Novartis Announces Phase IIIb ARGON Study of Enerzair® Breezhaler® Meets Primary Endpoint in Uncontrolled Asthma

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Novartis recently announced that the full results of the Phase IIIb ARGON study evaluating the single-inhaler triple therapy Enerzair Breezhaler (QVM149, IND/GLY/MF) for the treatment of asthma have been published in *Respiratory Medicine*.

The results demonstrated that once-daily high-dose and medium-dose Enerzair Breezhaler, administered via a single inhaler, were non-inferior to the combination regimen of twice-daily high-dose salmeterol xinafoate/fluticasone propionate (Sal/Flu) delivered via two separate inhalation devices plus once-daily tiotropium (Tio), in improving quality of life among patients with uncontrolled asthma. In the analysis of secondary endpoints, once-daily high-dose Enerzair Breezhaler improved lung function, asthma control, and health status, while reducing moderate asthma exacerbations, compared with high-dose Sal/Flu plus Tio.

Enerzair Breezhaler is a fixed-dose combination product comprising indacaterol acetate (IND, a long-acting beta2-agonist [LABA]), glycopyrronium bromide (GLY, a long-acting muscarinic antagonist [LAMA]), and mometasone furoate (MF, an inhaled corticosteroid [ICS]). It precisely combines the bronchodilatory effect of IND, the antimuscarinic action of GLY, and the anti-inflammatory properties of ICS. The product is administered via the Breezhaler device, which features a dose confirmation mechanism, enabling once-daily inhalation therapy using a single inhaler.

ARGON is a multicenter, randomized, 24-week, parallel-group, non-inferiority, open-label (blinded to the two IND/GLY/MF investigational doses), active-controlled study enrolling patients with asthma who are receiving maintenance therapy with moderate or high stable doses of LABA/ICS but have uncontrolled disease. All patients were symptomatic at screening, with an Asthma Control Questionnaire-7 (ACQ-7) score ≥1.5. The study compared the efficacy and safety of IND/GLY/MF with the regimen of salmeterol/fluticasone propionate (Sal/Flu) plus tiotropium (Tio). The objective was to demonstrate that two doses of IND/GLY/MF (high dose: 150/50/160 μg; medium dose: 150/50/80 μg) are non-inferior in efficacy to the free combination of Sal/Flu (50/500 μg) and Tio (5 μg) in patients with asthma.

In the study, 1,251 adult patients (aged ≥18 years) with uncontrolled asthma were randomized in a 1:1:1 ratio to receive one of the following three treatment regimens: medium-dose IND/GLY/MF, high-dose IND/GLY/MF, or open-label high-dose Sal/Flu + Tio.

The primary objective is to demonstrate the non-inferiority of high-dose and medium-dose IND/GLY/MF versus Sal/Flu + Tio, as assessed by the Asthma Quality of Life Questionnaire (AQLQ) after 24 weeks of treatment. Secondary objectives include comparing the efficacy of high-dose and medium-dose IND/GLY/MF with Sal/Flu + Tio through improvements in trough forced expiratory volume in one second (FEV1) after 24 weeks of treatment, as well as improvements in AQLQ scores, ACQ-7 scores, and lung function during the 24-week treatment period.

The results showed that the study met its primary endpoint: high-dose and medium-dose IND/GLY/MF demonstrated non-inferiority compared with Sal/Flu+Tio in terms of change from baseline in AQLQ scores (high dose: 0.073; medium dose: 0.038; both p < 0.001).

Analysis of secondary endpoints demonstrated that high-dose IND/GLY/MF improved asthma control (as measured by the ACQ: ACQ-7 score [-0.124]; p=0.004) and lung function (as measured by trough FEV1 [96 mL; p<0.001]) compared with high-dose Sal/Flu + Tio. Additional exploratory analyses showed that high-dose IND/GLY/MF improved health status (as measured by the St. George’s Respiratory Questionnaire; SGRQ [-2.00; p=0.04]) and peak expiratory flow (morning [9.56 L/min; p=0.005]; evening [9.15 L/min; p=0.006]) compared with high-dose Sal/Flu + Tio. Furthermore, high-dose IND/GLY/MF significantly reduced the rate of moderate exacerbations by 43% (p=0.04) compared with high-dose Sal/Flu + Tio, while rates of exacerbations of other severities were comparable. Medium-dose IND/GLY/MF showed comparable efficacy to high-dose Sal/Flu + Tio for these endpoints, but with a lower steroid dose. In terms of safety, adverse events were comparable across treatment groups.

From a regulatory perspective, the drug is currently undergoing review in multiple countries. Recently, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion, recommending the approval of Enerzair Breezhaler as a maintenance therapy for adult patients with asthma whose condition is not adequately controlled with a maintenance regimen of a long-acting beta2-agonist (LABA) and high-dose inhaled corticosteroid (ICS) combination, and who have experienced one or more acute exacerbations in the previous year. The European Commission is expected to make a final approval decision in June this year. If approved, the drug will become the first fixed-dose combination product containing a LABA, a long-acting muscarinic antagonist (LAMA), and an ICS for the population of asthma patients whose condition is not controlled by LABA/ICS maintenance therapy, providing an important, effective, and convenient alternative treatment option.

Reference Source: Novartis Phase IIIb ARGON study meets primary endpoint in a comparison of Enerzair® Breezhaler® (QVM149) versus a free combination of two existing inhaled treatments in uncontrolled asthma