Efficacy, pharmacokinetics, and safety of nebulized HL231 inhalation solution in patients with chronic obstructive pulmonary disease: a randomized trial

Background: Long-acting beta-agonist (LABA) plus long-acting muscarinic antagonist (LAMA) is superior to monotherapy or corticosteroid/LABA in terms of improving lung function, alleviating symptoms and educe chronic obstructive pulmonary disease (COPD) exacerbations. This study aimed to establish optimal dosage of nebulized HL231 inhalation solution (HL231), comparable to Ultibro^® (110 µg indacaterol maleate/50 µg glycopyrronium bromide), for bronchodilatation, pharmacokinetics, and safety in COPD.

Methods: This study employed a multicenter, randomized, single-dose, single-blind, crossover design and featured two parts. The randomization schedule was generated by the statistical team using the block randomization procedure in SAS software. Chinese adults aged 40 years or older who were diagnosed with moderate-to-severe COPD using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria were eligible for the study. Blinding was implemented for the personnel conducting pulmonary function tests. In Part A, patients were randomized to receive a single dose of HL231 (132 µg/72 µg, 261 µg/141 µg, or 516 µg/279 µg), Ultibro^®, or placebo in a randomized sequence with a washout period of at least 14 days between two visits. The primary efficacy endpoint was the change in the area under the curve (AUC) of FEV₁ from baseline to 12 h after administration (ΔFEV₁ AUC_0-12h). In Part B, patients were randomized to receive a single dose of HL231 (261 µg/120 µg and 261 µg/141 µg), or Ultibro^® in a randomized sequence. The primary endpoints were pharmacokinetic parameters, including the AUC from time 0 to the last detectable time point (AUC_0-t), AUC from time 0 to infinity (AUC_0-∞), and peak concentration (C_max). Safety was evaluated in both parts.

Results: The study was initiated and completed between December 2021 and May 2023, with 173 and 29 patients screened in Part A and Part B respectively, resulting in 84 and 18 randomized patients, of whom 83 and 18 completed at least one treatment cycle. In Part A, the least squares (LS) mean differences in ΔFEV₁ AUC_0-12h for HL231 doses (132 µg/72 µg, 261 µg/141 µg, and 516 µg/279 µg) and Ultibro^® versus placebo were 2.30, 2.58, 2.68, and 2.33 L·h (all P<0.001), respectively, while compared to Ultibro^®, differences were −0.04 (P=0.83), 0.24 (P=0.14), and 0.35 L·h (P=0.04), respectively. Moreover, the LS means of ΔFEV₁ AUC0-12h for these doses were 2.30, 2.58, and 2.69 L·h, indicating a dose-response relationship. In Part B, HL231 261 µg/141 µg demonstrated peak concentration (C_max) of indacaterol and glycopyrronium at 86% and 54% of Ultibro^®, with comparable AUC_0-t. Safety was acceptable, with most treatment-emergent adverse events (TEAEs) being grade 1–2.

Conclusions: HL231 (261 µg/141 µg) is highly comparable to Ultibro^® in bronchodilatation, pharmacokinetics, and safety, making it a potential alternative for COPD patients.

Trial Registration: This study was registered at Chinese Clinical Trials Registration (ChiCTR2300068316) and clinicaltrials.gov (NCT06619210, retrospectively registered).

Keywords: HL231 inhalation solution; bronchodilatation; indacaterol; glycopyrronium; chronic obstructive pulmonary disease (COPD)


 

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Key findings

• The study demonstrated that HL231, a once-daily nebulized long-acting beta-agonist/long-acting muscarinic antagonist formulation at 261 µg/141 µg dose, achieved comparable bronchodilation efficacy, pharmacokinetic profiles [area under the curve (AUC) and peak concentration (Cmax)], and safety outcomes to the established Ultibro^® dry powder inhaler (DPI), while showing a clear dose-response relationship at higher doses with predominantly mild-to-moderate adverse events.

What is known and what is new?

• Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition requiring effective bronchodilators. Ultibro^® (indacaterol maleate and glycopyrronium bromide) is a well-established LABA/LAMA treatment delivered via DPI. However, some patients, particularly older individuals or those with difficulty using DPIs or pressurized metered-dose inhalers (pMDIs), may require alternative delivery methods.

• This study provides the first evidence that HL231 offers equivalent efficacy as a nebulized alternative, establishing its optimal dose (261/141 µg) and validating comparable pharmacokinetics between the two formulations, thereby addressing a significant unmet need in patient care. The findings suggest that HL231 (261 µg/141 µg) could serve as a viable alternative to Ultibro^® for COPD patients, particularly those who struggle with DPIs or pMDIs. This expands treatment options and may improve adherence in patients who benefit from nebulized administration.

What is the implication, and what should change now?

• 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.


Cite this article as: Hu Q, Zhao L, Yang G, et al. Efficacy, pharmacokinetics, and safety of nebulized HL231 inhalation solution in patients with chronic obstructive pulmonary disease: a randomized trial. J Thorac Dis 2025;17(10):7459-7472. doi: 10.21037/jtd-2025-1130