Guest Column | September 3, 2025

Beyond The Inhaler: Expanding COPD Care With Nebulized Combination Therapy

By Ahmet Tutuncu, MD, Ph.D., CEO and co-founder, AeroRx Therapeutics

Inhalers, asthma-GettyImages-868815768

Chronic obstructive pulmonary disease (COPD) continues to impose a heavy clinical and economic burden globally. Despite advances in pharmacologic therapy, many patients remain symptomatic, experiencing persistent breathlessness, reduced functional capacity, and frequent exacerbations that can lead to hospitalizations and disease progression.

While international guidelines now recommend long-acting dual bronchodilation with long-acting beta2 agonist (LABA) and long-acting muscarinic antagonist (LAMA) as the preferred first-line maintenance therapy for moderate to severe COPD, this standard of care is not accessible to all patients. A significant subset, including older, sicker individuals who struggle to use handheld inhalers, is not receiving the full benefit of these treatments.

This disconnect between treatment guidelines and real-world usability and patient capability represents one of the most actionable gaps in COPD care today. And it’s one that next-generation nebulized combination therapies are uniquely positioned to address.

The Inhaler Gap: When Standard Of Care Isn’t Accessible

Globally, COPD affects an estimated 390 million people today and is projected to exceed 600 million by 2050, driven by population aging, persistent smoking rates, and worsening air pollution. In the United States, more than 16 million adults are diagnosed with COPD, with nearly $30 billion in direct healthcare costs, each year.1–3

The COPD treatment landscape is dominated by handheld inhalers, including metered-dose (MDIs), dry powder (DPIs), and soft mist inhalers (SMIs). These devices account for the vast majority of prescribed maintenance therapies. Yet despite their widespread use, multiple real-world studies have shown that up to 75% of patients do not receive an optimal dose from inhalers due to poor technique, limited coordination, or underlying disease severity.4–6

This challenge is particularly acute in older adults and individuals living with physical or cognitive impairments such as arthritis or dementia. These groups are also at higher risk for exacerbations, hospitalization, and disease progression. For these patients, even first-line dual bronchodilation delivered via an inhaler can fall short, simply because the medication never reaches the lungs effectively.

Even among patients who do receive FDA‑approved LABA/LAMA inhaler therapy, outcomes remain suboptimal: up to 50 percent continue to experience daily breathlessness, activity limitation, and frequent exacerbations that drive emergency visits and hospitalizations.7,8 This underscores the urgency of delivery methods to benefit patients with a full therapeutic dose that reaches the airways.

This disconnect between guideline-recommended care and real-world usability is a critical — and addressable — gap. It calls for delivery methods that are not just clinically effective but also accessible to those with the greatest need.

Nebulization: A Proven, Underleveraged Modality

For decades, innovation in COPD maintenance therapy has focused primarily on new molecules and combinations delivered almost exclusively via handheld inhalers. This strategy implicitly assumes that patients can use these devices effectively. But as the COPD population ages, delivery methods that account for real-world limitations are becoming increasingly essential.

Nebulization offers a compelling alternative. Once associated mainly with acute care or advanced disease, it has evolved into a viable platform for chronic maintenance treatment. Advances in formulation science and device usability have expanded nebulization’s role across home, outpatient, and even early-stage care settings.

What makes nebulization so impactful is its ability to deliver medication through passive tidal breathing, providing consistent dosing regardless of inspiratory effort or technique. It is already widely used in home and hospital settings for patients who struggle with handheld inhalers. Nebulized monotherapies such as revefenacin, formoterol, and arformoterol have demonstrated clinical utility and sustained adoption in the market.

However, no LABA/LAMA combination bronchodilator is currently approved for nebulized delivery. This is a striking gap in the treatment landscape, especially given that fixed-dose combinations improve adherence, reduce exacerbations, and are now preferred over monotherapy in GOLD guidelines.9

Bridging The Gap: Nebulized LABA/LAMA As First-Line Therapy

Next-generation nebulized formulations are being designed to deliver dual bronchodilation efficiently and reliably, with minimal patient burden. Clinical-stage programs such as AERO-007 are testing this hypothesis with rigor. Developed under the 505(b)(2) regulatory pathway, AERO-007 is a proprietary formulation of indacaterol and glycopyrrolate, optimized for delivery via 510(k)-cleared standard jet nebulizer.

In a recent Phase 2a study, both low- and high-dose AERO-007 was well tolerated and achieved rapid and sustained 24-hour bronchodilation. Importantly, AERO-007 is being developed as first-line maintenance therapy, not as an add-on for patients already on inhalers. This sets it apart from other nebulized assets, such as PDE3/4 inhibitors, that are adjunctive in nature.

This first-line positioning is critical. By intervening earlier in the disease course, before patients cycle through less effective options, a nebulized LABA/LAMA combination therapy aims to prevent exacerbations, reduce healthcare utilization, and preserve lung function in populations that are not benefitting from inhaler-based regimens.

