Understanding Fibrosis and Current Treatments
Fibrosis is a pathological process involving the excessive formation of scar tissue in an organ, leading to dysfunction and failure [1.6.1]. Idiopathic pulmonary fibrosis (IPF) is a prime example, a progressive and fatal lung disease characterized by a steady decline in lung function [1.2.3, 1.5.5]. For the last decade, the standard of care has revolved around two FDA-approved drugs: pirfenidone and nintedanib [1.2.3]. While these therapies can slow the rate of lung function decline, they do not halt or reverse the disease and are often associated with significant gastrointestinal side effects that can lead to discontinuation [1.2.3, 1.7.4]. This has created a significant unmet need for more effective and better-tolerated treatments [1.2.3].
What is the new anti-fibrotic drug? Spotlight on Nerandomilast
In 2025, the most prominent answer to this question is nerandomilast (BI 1015550) [1.2.2]. Developed by Boehringer Ingelheim, this orally administered drug has shown great promise in late-stage clinical trials, positioning it as the first potential new anti-fibrotic agent for interstitial lung disease (ILD) in over ten years [1.2.1].
Mechanism of Action
Nerandomilast is a preferential inhibitor of phosphodiesterase 4B (PDE4B) [1.2.3]. The inhibition of PDE4B leads to an increase in intracellular cyclic adenosine monophosphate (cAMP), which has known anti-inflammatory and anti-fibrotic effects [1.6.2]. Preclinical models demonstrated that nerandomilast has both anti-fibrotic and immunomodulatory properties [1.2.3].
Clinical Trial Success
Nerandomilast has successfully completed its Phase 3 FIBRONEER program, which included trials for both IPF (FIBRONEER-IPF) and progressive pulmonary fibrosis (FIBRONEER-ILD) [1.5.1, 1.5.2]. Results published in May 2025 and earlier showed that nerandomilast significantly slowed the decline in forced vital capacity (FVC), a key measure of lung function, compared to placebo [1.2.1, 1.2.4]. A notable finding was its efficacy both as a monotherapy and as an add-on to existing treatments like pirfenidone and nintedanib [1.2.1]. Following these positive results, Boehringer Ingelheim submitted a New Drug Application (NDA) to the U.S. FDA, which was granted priority review with an anticipated action date in the fourth quarter of 2025 [1.2.5].
The Broader Anti-Fibrotic Pipeline
While nerandomilast is in the spotlight, the drug development pipeline contains other promising candidates. The journey, however, is fraught with challenges, as evidenced by several high-profile discontinuations.
Promising Agents
- Admilparant (BMS-986278): A lysophosphatidic acid receptor 1 (LPAR1) antagonist from Bristol Myers Squibb, currently in Phase 3 trials with completion expected by October 2026 [1.5.6]. It has received Breakthrough Therapy Designation from the FDA [1.6.2].
- Brensocatib (Brinsupri): In August 2025, the FDA approved brensocatib for non-cystic fibrosis bronchiectasis [1.4.2, 1.4.3]. It works as a reversible inhibitor of dipeptidyl peptidase 1 (DPP1), targeting neutrophilic inflammation [1.4.4].
- Resmetirom (Rezdiffra): Approved in March 2024, resmetirom became the first treatment for non-cirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis [1.4.1].
Notable Setbacks
The path to a new anti-fibrotic drug is difficult. In June 2025, Pliant Therapeutics discontinued the development of bexotegrast for IPF after its Phase 2b/3 trial was halted due to safety concerns, despite showing early evidence of efficacy [1.3.2, 1.3.3]. Bexotegrast was a dual inhibitor of αvβ6/αvβ1 integrins [1.6.3]. Similarly, development of ziritaxestat, an autotaxin inhibitor, was halted by Galapagos and Gilead in 2021 after a Phase 3 review concluded its benefit-risk profile was no longer supported [1.8.1, 1.8.2]. These instances highlight the high-risk nature of fibrosis drug development [1.2.2].
Comparison of Key Anti-Fibrotic Drugs
| Feature | Pirfenidone (Esbriet) | Nintedanib (Ofev) | Nerandomilast (Investigational) |
|---|---|---|---|
| Mechanism of Action | Not fully understood; exhibits anti-fibrotic and anti-inflammatory properties [1.6.1, 1.7.4] | Tyrosine kinase inhibitor (TKI), targeting multiple pathways involved in fibrosis [1.5.5] | Preferential inhibitor of phosphodiesterase 4B (PDE4B), with anti-fibrotic and immunomodulatory effects [1.2.3, 1.6.2] |
| Primary Indication | Idiopathic Pulmonary Fibrosis (IPF) | IPF, Systemic Sclerosis-Associated ILD (SSc-ILD), other chronic fibrosing ILDs with a progressive phenotype [1.2.4] | Investigated for IPF and Progressive Pulmonary Fibrosis (PPF) [1.2.1, 1.2.4] |
| Administration | Oral | Oral | Oral [1.2.3] |
| Common Side Effects | Nausea, rash, fatigue, photosensitivity, diarrhea [1.7.4] | Diarrhea, nausea, vomiting, abdominal pain, liver enzyme elevation [1.2.3, 1.7.4] | Diarrhea and headache reported as dominant adverse effects in trials [1.6.2] |
Conclusion: A New Era in Fibrosis Treatment
The anticipated arrival of nerandomilast in late 2025 or early 2026 marks a potential turning point for patients with fibrosing lung diseases [1.2.2]. It represents a new mechanistic class and offers hope as both a standalone and add-on therapy, potentially with a more manageable side effect profile [1.2.1, 1.5.1]. The robust pipeline, despite setbacks like bexotegrast and ziritaxestat, shows a continued commitment to addressing this critical unmet medical need through diverse pharmacological approaches. The focus on more targeted therapies and combination treatments signals a hopeful future for managing and treating fibrosis. For more information on ongoing research, you can visit the Pulmonary Fibrosis Foundation.
