Efficacy, pharmacokinetics, and safety of nebulized HL231 inhalation solution in patients with chronic obstructive...

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.

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.

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.

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

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