nerandomilast (BI 1015550) / Boehringer Ingelheim - LARVOL DELTA

Efficacy and safety of nerandomilast in patients with autoimmune disease–related progressive pulmonary fibrosis: subgroup analysis of the FIBRONEER-ILD trial (EULAR 2025) - "Use of cyclophosphamide, tocilizumab, mycophenolate, or rituximab was not permitted at enrolment but could be initiated after 6 months to manageworsening systemic disease. Prednisone >15 mg/day (or equivalent) was not permitted at enrolment but could be prescribed during the trial for acute exacerbation of ILD...At baseline, among patients with autoimmune ILDs, 212 (65.2%) were female, mean (SD) age was 63.4 (11.2) years, FVC was 71.5 (15.0) % predicted, diffusing capacity for carbon monoxide (DLco) was 51.5 (16.8) % predicted; 111 (34.2%) patients were taking nintedanib... In the FIBRONEER-ILD trial, the efficacy of nerandomilast on slowing decline in FVC in patients with autoimmune ILDs was consistent with that observed in the overall trial population. Nerandomilast had an acceptable safety and tolerability profile, with serious adverse events and treatment discontinuations being no more common in patients who received nerandomilast than placebo."

Clinical • Late-breaking abstract • Idiopathic Pulmonary Fibrosis • Immunology • Inflammatory Arthritis • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Sclerosis

Initiation of Supplemental Oxygen in the FIBRONEER-IPF Trial of Nerandomilast in Patients With Idiopathic Pulmonary Fibrosis (ATS 2025) - " Patients with IPF were randomized 1:1:1 to receive nerandomilast 9 mg bid, nerandomilast 18 mg bid, or placebo, stratified by background antifibrotic therapy (nintedanib/pirfenidone vs none). In the FIBRONEER-IPF trial in patients with IPF, a reduced risk of initiation of supplemental oxygen during follow-up was observed in patients receiving nerandomilast 9mg bid versus placebo."

Clinical • Late-breaking abstract • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Inhaled PDE4 Inhibitor F2008 Alleviates Bleomycin-Induced Pulmonary Fibrosis (ATS 2025) - "A bleomycin-induced PF mouse model was established, and inhalation with 2mg/kg F2008 was administered from Day 2 to Day 21 (oral administration of nintedanib or BI-1015550 was used as a positive control). F2008 inhalation achieves high pulmonary retention, and exhibiting robust anti-inflammatory and antifibrotic effects in a bleomycin-induced PF mouse model. Collectively, F2008 represents a promising inhaled PDE4i for the treatment of IPF."

Late-breaking abstract • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • IL6 • TGFB1

Cyclic AMP Signaling Within Lung Fibroblasts Promotes the Clearance of Pathologic Epithelial and Macrophage Subtypes During Spontaneous Fibrosis Resolution (ATS 2025) - "Although the molecular mechanisms and cellular crosstalk that promote clearance of these cells remains a critical gap in knowledge, spontaneously resolving models of pulmonary fibrosis - such as single-dose bleomycin in young mice - provide a unique opportunity to identify endogenous molecular brakes responsible for orchestrating these crucial events. The second messenger cyclic AMP (cAMP) has garnered renewed attention with nerandomilast (a PDE4B inhibitor that increases intracellular cAMP) recently achieving its primary endpoint in a phase 3 trial...Tamoxifen chow was introduced to abolish Gαs expression in fibroblasts at day 21 (peak fibrosis)... Lung fibroblast-specific cAMP generation is a crucial endogenous brake that promotes fibrosis resolution through fibroblast deactivation/apoptosis and timely clearance of aberrant macrophages and epithelial cells. These findings highlight the importance of fibroblast-mediated cellular crosstalk in fibrosis resolution and..."

Late-breaking abstract • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • C1QB • CLDN4 • COL1A2 • GNAS • ITGAX

Nerandomilast Paves the Way for Novel Strategies in IPF Drug Discovery (ATS 2025) - "These effects were linked to activated cAMP-associated pathways, G-protein-coupled receptor (GPCR) signaling events, mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta 1(TGFβ1) signaling. Nerandomilast's efficacy in IPF may be attributable to effects on an array of patho-mechanisms in epithelial, endothelial, and immune cells, in addition to fibroblasts. Cutting edge technologies can build on such principles to transform drug discovery strategies. Next generation targets will influence our newly characterized pathologic niches, with the bold aim to not only limit disease but return functionality to the lung."

