Potential of phosphodiesterase 4B inhibitors in the treatment of interstitial lung disease associated with autoimmune diseases
Patients with autoimmune disease–associated interstitial lung disease (ILD) are at risk of developing pulmonary fibrosis, which can progress over time. Progressive pulmonary fibrosis (PPF) is linked to poor clinical outcomes. While antifibrotic therapies have shown benefit in managing PPF in this population, additional treatment options are needed to further slow or halt disease progression.
Phosphodiesterases (PDEs) are enzymes responsible for breaking down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Preclinical studies suggest that selective inhibition of PDE4B may slow the progression of pulmonary fibrosis by modulating inflammatory and fibrotic signaling pathways, with a potentially reduced risk of gastrointestinal side effects compared to non-selective (pan-) PDE4 inhibitors.
Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor with demonstrated anti-inflammatory and antifibrotic activity in preclinical models. In a phase II trial involving patients with idiopathic pulmonary fibrosis (IPF), nerandomilast—administered alone or alongside background antifibrotic therapy—helped preserve lung function over 12 weeks and was well tolerated.
The ongoing phase III FIBRONEER-ILD trial is investigating the efficacy and safety of nerandomilast in patients with PPF, including those with autoimmune disease–related PPF, both as monotherapy and in combination with nintedanib.
In this article, we review the therapeutic potential of PDE4B inhibition for autoimmune disease–associated ILD, summarizing the available preclinical and early clinical evidence to date.