Designing For Delivery: Putting Patients First

For COPD patients who struggle with handheld inhalers, nebulization offers a more accessible mode of drug delivery. Unlike inhalers, which require precise coordination and sufficient inspiratory effort, nebulizers deliver medication through normal, passive breathing, providing consistent dosing regardless of disease severity or technique. This is especially important for older adults and others with physical or cognitive limitations, for whom handheld inhaler devices may be ineffective.

As combination therapies move toward nebulized formats, selecting devices that are familiar to both clinicians and patients can help streamline adoption and integrate new options into established care pathways. In AeroRx’s case, the decision to pair its novel combination formulation with a standard, already widely used jet nebulizer reflects a commitment to pragma

Choosing devices that are already familiar to clinicians and caregivers can smooth adoption and help innovative therapies fit seamlessly into established treatment routines.

Looking Ahead: Expanding To Triple Therapy

While dual bronchodilation remains the preferred starting point for moderate to severe COPD, many patients ultimately require escalation to triple therapy — adding an inhaled corticosteroid (ICS) to LABA/LAMA treatment. These regimens are now standard in inhaler form, yet no nebulized triple combinations have reached the market.

We believe AERO-011 is the first nebulized LABA/LAMA/ICS therapy in development. Formulation feasibility work has already begun to evaluate co-delivery of the ICS with LABA/LAMA combinations in nebulized format, offering a promising path toward the first triple therapy via nebulizer, potentially transforming the treatment of patients with advanced diseases.

Conclusion

With the burden of COPD growing globally, and a disproportionate impact on aging populations, the need for patient-centric, accessible drug delivery has never been greater. Nebulized dual and triple therapies offer a route to bring guideline-preferred care to the patients most in need.

The future of COPD treatment must not only focus on what we deliver but how — and to whom. Nebulized combinations guided by thoughtful formulation and patient‑centered delivery may well define the next chapter in respiratory care.

References

  1. American Lung Association. COPD Trends Brief. American Lung Association website. https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief. Accessed August 27, 2025.
  2. World Health Organization. Global Report on the Epidemiology and Burden of COPD. Geneva, Switzerland: WHO; 2023.
  3. Liu Y, Carlson SA, Watson KB, Xu F, Greenlund KJ. Trends in the prevalence of chronic obstructive pulmonary disease among adults aged ≥18 years—United States, 2011–2021. MMWR Morb Mortal Wkly Rep. 2023;72(46):1250–1256. doi:10.15585/mmwr.mm7246a1.
  4. Kocks JWH, Bosnic-Anticevich S, van Cooten J, Correia de Sousa J, Cvetkovski B, Dekhuijzen R, Dijk L, Garcia Pardo M, Gardev A, Gawlik R, van der Ham I, Janse Y, Lavorini F, Maricoto T, Meijer J, Metz B, Price D, Roman Rodriguez M, Schuttel K, Stoker N, Tsiligianni I, Usmani O, Voorham J, Leving MT. Identifying critical inhalation technique errors in Dry Powder Inhaler use in patients with COPD based on the association with health status and exacerbations: findings from the multi-country cross-sectional observational PIFotal study. BMC Pulm Med. 2023;23(1):302. doi:10.1186/s12890-023-02566-6.
  5. Molimard M, Raherison C, Lignot S, Balestra A, Lamarque S, Chartier A, Droz-Perroteau C, Lassalle R, Moore N, Girodet PO. Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients. Eur Respir J. 2017;49(2):1601794. doi:10.1183/13993003.01794-2016.
  6. Sanchis J, Gich I, Pedersen S; Aerosol Drug Management Improvement Team (ADMIT). Systematic review of errors in inhaler use: Has patient technique improved over time? Chest. 2016;150(2):394-406. doi:10.1016/j.chest.2016.03.041.
  7. Mahler DA, Ohar JA, Barnes CN, Moran EJ, Pendyala S, Crater GD, Humphries MJ, Martinez FJ. Nebulized versus dry powder long-acting muscarinic antagonist bronchodilators in patients with COPD and suboptimal peak inspiratory flow rate. Chronic Obstr Pulm Dis. 2019;6(4):321–331. doi:10.15326/jcopdf.6.4.2019.0137.
  8. Bogart M, Bengtson LGS, Johnson MG, Bunner SH, Gronroos NN, DiRocco KK. Outcomes following initiation of triple therapy with fluticasone furoate/umeclidinium/vilanterol versus multiple-inhaler triple therapy among Medicare Advantage with Part D beneficiaries and those commercially enrolled for health care insurance in the United States. Int J Chron Obstruct Pulmon Dis. 2024;19:97-110. doi:10.2147/COPD.S424497.
  9. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of COPD. 2025 Report. https://goldcopd.org. Accessed August 27, 2025.

About The Author:

Ahmet Tutuncu, M.D., Ph.D., is the CEO and co-founder of AeroRx Therapeutics. He is a physician-scientist with more than 25 years of experience in respiratory drug development and was a cofounder of Elevation Pharmaceuticals and Patara Pharma. Tutuncu has helped lead the development of three approved inhaled therapies and is now advancing proprietary combination products for nebulized delivery to improve the treatment of chronic respiratory diseases.