touchRESPIRATORY coverage from ERS 2025:

Itraconazole, a triazole antifungal recommended in allergic bronchopulmonary aspergillosis (ABPA), is limited by poor oral bioavailability, systemic toxicity, and inadequate airway penetration. A novel inhaled dry powder formulation, developed to deliver high local concentrations directly to the lungs, is being investigated in a phase 2 study. The study will assess the efficacy, safety, and optimal dosing of inhaled itraconazole in ABPA-complicating asthma.

In this interview, we caught up with Dr Ritesh Agarwal (Postgraduate Institute of Medical Education and Research, Chandigarh, India) to discuss the challenges associated with treating ABPA-complicating asthma, the new inhaled formulation of itraconazole, and the aims, design and findings from the phase 2 study.

The abstract “A phase 2, dose-finding study of inhaled itraconazole in ABPA-complicating asthma” was presented at ERS 2025, 27 September–1 October, Amsterdam.

Q. What are the challenges associated with treating ABPA-complicating asthma?

For acute-stage ABPA, the first-line guideline options include oral corticosteroids or itraconazole, each for 4 months. Systemic corticosteroids carry significant long-term risks including metabolic complications (diabetes, weight gain, osteoporosis), cardiovascular disease, increased infection risk, and adrenal suppression. Oral itraconazole has variable and unpredictable bioavailability (20-55%), extensive drug-drug interactions via CYP3A4 inhibition, hepatotoxicity and other systemic side effects (nausea, hypokalemia, heart failure), and most importantly, poor penetration into airway secretions where Aspergillus colonizes.

All current treatments are used off label with limited evidence base. There is an unmet medical need for targeted therapies that deliver high antifungal concentrations directly to the site of disease (airway lumen) while minimizing systemic exposure and toxicity.

Q. What is the mechanism of action of itraconazole and what do we already know about this therapy?

Itraconazole inhibits fungal cytochrome P450-dependent 14α-lanosterol demethylase, which is essential for ergosterol biosynthesis, a critical component of fungal cell membranes. Disruption of ergosterol synthesis leads to accumulation of toxic sterol precursors, altered membrane permeability and function, and inhibition of fungal growth and reproduction.

Multiple randomized-controlled trials have demonstrated efficacy of oral itraconazole in ABPA. It reduces exacerbation frequency, decreases serum IgE levels and peripheral eosinophilia, improves pulmonary function and symptom control, and decreases oral corticosteroid requirements (steroid-sparing effect). The ISHAM 2024 guidelines recommend it as a primary therapy for ABPA.¹ The typical dose is 400mg (or 260mg of SUBA preparation) daily for 4–6 months.

Phase 1 studies show that oral itraconazole 200mg achieves sputum concentrations below the MIC₉₀ for A. fumigatus in the majority of patients. Serum drug levels poorly correlate with clinical response, and high inter-patient variability in absorption necessitates therapeutic drug monitoring

Q. What are the clinical benefits of a dry powder inhaled formulation of itraconazole?

The dry powder inhaled formulation of itraconazole has been developed using a particle-engineered platform called iSPERSE. This platform does not require a drug carrier and can deliver high concentrations of the drug directly to the site of fungal colonization and immune activation. Inhaled formulation achieves 70-fold higher sputum concentrations compared to oral itraconazole (phase 1 data: PUR1900 20mg vs oral 200mg), leading to superior antifungal efficacy. Also, there is negligible plasma concentration, which reduces risk of systemic toxicity. This feature avoids systemic itraconazole toxicities and drug interactions.

Q. What were the aims, design and inclusion criteria of the phase 2 study?

We evaluated the preliminary efficacy, safety, and optimal dosing of inhaled itraconazole (PUR1900) in adults with ABPA. We compared 20mg vs 40mg once-daily dosing to inform phase 3 development and demonstrate that targeted pulmonary antifungal delivery improves clinical outcomes in ABPA.

This was a phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial conducted across 14 tertiary care centres across India between January 2023 and June 2024. We randomized participants 2:2:1 to PUR1900 20mg, 40mg, or placebo (2-week run-in, 16 weeks active treatment, 4 weeks safety follow-up).

Efficacy endpoints assessed as change from baseline to week 16 included: pre-dose FEV₁ (lung function); serum total IgE (immunological biomarker); blood eosinophil counts (inflammatory marker); ACQ-7 and ACQ-6 scores (asthma symptom control); peak expiratory flow (lung function variability); and AQLQ score (disease-specific quality-of-life).

Q. What were the efficacy and safety findings from the study?

We observed a clear dose-dependent efficacy observed across multiple endpoints. PUR1900 40mg demonstrated consistent, clinically meaningful improvements, while PUR1900 20mg showed numerical trends without statistical significance.

PUR1900 40mg results vs placebo at week 16:

• Lung function (FEV₁): +0.28 L improvement (p=0.036), exceeds 100–200mL minimum clinically important difference (MCID) threshold.
• Asthma control (ACQ-7): -0.51-point improvement (p=0.030), exceeds 0.5-point MCID.
• Immunological biomarkers (serum total IgE): -2619kU/L reduction (p=0.059), approached statistical significance despite high variability.
• Quality of life (AQLQ): +0.89 improvement (exceeded 0.5 MCID), not statistically significant vs placebo, but clinically meaningful.

The safety profile was comparable to placebo with no serious adverse events in any active treatment group and no treatment-related discontinuations in the 40mg group. Transient FEV₁ declines occurred equally across all groups (including placebo), were asymptomatic and resolved quickly. There were no hepatotoxicity or systemic itraconazole-related adverse events. Comprehensive monitoring showed no ECG, laboratory, or vital sign abnormalities

Our phase 2 study established the proof-of-concept that inhaled antifungal therapy effectively treats ABPA. We identified 40mg once daily as the optimal dose providing the best benefit-risk profile, with benefits across lung function, symptoms, and biomarkers. This paradigm-shifting study demonstrates that site-targeted delivery addresses the fundamental disease mechanism.

What are the next steps in the development of inhaled itraconazole?

The next steps will be the rapid transition to a phase 3 program with larger randomized controlled trials (including 200–400 patients) for definitive efficacy/safety; an extended duration (24–52 weeks) to assess exacerbation reduction, long-term safety, tolerability, and sustained efficacy; an expanded patient population with broader FEV₁ range and those with acute-stage ABPA; and enhanced endpoints, primarily frequency of exacerbations.

References

1. Agarwal R, Sehgal IS, Muthu V, et al. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J. 2024;63(4):2400061.