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January 06, 2026
4 min read
Key takeaways:
- There is a need for a nebulized LABA/LAMA formulation in COPD.
- Bronchodilation, pharmacokinetics and safety of a nebulized product were assessed against a dry powder inhaler.
- Comparable results were found.
In adults with COPD, bronchodilation efficacy and safety were similar between a nebulized inhalation solution and a dry powder inhaler made up of indacaterol and glycopyrronium, according to data published in Journal of Thoracic Disease.
The dose of the nebulized HL231 inhalation solution (Haisco Pharmaceutical Group) that achieved this was 261 μg of the long-acting beta agonist indacaterol and 141 μg of the long-acting muscarinic antagonist glycopyrronium, according to researchers.
In adults with COPD, bronchodilation efficacy and safety were similar between a nebulized inhalation solution and a dry powder inhaler made up of indacaterol and glycopyrronium, according to study results. Image: Adobe Stock
“This expands treatment options and may improve adherence in patients who benefit from nebulized administration,” Qingyuan Hu, of Nantong University in China, and colleagues wrote.
In a two-part, multicenter, randomized, single-dose, single-blind, crossover study, Hu and colleagues evaluated Chinese adults aged at least 40 years with moderate to severe COPD to determine what dose of nebulized HL231 inhalation solution is similar to the Ultibro dry powder inhaler (110 μg indacaterol maleate/50 μg glycopyrronium bromide; Novartis) using three measures: bronchodilation, pharmacokinetics and safety.
“There is no nebulized LABA/LAMA combination approved for use in COPD,” Hu and colleagues wrote.
“HL231 is the first once-daily LABA/LAMA nebulized product, which is more suitable for older patients with COPD or patients who cannot effectively use a [dry powder inhaler], [pressurized metered-dose inhaler] or other inhalers,” they added. “It is also an alternative option for patients with COPD who prefer nebulized therapies.”
Part A of this study included 83 patients (mean age, 66.2 years; 84.3% men) who received a single dose of one of three HL231 options (132 μg/72 μg, 261 μg/141 μg or 516 μg/279 μg), Ultibro or placebo. The study outlined that 10 dosing sequence groups were created, and each group participated in five treatment visits. A washout period of at least 14 days was required between two visits.
During this part, researchers assessed changes in FEV1 area under the curve (AUC) from baseline (average of FEV1 measures at 45 and 15 minutes before administration) to 12 hours after administration.
Part B included 18 patients (mean age, 64.2 years; 88.9% men) who received a single dose of one of two HL231 options (261 μg/120 μg or 261 μg/141 μg) or Ultibro. According to the study, this part had six treatment sequence groups, and each group completed three cycles of treatment. Again, a washout period of at least 14 days was set between two cycles.
The focus of part B was on AUC from time 0 to the last detectable time point, AUC from time 0 to infinity and peak concentration.
Part A, B findings
When placed against placebo, researchers found a significant improvement in FEV1 AUC from baseline to 12 hours after administration with each HL231 dose based on least-squares mean differences: 2.3 L/hour with 132 μg/72 μg, 2.58 L/hour with 261 μg/141 μg and 2.68 L/hour with 516 μg/279 μg.
According to the study, the above values show a dose-response relationship.
Similar to above, receipt of Ultibro resulted in a significantly improved FEV1 AUC from baseline to 12 hours after administration vs. placebo (least-squares mean difference, 2.33 L/hour).
The only HL231 dose that significantly differed from Ultibro in FEV1 AUC from baseline to 12 hours after administration was 516 μg/279 μg, with a least-squares mean difference of 0.35 L/hour (P = .04).
Researchers continued to find significantly better lung function with HL231 vs. placebo, as well as a dose-response relationship when evaluating FEV1 AUC from 0 to 24 hours and FEV1 AUC from 0 to 4 hours. None of the HL231 doses significantly differed from Ultibro in these two lung function measures.
“Overall, the improvement in lung function in patients with COPD was positively correlated with the dose of HL231, and the bronchodilatation effect for HL231 at a dose of 261 μg/141 μg group was most comparable to that of Ultibro,” Hu and colleagues wrote.
Considering the HL231 dose of 261 μg/141 μg, researchers reported a peak concentration of indacaterol that was 86% of the peak concentration of Ultibro and a peak concentration of glycopyrronium that was 54% of that of Ultibro.
Further, HL231 261 μg/141 μg and Ultibro had similar AUCs from time 0 to the last detectable time point of indacaterol, and this was also the case for glycopyrronium.
“These findings indicate that the pharmacokinetics of the two active ingredients of HL231 at a dose of 261 μg/141 μg is comparable to that of Ultibro,” Hu and colleagues wrote.
Overall safety
In terms of safety, 57 treatment-emergent adverse events occurred in 30 patients from part A (36.1%), whereas 16 treatment-emergent adverse events occurred in nine patients from part B (50%). All but three treatment-emergent adverse events were deemed grade 1 to 2, and researchers reported that these three serious adverse events were “definitely unrelated to the study drug.”
Of the four drug-related treatment-emergent adverse events analyzed (bloating, dizziness, dry mouth and elevated blood glucose), dizziness was the only one that occurred in the HL231 groups, and it was only reported by one patient who received the 261 μg/141 μg dose.
“A single dose of HL231 at low, medium or high doses was well tolerated in patients with COPD,” Hu and colleagues wrote.
“These findings should prompt clinicians to consider HL231 for device-challenged patients, guide updates to treatment guidelines to include nebulized options, and stimulate further research into long-term outcomes and cost-effectiveness, while advocating for the development of standardized protocols for nebulized therapy initiation in COPD management,” they added.
Perspective
The findings in this early-stage study describe a nebulized formulation of a LAMA/LABA combination treatment and compare the bronchodilator efficacy of this formulation with an inhaler-based delivery system. The results demonstrate comparable efficacy and safety, which is expected in a population without appreciable difficulty utilizing inhaler-based delivery systems.
In the United States, critical failure with inhaler technique resulting in incomplete or inadequate response to treatment is common. Often, elderly patients or those with physical or cognitive impairments cannot utilize traditional inhalers due to issues with coordination, articulation of their mouth around the device to create a seal or inadequate inspiratory flow rates. Inadequate treatment responses due to these underlying patient factors can result in worse disease control, poor quality of life and adverse outcomes. Nebulizer-based therapies can serve as a way to address this issue in such populations. However, options using this delivery system are limited.
Physicians should evaluate for underlying patient factors when prescribing inhaler-based therapies and consider alternative nebulized options as appropriate.
Future work should evaluate this therapy in a larger, more diverse COPD population with demonstrated physical or cognitive impairments that reduce efficacy of more traditional inhaler treatments. Such a study could provide needed evidence of improved outcomes with nebulized LABA/LAMA formulations in COPD patients with critical failure in inhaler technique.
R. Chad Wade, MD, MBA
Disclosures: Wade reports being an employee of the University of Alabama at Birmingham and receiving consulting funds from Berlin-Chemie, Sanofi and Verona.
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