Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.

Lung regeneration: diverse cell types and the therapeutic potential

“…Pamrevlumab is an anti‐CTGF antibody that is studied for the treatment of IPF. Unfortunately, the phase 3 study on pamrevlumab was not effective at preserving lung function in patients with IPF 234 …”

“…225 Unfortunately, the phase 3 clinical trial was prematurely stopped due to futility after having enrolled 655 IPF patients with less functional benefit than severe adverse effects. 234 Connective tissue growth factor (CTGF) is a mediator of tissue remodeling, which acts on connective tissue cells downstream of TGF-β and stimulates fibroblast proliferation and ECM production. Pamrevlumab is an anti-CTGF antibody that is studied for the treatment of IPF.…”

“…Unfortunately, the phase 3 study on pamrevlumab was not effective at preserving lung function in patients with IPF. 234 Cell therapy with stem cells is a promising therapeutic alternative with great potential for applicability. The regenerative approach for the lung aims to repair injured tissue through the delivery of either stem cells or products of stem cells that boost lung regeneration.…”

“…Phase 2 results showed that IPF patients receiving recombinant protein showed a slower rate of decline in lung function than the comfort group, with the main adverse events being cough, fatigue, and nasopharyngeal inflammation 225 . Unfortunately, the phase 3 clinical trial was prematurely stopped due to futility after having enrolled 655 IPF patients with less functional benefit than severe adverse effects 234 . Connective tissue growth factor (CTGF) is a mediator of tissue remodeling, which acts on connective tissue cells downstream of TGF‐β and stimulates fibroblast proliferation and ECM production.…”

Unlocking the Future: Pluripotent Stem Cell-Based Lung Repair

“…PF is a chronic, progressive, and incurable interstitial lung disease characterized by abnormal accumulation of fibrotic tissue constituents, inducing alveolar histoarchitecture destruction and resulting in respiratory failure [1,2]. The pathogenesis of PF involves an interplay of genetic predisposition, environmental factors, recurrent microinjuries of a predisposed alveolar epithelium, and aberrant wound healing responses characterized by excessive collagen deposition [3,4]. Several risk factors and fibrogenic triggers could be identified to trigger PF, like smoking, virus infections, radiation, autoimmune reactions, aging, genetic predisposition, and environmental noxae [1,2,[5][6][7].…”