Phase III FIBRONEER-IPF Trial of Nerandomilast in Patients With Idiopathic Pulmonary Fibrosis

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterized by decline in lung function. Nerandomilast is an orally administered preferential inhibitor of phosphodiesterase 4B that has antifibrotic and immunomodulatory effects in preclinical studies. The FIBRONEER-IPF trial investigated the efficacy and safety of nerandomilast in patients with IPF. Study design including participants: FIBRONEER-IPF was a Phase III randomized, double-blind, placebo-controlled trial of nerandomilast. Patients with IPF who were taking nintedanib or pirfenidone (for ≥12 weeks) or not taking nintedanib or pirfenidone (for ≥8 weeks) were eligible to participate. Patients were randomized 1:1:1 to receive nerandomilast 9 mg twice daily (bid), nerandomilast 18 mg bid, or placebo, stratified by use of background therapy (nintedanib/pirfenidone versus neither). The primary endpoint was absolute change from baseline in forced vital capacity (FVC) (mL) at week 52. The key secondary endpoint was the time to first acute exacerbation, hospitalization for respiratory cause, or death, over the duration of the trial. Key existing data and/or data trends: Nintedanib and pirfenidone have become standard of care for IPF, but have limitations in their efficacy and tolerability. New therapies that can be used as monotherapy or with existing therapies are needed to preserve lung function and improve patient outcomes. In a Phase II trial in 147 patients with IPF, nerandomilast 18 mg bid stabilized lung function over 12 weeks, with acceptable safety and tolerability [N Engl J Med 2022;386:2178-87]. Anticipated main outcomes and timeline: In the FIBRONEER-IPF trial, 1177 patients received trial medication, of whom 77.7% were taking nintedanib/pirfenidone. Analyses based on the first database lock (which took place after the last patient had completed the week 52 visit) are available. Analyses of data from the whole trial will be available for presentation at ATS 2025. Adjusted mean changes in FVC (mL) at week 52 were −183.5 (95% confidence interval [CI]: −210.9, −156.1) in the placebo group, −138.6 (−165.6, −111.6) in the nerandomilast 9 mg bid group (difference vs placebo: 44.9 [95% CI: 6.4, 83.3]; p=0.02), and −114.7 (−141.8, −87.5) in the nerandomilast 18 mg bid group (difference vs placebo: 68.8 [30.3, 107.4]; p<0.001). Plasma concentrations of nerandomilast were reduced by approximately 50% in patients taking pirfenidone compared to nintedanib or no background therapy. Among patients not taking nintedanib/pirfenidone, adjusted mean changes in FVC (mL) at week 52 were −148.7, −70.4 and −79.2 in the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups; among patients taking nintedanib, changes were −191.6, −130.7 and −118.5; among patients taking pirfenidone, changes were −197.0, −201.8 and −133.7, respectively. Up to first database lock, nerandomilast had no effect on time to first acute exacerbation, hospitalization for respiratory cause, or death. Over 52 weeks, adverse events led to treatment discontinuation in 10.7%, 11.7% and 14.0% of patients in the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups, respectively. The most frequent adverse event in patients treated with nerandomilast was diarrhea. Significance of study: These results show that treatment with nerandomilast slows disease progression in patients with IPF. Boehringer Ingelheim has submitted a new drug application for nerandomilast for the treatment of IPF to the US FDA. Results from high-profile Phase II and Phase III clinical trials: Since the positive Phase III trials of nintedanib (N Engl J Med 2014;370:2071-2082) and pirfenidone (N Engl J Med 2014;370:2083-92) were published in 2014, several Phase II and III trials in patients with IPF (including Phase III trials of ziritaxestat [JAMA 2023;329:1567-1578], pamrevlumab [JAMA 2024;332:380-389], and zinpentraxin alfa [Am J Respir Crit Care Med 2024;209:1132-1140]) did not meet their primary endpoint or were terminated early.