Idiopathic pulmonary fibrosis - Emerging treatments

Nerandomilast

Nerandomilast, an oral phosphodiesterase-4 (PDE-4) inhibitor, has been approved by the US Food and Drug Administration (FDA) as a treatment for idiopathic pulmonary fibrosis (IPF) in adult patients.[107][108] One multicentre phase 3 double-blind clinical trial showed that treatment with nerandomilast, alone or with background use of an antifibrotic agent, reduces the decline in forced vital capacity (FVC) compared with placebo over a 1-year period.[107] Patients with IPF in this trial met the following criteria: aged ≥40 years, FVC ≥45% predicted, and diffusing capacity of the lung for carbon monoxide (DLCO) ≥25% predicted.[107] Treatment is expected to benefit patients with intolerance to an antifibrotic agent or who demonstrate continued worsening in lung function despite use of an antifibrotic agent.

Therapies for acute exacerbations

Cohort studies have provided inconclusive evidence about the roles of several therapies that are sometimes used in clinical practice. These include ciclosporin, rituximab plus plasma exchange plus intravenous immunoglobulin (IVIG), tacrolimus, intravenous thrombomodulin, corticosteroids with or followed by other immunomodulatory therapies, broad-spectrum antibiotics (including macrolides), and polymyxin B-immobilised fibre column perfusion.[15][66] However, caution is advised when considering these options as it is uncertain whether observed beneficial effects reflect the intervention, natural history, unmeasured variables, or confounding. Further research into the management of acute exacerbations is urgently needed.

Axatilimab

Axatilimab is an investigational anti-CSF-1R monoclonal antibody. It has been granted orphan drug designation by the FDA for the treatment of IPF. One phase 2 study is underway to evaluate its efficacy and safety.[109]

Lixumistat

Lixumistat is an investigational protein complex 1 inhibitor.[110] It has been granted FDA fast-track designation for IPF.

Autotaxin inhibitors

Autotaxin, a secreted lysophospholipase D, hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). Together, autotaxin and LPA promote several pathophysiologic processes, including pulmonary fibrosis.[111] Phase 2 trials are underway to evaluate the efficacy, safety, and tolerability of the investigational autotaxin inhibitors, BBT-877 and cudetaxestat, in patients with IPF.[112][113]

Bexotegrast

Bexotegrast is an investigational dual-selective alpha(v)beta₆/alpha(v)beta₁ integrin inhibitor. Integrins affect the development and progression of pulmonary fibrosis by activating latent transforming growth factor-beta, a key cytokine in fibroblast-to-myofibroblast transition and collagen deposition.[114] Bexotegrast has been granted fast-track designation by the FDA. One multi-centre phase 2a study is underway to evaluate the safety, tolerability, and pharmacokinetics of bexotegrast in patients with IPF.[115]