Nerandomilast in progressive pulmonary fibrosis: data from the whole follow-up period of the FIBRONEER-ILD trial

Clinical Snapshot

Key Findings

• P Value: Not explicitly stated in the abstract; CIs for composite endpoint just include or touch 1.00 for overall population (borderline significance); mortality CI clearly excludes 1.00 (statistically significant)

• Effect Size: Key secondary composite endpoint (acute exacerbation of ILD, respiratory hospitalisation, or death): HR 0.78 (nerandomilast 9 mg) and HR 0.77 (nerandomilast 18 mg) vs placebo. All-cause mortality: HR 0.51 for both doses vs placebo. In patients not on nintedanib: composite HR 0.69 (9 mg) and 0.65 (18 mg). In patients on nintedanib: composite HR 0.90 (9 mg) and 0.93 (18 mg).

• Primary Outcome: Rate of FVC decline at week 52 (previously reported as primary endpoint of FIBRONEER-ILD; this paper focuses on extended follow-up time-to-event secondary endpoints)

• Nnt Or Sensitivity: NNT not calculable from abstract data alone (absolute event rates not provided). Relative risk reduction for mortality: approximately 49% for both doses. Relative risk reduction for composite endpoint: approximately 22–23% overall; 31–35% in non-nintedanib users.

• Confidence Interval: Composite endpoint: 9 mg HR 0.78 (95% CI 0.61–1.00); 18 mg HR 0.77 (95% CI 0.60–0.99). Mortality: both doses HR 0.51 (95% CI 0.34–0.78). Non-nintedanib subgroup: 9 mg HR 0.69 (95% CI 0.49–0.97); 18 mg HR 0.65 (95% CI 0.46–0.92). Nintedanib subgroup: 9 mg HR 0.90 (95% CI 0.63–1.30); 18 mg HR 0.93 (95% CI 0.65–1.34).

Clinical Application

Nerandomilast is an oral twice-daily agent, which is practical for outpatient management. The tolerability profile (adverse event discontinuation rates equivalent to placebo at ~12%) suggests excellent real-world feasibility. Twice-daily dosing aligns with existing antifibrotic regimens. The 9 mg and 18 mg doses showed comparable efficacy and tolerability, which may inform dose selection in clinical practice. As an investigational agent, availability is currently limited to clinical trial settings. Nerandomilast is not currently TGA-approved or PBS-listed in Australia. The existing PBS-listed antifibrotics for IPF (nintedanib and pirfenidone) provide a comparator framework. The FIBRONEER-ILD trial's inclusion of a broad PPF population (not restricted to IPF) is particularly relevant to Australian practice, where RACGP and Thoracic Society of Australia and New Zealand (TSANZ) guidelines increasingly recognise PPF as a clinical entity requiring treatment beyond IPF-specific agents. The finding of attenuated benefit in patients on background nintedanib has direct implications for PBS prescribing pathways, where nintedanib is commonly used as first-line therapy. Australian ILD centres would need to consider whether nerandomilast, if approved, would be positioned as monotherapy, combination therapy with nintedanib, or as an alternative in nintedanib-intolerant patients. TGA submission and PBS listing processes would require the full primary trial data package. Adults with progressive pulmonary fibrosis of various underlying aetiologies (including but not limited to IPF, connective tissue disease-associated ILD, hypersensitivity pneumonitis, and other fibrosing ILDs meeting PPF criteria), with or without background antifibrotic therapy with nintedanib. The differential benefit observed in patients not on nintedanib suggests nerandomilast may be most impactful as monotherapy or in nintedanib-naïve patients.

Abstract

BACKGROUND: In the FIBRONEER-ILD trial in patients with progressive pulmonary fibrosis (PPF), nerandomilast 9 mg twice daily and 18 mg twice daily (hereafter nerandomilast 9 mg and 18 mg, respectively) reduced the decline in forced vital capacity at week 52 compared with placebo (primary end-point). We assessed the effects of nerandomilast up to the final database lock. METHODS: Time to first acute exacerbation of interstitial lung disease, hospitalisation for respiratory cause or death (key secondary end-point) and other time-to-event end-points were assessed. RESULTS: 1176 patients, of whom 512 were taking background nintedanib, received nerandomilast or placebo. At the final database lock, the mean±sd exposure to trial medication was 15.1±5.7 months and the mean±sd observation period was 17.0±4.1 months. Compared with placebo, the hazard ratio for the key secondary end-point was 0.78 (95% CI 0.61-1.00) for nerandomilast 9 mg and 0.77 (95% CI 0.60-0.99) for nerandomilast 18 mg; hazard ratios were lower among patients not taking nintedanib (0.69 (95% CI 0.49-0.97) and 0.65 (95% CI 0.46-0.92), respectively) than among those taking background nintedanib (0.90 (95% CI 0.63-1.30) and 0.93 (95% CI 0.65-1.34), respectively). For death, the hazard ratio versus placebo was 0.51 (95% CI 0.34-0.78) for both nerandomilast doses. Adverse events led to discontinuation of trial medication in 12.5%, 12.0% and 12.3% of the placebo, nerandomilast 9 mg and nerandomilast 18 mg groups, respectively. CONCLUSIONS: In the FIBRONEER-ILD trial in patients with PPF, nerandomilast reduced the risk of clinically important outcomes, including death, over the whole trial. Nerandomilast had a favourable safety and tolerability profile.