseases, the spokesperson said, including chronic rhinosinusitis with nasal polyps (ANCHOR-1 and ANCHOR-2), eosinophilic granulomatosis with polyangiitis (OCEAN) and hypereosinophilic syndrome (DESTINY).
“The clinical development program for depemokimab in asthma also includes two additional studies, NIMBLE and AGILE, that will further evaluate the efficacy and safety profile of this new medicine,” the spokesperson said.
References:
- Depemokimab late-breaking data presented at ERS show a 54% reduction in severe asthma exacerbations. https://www.gsk.com/en-gb/media/press-releases/depemokimab-late-breaking-data-presented-at-ers-show-a-54-reduction-in-severe-asthma-exacerbations/. Published Sept. 9, 2024. Accessed Sept. 9, 2024.
- Jackson DJ, et al. N Engl JMed. 2024;doi:10.1056/NEJMoa2406673.
Perspective
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Depemokimab represents a step forward in our care of asthmatic patients. Although we now have several biologics available, with different mechanisms of action, this is the first therapy to be given only twice yearly.
Recent research shows not surprisingly that in the real world, even biologics, which require doses ranging from twice a month to once every other month, are still not adhered to. Having an agent that requires only two injections per year will be a wonderful option.
Also, prior studies of depemokimab have demonstrated pharmacokinetic-positive results with dosing every 6 months. Now we have clinical data to confirm it. Again, this much less frequent dosing requirement will be game changing.
We must consider use of biologics, especially one requiring only twice-yearly dosing, earlier in our paradigm of care, such as patients with moderate persistent asthma. This will make their medical regimen much easier.
The recent SHAMAL study demonstrated that use of the biologic benralizumab (Fasenra, AstraZeneca) allowed tapering of inhaled corticosteroids and long-acting beta agonists with continued control. Can we rely upon solely a twice-yearly injection in less severe asthma as their only intervention?
Next, research should further validate the efficacy of this treatment as well as consider the determining characteristics of super-responders and the utility of depemokimab as sole therapy in more mild disease.
References:
Jackson DJ, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)02284-5.
Ledford DK, et al. Ann Allergy Asthma Immunol. 2023;doi:10.1016/j.anai.2023.07.017.
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Jackson DJ, et al. Depemokimab efficacy/safety in patients with asthma on medium/high-dose ICS: The hase IIIA randomied SWIFT-1/2 studies. Presented at European Respiratory Society International Congress; Sept. 7-11, 2024; Vienna.
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