Nerandomilast safe, effective in autoimmune disease-related PPF

Treatment with nerandomilast demonstrates efficacy in slowing forced vital capacity (FVC) decline in patients with autoimmune interstitial lung disease (ILD) similar to that seen in the overall trial population, reveals a subgroup analysis of the FIBRONEER-ILD study.

“Among patients with autoimmune ILDs and progressive pulmonary fibrosis (PPF) in the FIBRONEER-ILD trial, the efficacy of nerandomilast … was consistent with that observed in the overall trial population,” said lead author Dr Anna-Maria Hoffmann-Vold from the Department of Rheumatology, Oslo University Hospital, Oslo, Norway and the University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Hoffmann-Vold and her team included a total of 1,176 patients with PPF, excluding idiopathic pulmonary fibrosis, of whom 325 (mean age 63.4 years, 65.2 percent female, FVC 71.5 %predicted, diffusing capacity for carbon monoxide 51.5 %predicted) had autoimmune ILDs. Some 111 patients (34.2 percent) were taking nintedanib.

Those with autoimmune ILDs were randomized to receive nerandomilast 9 mg bid (n=112), nerandomilast 18 mg bid (n=113), or placebo (n=100). Rheumatoid arthritis (36.3 percent) was the most common autoimmune disease diagnosis, followed by systemic sclerosis (23.1 percent) and mixed connective tissue disease (14.5 percent). [EULAR 2025, abstract LB0003]

FVC decline

At week 52, the adjusted mean changes in FVC were ‒107.1 mL (95 percent confidence interval [CI], ‒156.1 to ‒58.0) in the placebo group, ‒61.2 mL (95 percent CI, ‒1.06.9 to ‒15.5) in the nerandomilast 9-mg bid group (difference vs placebo, 45.9, 95 percent CI, ‒20.8 to 112.6), and ‒64.9 mL (95 percent CI, ‒111.0 to ‒18.7) in the nerandomilast 18-mg bid group (difference, 42.2, 95 percent CI, ‒24.9 to 109.3).

Compared with placebo, the hazard ratios for time to first acute exacerbation of ILD, hospitalization for respiratory cause, or death were 0.71 (95 percent CI, 0.43‒1.20) for nerandomilast 9 mg bid and 0.56 (95 percent CI, 0.33‒0.96) for nerandomilast 18 mg bid.

“Consistent with observations in the overall population, nerandomilast had a numerical benefit on the risk of acute exacerbation, hospitalization for respiratory cause, or death and was associated with a reduced risk of death,” Hoffman-Vold said.

Safety profile

Serious adverse events (AEs) occurred in 33.0 percent and 39.8 percent of patients treated with nerandomilast 9 and 18 mg, respectively, and in 39.0 percent of those on placebo. AEs led to treatment discontinuation in 6.3 percent and 10.6 percent of patients in the nerandomilast arms and in 11.0 percent of those in the placebo group. Diarrhoea was the most common AE.

“Nerandomilast had an acceptable safety and tolerability profile, with serious AEs and treatment discontinuations being no more common in patients who received nerandomilast than placebo,” Hoffmann-Vold said.

In the FIBRONEER-ILD trial, patients taking or not taking nintedanib were eligible to participate. The use of cyclophosphamide, tocilizumab, mycophenolate, or rituximab was not allowed upon enrollment, but it was permitted after 6 months to manage the worsening systemic disease. Prednisone >15 mg/day was likewise not allowed at enrollment but could be prescribed during the trial for acute ILD exacerbation.

In the subgroup of patients with autoimmune ILDs, Hoffmann-Vold and colleagues assessed the absolute change from baseline in FVC at week 52; time to first acute exacerbation of ILD, hospitalization for respiratory cause, or death up to first database lock; and AEs up to first database lock.

“Nerandomilast is an orally administered preferential inhibitor of phosphodiesterase 4B that has antifibrotic and immunomodulatory properties,” Hoffman-Vold said. [Front Pharmacol 2022;13:838449; Br J Pharmacol 2024;181:4766-4781]

Currently, nintedanib is the only approved therapy for PPF. Although it slows decline in lung function, its AEs often lead to treatment discontinuation. [N Engl J Med 2019;381:1718-1727]