Werner Mertens

Figure 2. Schematic representation of diagnostic process as per American Thoracic Society 2019 guidelines.(3) BAL: bronchoalveolar lavage; HRCT: high resolution computed tomography; MDD: multidisciplinary discussion; UIP: usual interstitial pneumonia.

Therapies in managing IPF

IPF is a chronic, relentless, and insidious progressive disease, thereby making it difficult to manage. The treatment approaches are based on the perception that inflammation results in injury and fibrosis in the lungs and thus, the focus has been on eliminating or suppressing the agents causing inflammatory response. IPF treatment strategies largely rely on a combinatorial approach of pharmacologic and non-pharmacologic regimens and are focused on interfering with disease progression and prevention of acute exacerbations. (2)

The older therapeutic regimens included multiple combinations of cytotoxic, immunosuppressive, and anti-inflammatory agents such as corticosteroids, cyclophosphamide, colchicine, azathioprine + N-acetylcysteine + prednisone, N-acetylcysteine, interferon-gamma, warfarin, sildenafil, endothelin receptor antagonists, and imatinib. As therapeutic trials with these agents failed to find any significant reductions in mortality, they have been replaced by newer treatment regimens that target the signaling pathways and thereby alter disease progression. (2)

Disease-modifying agents (tyrosine-kinase inhibitors) in IPF

Currently approved therapies in IPF consist of two drugs Pirfenidone and Nintedanib. The latter is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). Nintedanib exerts both anti-inflammatory and anti-fibrotic activity by competitively binding with the ATP binding pocket of these receptors. This binding interferes in migration, fibroblast proliferation, differentiation, and collagen secretion; all of which are key processes in lung fibrosis. (2)

Three large-scale international trials TOMORROW, INPULSIS-1, and INPULSIS-2 have found that Nintedanib is both safe and effective in patients with IPF. There was a significant reduction in the rate of annual FVC decline found in the patients treated with Nintedanib as compared to placebo intervention. The INPULSIS-ON trial was an extension of the INPULSIS trial which found that the benefit on the rate of FVC decline persisted up to 3 years in patients receiving Nintedanib regimen post 52 weeks of the INPULSIS trial intervention. (1)

A retrospective study conducted by Cameli et al. (2020) confirmed the efficacy of antifibrotic therapy with Nintedanib in terms of mortality and functional disease progression in long-term follow-up of IPF patients. Nintedanib was well tolerated in the study group with lesser side effects compared to Pirfenidone. (5)

Nintedanib in early and advanced IPF

There have been apprehensions regarding Nintedanib therapy in patients with preserved lung function in the early stages of IPF. Studies have found that irrespective of the baseline FVC, the Nintedanib regimen caused a reduction in FVC decline, thereby leading to the recommendation of the use of Nintedanib early in the course of the disease, at the time of diagnosis itself. (1)

Similarly, there have been concerns about the use of Nintedanib in patients with advanced stages of the disease. A post hoc analysis conducted in patients enrolled for INPULSIS-ON having FVC ≤ 50% and FVC > 50% predicted at baseline found that the rate of FVC decline in both groups was similar, but the adverse effect profile was more severe in patients with advanced disease. (1)

Nintedanib is approved by both USFDA and EC for the treatment of IPF. With Nintedanib receiving approvals for IPF treatment in India and several other countries, there is now a glimmer of hope for patients who were otherwise battling a grim disease with a paucity of effective treatments.

Disclaimer: The views expressed in the above article are solely those of the author/agency in his/her private capacity and DO NOT represent the views of Medical Dialogues.

References:

1. Singh A, Kishore K, Verma AK, Singh A. Nintedanib for the treatment of idiopathic pulmonary fibrosis: An Indian perspective. The Journal of Association of Chest Physicians. 2020 Jul 1;8(2):48.

2. Suri, G. S., Kaur, G., Jha, C. K., & Tiwari, M. (2021). Understanding idiopathic pulmonary fibrosis - Clinical features, molecular mechanism, and therapies. Experimental Gerontology, 153, 111473.