Late-breaking abstract • Acute Lung Injury • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease

A Phosphodiesterase-4b Inhibitor, Nerandomilast Ameliorates Silica-induced Lung Inflammation and Fibrosis in Mice by Inhibiting NLRP3 Inflammasome Activation and the TGF-β/SMAD Pathway (ATS 2025) - "Fibronectin and collagen I expression in MRC-5 fibroblasts, cultured with silica-treated macrophage supernatants, were elevated but decreased following Nerandomilast treatment. CONCLUSIONS The PDE4B inhibitor, Nerandomilast effectively suppressed silica-induced inflammation via the NLRP3 Inflammasome pathway and lung fibrosis through the TGF-β/Smad pathway, highlighting its potential as a therapeutic option for the currently untreatable silicosis."

Late-breaking abstract • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pneumonia • FN1 • NLRP3 • TGFB1

Exploration of Mechanism of Action of Nerandomilast in Pulmonary Fibrosis Through Single Cell Rna Sequence and Spatial Transcriptomic Analysis (ATS 2025) - "Bleomycin (BLM)-challenged mice were treated with Nerandomilastor placebo twice daily, starting 8 days after BLM administration. CONCLUSIONS Nerandomilast reducedlung fibrosis and inflammatory response. The abundance of fibrosis specimensand detailed analysis of mouse models, coupled with scRNA-seq and spatialtranscriptomic analysis, revealed the details of Nerandomilast's mechanism ofaction on fibrosis and inflammation."

Omic analysis • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Buloxibutid Potently Inhibits Fibrosis Biomarkers in the Scar-in-a-Jar Primary Human Lung Fibroblast Assay (ATS 2025) - "This abstract is funded by: Vicore Pharma RATIONALE In a recent open-label Phase 2a clinical trial, the selective, orally available angiotensin II type 2 receptor (AT2R) agonist buloxibutid (also known as C21) improved lung function in patients with idiopathic pulmonary fibrosis (IPF) over a 36-week period. CONCLUSION The findings demonstrate that buloxibutid potently inhibits collagen synthesis in activated human lung fibroblasts, demonstrating its potential as an effective antifibrotic IPF therapy. Buloxibutid was more potent than nintedanib and nerandomilast."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TGFB1

Analysis of Local Distribution and Residence Time of Nerandomilast in Lung Tissue Using Mass Spectrometry Imaging (ATS 2025) - "In this study, we investigated the local distribution and residence time of nerandomilast in lung tissue using MSI, and compared them with nintedanib. Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study . Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations.]"

Immunology • Pulmonary Disease • Respiratory Diseases

Effects of Itraconazole, a Strong CYP3A Inhibitor, on Pharmacokinetics of Nerandomilast, a Preferential PDE4B Inhibitor (ATS 2025) - "Drugs that are strong CYP3A inhibitors may increase the exposure of nerandomilast up to 2-fold. A less prominent exposure increase is expected when nerandomilast is co-administered with moderate or mild CYP3A4 inhibitors."

PK/PD data • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease

Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Nerandomilast (Bi 1015550) in Participants With and Without Renal Impairment (ATS 2025) - "RI appears to slightly decrease Cmax for nerandomilast (by 3-14%) and moderately increase the overall exposure (by 29-37%) compared with participants with normal renal function. Nerandomilast demonstrated acceptable tolerability in participants regardless of RI."

Clinical • PK/PD data • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Renal Disease • Respiratory Diseases

Pharmacokinetics, Safety, And Tolerability Of A Single Oral Dose Of Nerandomilast (BI 1015550) In Participants With And Without Hepatic Impairment (ATS 2025) - "HI appears to decrease Cmax and increase the overall exposure to nerandomilast compared with normal hepatic function. Nerandomilast had an acceptable tolerability in participants with or without mild or moderate HI."

Clinical • PK/PD data • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Global phase III trials demonstrate that nerandomilast slowed lung function decline in IPF and PPF, with similar discontinuation rates to placebo (Boehringer Ingelheim Press Release) - P3 | N=1,177 | FIBRONEER-IPF (NCT05321069) | N=1,178 | FIBRONEER-ILD (NCT05321082) | Sponsor: Boehringer Ingelheim | "Boehringer Ingelheim announced today detailed findings from the Phase III FIBRONEER-IPF and FIBRONEER-ILD trials...Both trials met the primary endpoint at both doses, 9 mg and 18 mg, as measured by a reduction in the absolute change from baseline in forced vital capacity (FVC) [mL] decline at week 52 versus placebo. FVC is a measure of lung function...Across both trials, similar rates of permanent treatment discontinuation to placebo were observed: In FIBRONEER-IPF, adverse events led to permanent discontinuation of the trial regimen in 14.0% of the nerandomilast 18 mg group, 11.7% of the nerandomilast 9 mg group, and 10.7% of the placebo group....In FIBRONEER-ILD, adverse events led to permanent discontinuation of the trial regimen in 10.0% of the nerandomilast 18 mg group, 8.1% in the nerandomilast 9 mg group, and 10.2% in the placebo group."

