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Successful trials of new medications offer hope for people with pulmonary fibrosis.
Interstitial lung disease (ILD) is a complex group of over 200 inflammatory and fibrosing parenchymal lung diseases. They are often referred to as pulmonary fibrosis due to the frequency with which they are associated with irreversible scarring. ILD is often progressive and associated with high morbidity and mortality with symptoms of dyspnoea, reduced exercise tolerance, fatigue and poor health-related quality of life. ILD is classified broadly into the idiopathic interstitial pneumonias, diseases of known cause, granulomatous diseases and other rare forms.
The global incidence and prevalence of ILDs is increasing, with the Global Burden of Disease Study in 2019 estimating a 118.6% increase since 1990. The most common subtype, idiopathic pulmonary fibrosis (IPF), has an Australian incidence of 10.4 per 100 000 person years and prevalence of 32.6 per 100 000 persons. It imposes a substantial symptom burden, overall poor prognosis, and health care costs that are approximately four times higher than the average national per capita health expenditure in Australia. Non-IPF ILD may display similar features to IPF, with up to 40% displaying a progressive fibrosing phenotype characterised by progressive, irreversible scarring, worsening symptoms and lung physiology despite standard of care therapy. Progressive pulmonary fibrosis (PPF) has a particularly high prevalence in fibrotic hypersensitivity pneumonitis and connective tissue disease-associated ILD (CTD-ILD).
The current treatment landscape
Since 2014, the mainstay of pharmacological treatment for IPF has been two antifibrotic medications — nintedanib and pirfenidone. Each has demonstrated efficacy in reducing physiologic progression by approximately 50%, with post-hoc analysis demonstrating reduced mortality. Subsequently, nintedanib has been shown to be efficacious in the treatment of scleroderma-related ILD and PPF, and been listed on the Pharmaceutical Benefits Scheme (PBS) for use for the latter indication. While providing physiological and mortality benefits, they have not been shown to improve symptoms or quality of life, and their side effects often result in drug cessation such that approximately 50% of those prescribed therapy cease use after 12 months.
In that setting, there is ongoing urgent need for antifibrotic therapies that not only slow disease progression but also are better tolerated, improve symptoms, or ideally, reverse fibrosis. In recent years, there has been significant advances in identifying mechanisms of pulmonary fibrosis. Current paradigms generally include an aberrant response to epithelial cell injury (as in IPF) or immune activation (eg, in CTD-ILD) that leads to fibroblast activation, collagen deposition in the extracellular matrix and tissue remodelling. An abundance of aberrant cell populations and cell signalling pathways have been identified within this paradigm, providing a range of new treatment targets and the development of several novel agents that have advanced towards clinical use.
Trials for new treatments
Among these, nerandomilast — a preferential oral phosphodiesterase 4B inhibitor — has shown the most promise, meeting its primary endpoints in two large phase 3 trials: FIBRONEER-IPF (in idiopathic pulmonary fibrosis) and FIBRONEER-ILD (in progressive pulmonary fibrosis of other causes). In both studies, nerandomilast significantly reduced the rate of lung function decline over 52 weeks compared to placebo, with the 18 mg dose associated with a 38% reduction in forced vital capacity (FVC) decline in the IPF study and a 41% reduction in the PPF study. Nerandomilast was generally well tolerated, with rates of adverse events and treatment discontinuation comparable to placebo. The most common side effect was diarrhoea, affecting 26% of patients receiving 18 mg nerandomilast without concomitant antifibrotic — substantially lower rates than reported in the nintedanib trials.
Given its comparable efficacy and improved safety profile, nerandomilast appears likely to become a reasonable first-line therapy. However, its role as an add-on therapy remains uncertain due to its side effect profile and potential interactions with pirfenidone. Additionally, its safety and efficacy have not been evaluated in patients receiving immunosuppressants such as mycophenolate or rituximab, as these patients were excluded from the FIBRONEER trials. At present, nerandomilast is not yet listed on the PBS.
Admilparant is another experimental agent that has entered phase 3 clinical trial development for both IPF and PPF at multiple Australian ILD centres. It is an oral, small molecule antagonist of the lysophosphatidic acid receptor 1 (LPA1) that inhibits pathways of fibroblast recruitment and collagen deposition. Recently published phase 2 study data show that, at a high dose, admilparant reduced the rate of FVC decline by 54% in IPF and 74% in PPF cohorts, with similar rates of diarrhoea in treatment and placebo arms. Multiple earlier phase studies are occurring internationally and locally.
A number of agents have targeted autotaxin, including a currently recruiting trial using BI-1819479. These agents aim to reduce production of LPA and downregulate pro-fibrotic signalling. Other approaches have sought to reduce the side effect profile of established anti-fibrotics using inhaled formulations. The Avalyn MIST study of inhaled pirfenidone is a phase 2b randomised control trial of inhaled pirfenidone in patients with PPF. Inhaled formulations of pirfenidone are aimed at maximising drug concentrations in the lungs while reducing systemic side effects, and have been found to be safe and well tolerated in early phase studies.
Looking ahead
As we continue to strive for more effective disease-modifying therapies for pulmonary fibrosis, clinical trials play a crucial role in advancing our understanding of the disease and expanding treatment options. Offering clinical trial participation is now an integral part of care of patients with PF. The Pulmonary Fibrosis Australasian Clinical Trials (PACT) network provides an easily accessible web-based list of ILD clinical trials in Australasia as well as a number of other platforms to enhance trial availability for Australasian ILD patients. By joining the network, stakeholders can stay up to date with the latest in therapeutic developments for ILD.
In summary, the future is brighter for people living with pulmonary fibrosis, but there is an ongoing need for patients, clinicians and researchers to work together to develop safer and more efficacious therapeutic approaches.
Dr Sheetal Deshpande is a respiratory and sleep physician and currently the interstitial lung disease fellow at Alfred Health. She is also pursuing a PhD at Monash University, where her research focuses on the remote delivery of care for patients with ILD.
Professor Ian Glaspole is a respiratory and sleep physician and the director of the interstitial lung disease service at Alfred Health. He is also an adjunct professor at Monash University’s school of translation medicine and leads the PACT network.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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