Aerosol delivery in interstitial lung diseases - breakthrough or lost cause?

KEYWORDS:

• Interstitial pulmonary fibrosis
• pulmonary drug delivery
• inhalation
• inhalers
• aerosol deposition
• particle size

1. Introduction

Interstitial lung diseases (ILDs) encompass a heterogeneous group of lung disorders, each with its own etiology, clinical presentation, and progression, characterized by inflammation and fibrosis, affecting over 4.5 million people worldwide (Table 1) [1,2]. ILDs can be idiopathic (i.e. of unknown cause) or secondary to other conditions such as connective tissue diseases, environmental exposures or medication use. A hallmark feature of many ILDs is the progressive fibrosis of the interstitium surrounding the alveoli, resulting in impaired oxygen exchange and a range of debilitating symptoms. ILDs can be challenging to diagnose and manage due to their heterogeneity, with over 200 distinct types having been identified to date [1]. Most ILDs have a poor prognosis, with a life expectancy of around 3–5 years after diagnosis [3]. Pulmonary arterial hypertension (PAH) is a significant risk factor and patients with untreated PAH usually rapidly succumb to respiratory failure within 2–3 years after diagnosis [3].

Table 1. Common types of ILDs.

Common Types of ILDs
Idiopathic Pulmonary Fibrosis (IPF): A progressive and usually fatal form of ILD with unknown cause. It primarily affects older adults and is characterized by extensive lung fibrosis
Sarcoidosis: An immune system disorder causing inflammation in different organs, including the lungs. It can result in granulomas of inflammatory cells
Hypersensitivity Pneumonitis: An ILD triggered by the immune system’s reaction to inhaled allergens or irritants.
Non-specific interstitial pneumonitis: ILD that occurs in the context of autoimmune conditions such as rheumatoid arthritis, systemic sclerosis or dermatomyositis
Cryptogenic Organising Pneumonia (COP): A condition characterized by the presence of granulation tissue in the small airways and alveoli
Asbestosis: ILD caused by asbestos exposure

2. Current treatment and new pharmacological approaches

Treatment options for ILDs include immunosuppressive medications, anti-fibrotic drugs, supplemental oxygen therapy and pulmonary rehabilitation. Lung transplantation may be considered for end-stage ILDs when other treatments are ineffective [4]. Pirfenidone and nintedanib were both approved in 2014 and are the only antifibrotic medications available for IPF treatment to date [5]. Pirfenidone inhibits transforming growth factor-beta 1 (TGF-β1), hence, reducing collagen synthesis and extracellular matrix production. Nintedanib is a kinase inhibitor, also inhibiting growth factors implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), i.e. platelet-derived growth factor, vascular endothelial growth factor and fibroblast growth factor. Both drugs are given orally and decrease the rate of progression of IPF but they do not offer a cure. Antifibrotic medications may, nonetheless, have some benefit in other non-IPF ILDs [5]. The spectrum of adverse effects of both medications can be quite severe and may include diarrhea, nausea and other gastrointestinal side effects. Liver function can also be affected and should be monitored. In recent years, a plethora of new chemical entities targeting a wide spectrum of therapeutic targets has entered pre-clinical development and several compounds are now in clinical trials. The reader is directed to the following articles for more detailed information [6–8].

3. Inhalation therapy for ILDs

In inhalation therapy, several factors need to be considered such as the particle size of the aerosol and the inhalation maneuver carried out by the patient [9,10]. Particles should be small enough to avoid deposition in non-fibrotic regions of the lungs, but large enough to avoid exhalation. A study by Usmani and colleagues [11] provided evidence that small monodisperse particles (1.5 μm MMAD) can reach the peripheral areas in the lungs of IPF patients and Wright et al. [12], using similarly sized aerosols, observed an improved lung function when treating IPF patients with extra-fine particles of beclomethasone/formoterol. Hence, reaching the intended target site is likely not an issue.

The inhalation maneuver carried out by the patient is another important factor in guiding aerosols to their intended site of action, i.e. the distal lung in the case of ILDs. A slow and deep inhalation, coupled with a breath hold results in increased peripheral deposition, when compared to higher inhalation peak flow and shallow breathing [13].

Targeting drugs to the lungs for local treatment by oral inhalation minimizes systemic exposure and hence reduces the risk and severity of systemic side effects, particularly, in cases where the drug target is distributed ubiquitously in the body. Since inhaled drugs avoid efflux transporters and metabolic enzymes in the gastrointestinal tract and liver, aerosol therapy requires lower doses to achieve the desired therapeutic effect in the lungs, which further improves the drug’s safety profile [14]. As an example, when comparing oral with inhaled pirfenidone, oral administration (approved dose is 801 mg t.i.d.) resulted in mean C_max,plasma of 7.9 μg/mL [15] and an estimated C_max,ELF of 3.9 μg/mL [16]. A 100-mg inhaled dose of the drug lead a 15-fold lower systemic exposure and a 35-fold higher ELF concentration in IPF patients [16]. In the same study, no significant differences in C_max,ELF could be found between healthy volunteers and IPF patients, suggesting that lung pathology has no significant influence on free drug concentration at the target site. It should be noted that for pirfenidone, a correlation was found between C_max and reduction in decline of FVC% predicted and progression-free survival [15]. The higher ELF concentrations after inhalation might, therefore, also result in improved efficacy.

Inhalation usually provides a very fast onset of action, when compared to taking medications orally. For a maintenance therapy of ILD, however, this might not be a relevant factor. Lastly, inhalers are relatively convenient to use, which can result in better patient compliance and adherence, specifically compared to parenteral administration.

