As the therapeutic landscape for fibrotic interstitial lung diseases (ILDs) rapidly evolves, clinical trials are increasingly focused on targeted pathways, precision enrollment strategies, and innovative trial designs.

In this expert Q&A, Dr Tejaswini Kulkarni (The University of Alabama at Birmingham, Birmingham, AL, USA) explores emerging therapeutic targets, the role of biomarkers, recruitment challenges, and the methodological advances shaping the future of fibrotic ILD research and patient care.

The talk “Current State of Clinical Trials in Fibrotic ILD” was presented at CHEST 2025, 18–22 October 2025, Chicago, IL, USA.

touchIMMUNOLOGY coverage of CHEST 2025: 

Q. What are the most promising therapeutic targets currently being explored in fibrotic ILD trials?

In fibrotic ILDs, the normally coordinated host response to ongoing tissue injury —encompassing inflammation, repair, and complex interactions among diverse cells and soluble mediators—becomes dysregulated, leading to progressive fibrosis and architectural distortion. Current clinical research is increasingly directed toward modulating key pathways involved in this aberrant inflammatory and fibrotic cascade. The phosphodiesterase-4B inhibitor nerandomilast has recently received FDA approval for the treatment of patients living with idiopathic pulmonary fibrosis (IPF), following the FIBRONEER™-IPF (NCT05321069) clinical trial meeting its primary efficacy endpoint. Additional promising therapeutic strategies are under active investigation, including inhaled treprostinil, a prostacyclin analog with antifibrotic potential, and admilparant, an LPA1 receptor antagonist, both in phase 3 development. Alongside these, there are multiple phase 2 studies with agents targeting complementary fibrotic mechanisms.

Q. How are biomarkers and precision medicine shaping patient selection and trial design in this field?

Biomarkers hold significant promise to transform clinical trial design in fibrotic ILDs; however, progress has been constrained by the limited validation of many candidate markers. The ongoing PRECISIONS trial (NCT04300920) exemplifies a precision medicine approach, enrolling 200 patients with idiopathic pulmonary fibrosis (IPF) carrying the TOLLIPrs3750920 TT genotype and randomizing them 1:1 to receive oral N-acetylcysteine (600mg three times daily) or placebo, based on subgroup findings from the PANTHER-IPF study (NCT00650091). Similarly, the newly funded MAVRICK-IPF trial will be among the first to implement biomarker-guided enrollment, aiming to identify high-risk individuals who are most likely to benefit from early therapeutic intervention.¹

Q. What challenges remain in recruiting and retaining patients for fibrotic ILD studies?

Recruitment for fibrotic ILD trials remains challenging due to delayed diagnosis, limited disease awareness, and the relative rarity of these conditions. Stringent eligibility criteria often exclude individuals with advanced disease, preventing many from accessing investigational therapies. Retention poses additional difficulties, as progressive symptoms, travel demands, and trial fatigue contribute to participant dropout despite strong engagement efforts. Moreover, patients in underserved or rural communities frequently lack the resources and access needed to learn about or enroll in clinical studies, further hindering equitable participation.

Q. How are recent trials influencing clinical practice and treatment algorithms for progressive fibrotic ILD?

Historically, clinical trials in fibrotic ILD have predominantly focused on patients with IPF. The INBUILD trial (NCT02999178) marked a pivotal shift by demonstrating the efficacy of nintedanib in non-IPF progressive fibrotic ILDs, validating the broader use of antifibrotic therapy and prompting earlier intervention alongside more vigilant monitoring of disease progression. This success also catalysed innovation in trial design across the field. With the recent FDA approval of nerandolimast for IPF, the positive findings from the Fibroneer-ILD, and encouraging results from one of the TETON program studies (NCT05255991) evaluating inhaled treprostinil in IPF and progressive pulmonary fibrosis (PPF), alongside the completion of additional phase 3 programs, the therapeutic landscape for fibrotic ILDs is poised for a major transformation.^2,3

Q. Looking ahead, which innovations in trial methodology could accelerate the development of effective therapies?

Adaptive platform trials are transforming therapeutic research and may shape the future of fibrotic ILD studies. REMAP-ILD is a prime example to this approach, using a multifactorial, adaptive design that tests multiple interventions simultaneously, adding or removing arms based on interim results.⁴ This model is especially valuable for rare, heterogeneous diseases like ILD, where traditional trials face recruitment and statistical challenges. Integrating real-world data and digital biomarkers from wearables can provide real-time insights and reduce patient burden, while machine learning, particularly quantitative CT analysis, enhances early detection of progression and supports precision trial design.

References

1. 9th Annual IPF Summit. Stratifying Patients for Improved Trial Outcomes – High-Risk vs Low-Risk in the Maverick IPF Survival Trial. Available at: https://ipf-summit.com/seminar/stratifying-patients-for-improved-trial-outcomes-high-risk-vs-low-risk-in-the-maverick-ipf-survival-trial/ (accessed 22 October 2025).
2. Maher TM, Assassi S, Azuma A, et al. Nerandomilast in Patients with Progressive Pulmonary Fibrosis. N Engl J Med. 2025;392:2203–2214.
   
3. Nathan S, Behr J, Cottin V, et al. TETON phase 3 clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis. Presented at: ERS 2025, Amsterdam, 28 September 2025.
4. Kawano-Dourado L, Kulkarni T, Ryerson CJ, et al. Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases. Thorax. 2024;79:788–795.