Late-breaking abstract • P3 data • Idiopathic Pulmonary Fibrosis • Interstitial Lung Disease

Nerandomilast in Patients with Progressive Pulmonary Fibrosis. (PubMed, N Engl J Med) - P3 | "In patients with progressive pulmonary fibrosis, treatment with nerandomilast led to a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-ILD ClinicalTrials.gov number, NCT05321082.)."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. (PubMed, N Engl J Med) - P3 | "In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.)."

Journal • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase III Trial of Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis (ATS 2025) - No abstract available

Clinical • P3 data • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

A Comparative Study With ING-006, Nintedanib, Nerandomilast and Bexotegrast Using the In Vivo CAM-Patient-Derived IPF Model (ATS 2025) - "ING-006 also demonstrates superior inhibitory activity over fezagepras (formerly PBI-4050) in ZQ-16 stimulated-pErK lung fibroblasts as well as through inhibition of fibrotic gene expression. CAM-IPF is an efficient method to predict antifibrotic activity. Among other compounds currently used or under investigation for IPF treatment, ING-006 shows superior antifibrotic activity in fibroblasts and lung tissue xenografts from IPF patients, making it a promising candidate for IPF treatment."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • ACTA2 • COL1A1 • COL3A1 • CTGF • SERPINE1 • TGFB1

ING-006, A Novel Oral GPR40/GPR84 Fatty Acid Receptor Modulator: A Comparative Study With Nintedanib and Nerandomilast (BI-1015550) in Bleomycin-induced Lung Fibrosis and CAM-IPF Xenograft Models (ATS 2025) - "Taken together, the data show that ING-006 reduces well-established lung fibrosis and improves the PV-loop, FVC, FEV0.2, Cstat and IC more efficiently than nintedanib or nerandomilast. These results suggest that ING-006 could be a promising candidate for the treatment of IPF based on its ability to preserve lung function and act in synergy in combination with other antifibrotic compounds."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • IL6 • MMP2 • TIMP1

Nerandomilast - A Multifrontal Therapeutic Approach to Lung Fibrosis. (PubMed, Am J Respir Cell Mol Biol) - No abstract available

Journal • Fibrosis • Immunology • Respiratory Diseases

A Study to Test Whether Nerandomilast Helps People With Lungfibrosis Related to Rheumatic Diseases (clinicaltrials.gov) - P3 | N=400 | Not yet recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Mar 2027 ➔ Jul 2027 | Trial primary completion date: Mar 2027 ➔ Jul 2027

Trial completion date • Trial primary completion date • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Rheumatology

Insights Into the Cellular and Molecular Mechanisms Behind the Antifibrotic Effects of Nerandomilast. (PubMed, Am J Respir Cell Mol Biol) - "Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor (GPCR) signaling events while inhibiting mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta (TGFβ) signaling. These findings highlight nerandomilast's potential therapeutic use in IPF by providing insights into its cellular and molecular actions. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)."

Journal • Acute Lung Injury • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • VCAM1

FIBRONEER-ILD: A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs) (clinicaltrials.gov) - P3 | N=1178 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

BI 1015550 Improves Silica-Induced Silicosis and LPS-Induced Acute Lung Injury in Mice. (PubMed, Molecules) - "Furthermore, we found that BI 1015550 could also alleviate lung inflammation in a Lipopolysaccharide (LPS)-induced acute lung injury mouse model. The mechanism of action may involve the regulation of cAMP-related signaling pathways."

Journal • Preclinical • Acute Lung Injury • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis

A Study to Test Whether Nerandomilast Helps People With Lungfibrosis Related to Rheumatic Diseases (clinicaltrials.gov) - P3 | N=400 | Not yet recruiting | Sponsor: Boehringer Ingelheim | Initiation date: Mar 2025 ➔ Jul 2025

Trial initiation date • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Rheumatology

Boehringer’s nerandomilast meets primary endpoint in Phase III study FIBRONEER-ILD, in progressive pulmonary fibrosis (GlobeNewswire) - P3 | N=1178 | FIBRONEER-ILD (NCT05321082) | Sponsor: Boehringer Ingelheim | "Topline data from FIBRONEER-ILD show that the investigational compound nerandomilast met its primary endpoint, which was the absolute change from baseline in forced vital capacity [mL] at week 52 versus placebo; The FIBRONEER-ILD trial is the second Phase III trial in which the investigational compound nerandomilast has met its primary endpoint; Initial safety and tolerability results of the FIBRONEER-trials are generally consistent with the Phase II results in IPF; full efficacy and safety data from FIBRONEER-ILD will be shared in the second quarter of 2025; Boehringer Ingelheim will submit a new drug application for nerandomilast for the treatment of PPF to the US Food & Drug Administration (FDA) and other health authorities worldwide..."

P3 data: top line • Fibrosis • Pulmonary Disease