There also are a number of limitations associated with pulmonary drug delivery. Only relatively small doses (<100–150 mg) can be delivered effectively and without inconveniencing the patient. If larger doses are required, e.g. in the case of pirfenidone, administering a drug solution by nebulizer, which is a relatively time consuming method, might be the only option. Smaller doses can be aerosolised by ultra-portable pMDI, DPI or SMI devices, once a suitable formulation has been developed. Local side effects (e.g. cough or bronchospasm) need to be considered, as is the case in any other inhaled therapy. It should be noted that no severe lung-related adverse events were reported in the clinical programs of inhaled pirfenidone and nintedanib, so it can be assumed that the treatment was well tolerated [17].

Finally, the regulatory pathway for orally inhaled products is more complex and the costs of the development programs are higher, when compared to most other medications. ILDs are rare diseases and the price tags of the current (oral) treatments are significant (i.e. >US$100,000 per patient per year) [18]. The profit margin will, therefore, be smaller for aerosol therapies but should, nonetheless, be still attractive enough to warrant investments in clinical development programs.

However, so far inhaled treprostinil is the only approved orally inhaled treatment, and the drug is only approved for pulmonary hypertension associated with ILDs. There is a sizable number of pre-clinical programs, looking at new modalities and combinations or novel formulations of known drugs (Table 2). The reader is directed to the recent review by Diwan et al. for more information on new modalities and their mechanisms of action [27].

Table 2. Inhaled ILD therapies in pre-clinical development.

Compound	Developer	Target	References
Tranilast, NXP002	Nuformix	TGF-β/SMAD2 pathway inhibition	[19]
Pirfenidone and nintedanib, AP03	Avalyn	Fixed dose combination	[20]
Nintedanib, AP02-D	Avalyn	Dry powder inhaler	[21]
RC-0315	Remedy Cell	Mast stem cells derived secretome	[22]
undisclosed	University of Nottingham	EP2/4 receptor agonist	[23]
FGF19 mRNA	Inserm U1152/Sanofi	Lipid nanoparticles for FGF19 mRNA delivery	[24]
NOX4 Inhibitor	Fibronox	NADPH oxidase 4 inhibition	[25]
VYN-201	Vyne Therapeutics	Bromodomain & extra-terminal (BET) inhibition	[26]

Ongoing clinical development programs are summarized in Table 3. The clinical results from the INCREASE study of inhaled treprostinil demonstrated a beneficial effect on loss of lung function in patients with ILD, including IPF, and associated pulmonary hypertension. These findings, along with the preclinical evidence of antifibrotic activity of treprostinil, lead United Therapeutics to initiate the TETON phase 3 study [36]. Avalyn Pharma in their ATLAS study recently showed that aerosolised pirfenidone (delivered by a Pari eFlow nebulizer) can improve safety and efficacy compared with the oral route [28,29] and the company also studies inhaled nintedanib in phase 1 [32,33]. PRS-220 is an oral inhaled Anticalin protein under clinical development by Pieris Pharmaceuticals targeting connective tissue growth factor for the treatment of IPF. It is currently in phase 1 [35]. Arrowhead’s Targeted RNAi Molecule, or TRiM^TM, platform utilizes ligand-mediated delivery and is designed to enable tissue-specific targeting also recently entered clinical trials [34].

Table 3. Inhaled ILD therapy clinical pipeline. Gray font color indicates recently discontinued programs.

Compound	Drug product	Manufacturer	Technology	Dose	Status	References
Treprostinil	Tyvaso® Tyvaso® DPI	United Therapeutics	Opti-Neb® nebulizer Technosphere® Opti-Neb® nebulizer	18 µg q.i.d. 16 µg q.i.d. Up to 72 µg q.i.d.	FDA approved 2021 FDA approved 2022 Phase III ongoing
Pirfenidone	AP01	Avalyn	PARI eFlow®	100 mg b.i.d.	Phase I/II ongoing	[28,29]
Olitigaltin	GB0139; TD-139; galectin-3 inhibitor	Galecto Biotech	Plastiape DPI	3 mg q.d.	Phase IIb completed, endpoints not met	[30]
Integrin αVβ6 inhibitor	GSK3008348	GSK	InnoSpire Deluxe nebulizer	1 mg	Phase Ib terminated	[31]
Nintedanib	AP02	Avalyn	PARI eFlow®	0.5, 1 and 2 mg	Phase I ongoing	[32,33]
MMP7 RNAi	ARO-MMP7	Arrowhead	Nebulised solution		Phase I ongoing	[34]
Anticalin	PRS-220	Pieris	Nebulised solution		Phase I ongoing	[35]

There are, however, also failed developments in the field. The anti-fibrotic effect of GB0139, a small molecule Galectin-3 inhibitor developed by Galecto, for example, did not meet the clinical endpoints in the phase 2b GALACTIC-1 trial [30] and the development of GSK3008348, a selective inhaled small molecule αvβ6 integrin inhibitor, which was well tolerated in a phase 1 clinical trial, was discontinued, most likely due to strategic decisions [31].

In conclusion, the technology to reach the fibrotic regions of the lungs by aerosol delivery is available and a number of already (orally) approved drugs as well as new modalities are currently in pre-clinical and clinical trials to the inhalation treatment of ILDs. Delivering to the site of intended drug action reduces the systemic burden and hence increases the safety profile of the medicine. Finally, working in the rare disease space, with the associated reimbursement potential, makes developing aerosol therapies attractive for pharmaceutical companies. It is the author’s opinion that inhaled therapies for ILDs hold a lot of potential and are definitely not a lost cause.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.