Pirfenidone

INGELHEIM, Germany I September 16, 2024 I Boehringer Ingelheim announced today that the FIBRONEER™-IPF trial met its primary endpoint, which was the absolute change from baseline in Forced Vital Capacity [mL] (FVC) at week 52 versus placebo. FVC is a measure of lung function. 1 Based on these results, Boehringer Ingelheim will submit the new drug application for nerandomilast for the treatment of IPF to the US Food & Drug Administration (FDA) and other Health Authorities worldwide. The FDA granted Breakthrough Therapy Designation in IPF in 2022. 2 “This is the first IPF phase-III-trial in a decade to meet its primary endpoint 9 ,” said Ioannis Sapountzis, Head of Global Therapeutic Areas at Boehringer Ingelheim. “Today’s announcement represents the next step in our long history in the research of this disease. IPF has a high unmet need for patients, and we are continuously fostering our research activities to develop more options for one of the most common interstitial lung diseases.” Nerandomilast is an oral, investigational phosphodiesterase 4B (PDE4B) inhibitor and has not been approved for use, therefore safety and efficacy have not  been established. 3 It is being investigated as part of the FIBRONEER™ global program, which includes two Phase III studies —FIBRONEER™-IPF 4 in patients with IPF and FIBRONEER™-ILD 5 in people living with Progressive Pulmonary Fibrosis (PPF). About FIBRONEER™-IPF ( NCT05321069 ) 4 A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of nerandomilast Over at Least 52 Weeks in Patients With Idiopathic Pulmonary Fibrosis (IPF). Primary endpoint: Absolute change from baseline in Forced Vital Capacity (FVC) (mL) at Week 52. Key secondary endpoint: Participants are put into 3 groups randomly, which means by chance. Participants in 2 groups take different doses of nerandomilast as tablets twice a day. Participants in the placebo group take placebo tablets twice a day. Placebo tablets look like nerandomilast tablets but do not contain any medicine. The trial has been conducted in more than 30 countries, 1 and randomized 1177 patients. About the FIBRONEER™ clinical program 4,5 The FIBRONEER™ program includes two Phase III randomized, double-blind, placebo-controlled trials — FIBRONEER™-IPF ( NCT05321069 ) and FIBRONEER™-ILD ( NCT05321082 ) — to investigate the efficacy, safety and tolerability of nerandomilast over at least 52 weeks in patients with IPF and in patients with PPF. Patients participating in the FIBRONEER™-IPF trial were treated with either oral nerandomilast at twice-daily doses of 9 mg or 18 mg, or placebo, over at least 52 weeks. 1 The 18 mg twice-daily dose of nerandomilast is supported by the results from the Phase II study. 1 An additional 9 mg twice-daily dose of nerandomilast was added to evaluate the benefit-risk profile at a lower dose, as well as to provide further dose-response and exposure-response data. 1 In both trials, the primary endpoint is the absolute change from baseline in FVC at week 52. The key secondary endpoint is the time to the first occurrence of any of the components of the composite endpoint: time to first acute IPF/PPF exacerbation, first hospitalization for respiratory cause, or death (whichever occurs first) over the duration of the trials. 4,5 About nerandomilast Nerandomilast (BI 1015550) is an investigational oral, preferential inhibitor of phosphodiesterase 4B (PDE4B) that is being studied as a potential treatment for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). 2 This compound is an investigational agent and has not been approved for use. The efficacy and safety of this investigational compound has not been established. Nerandomilast was granted FDA Breakthrough Therapy Designation for the treatment of idiopathic pulmonary fibrosis (IPF) in February 2022. 2 The efficacy, safety, and tolerability of nerandomilast was studied in a Phase II randomized, double-blind, placebo-controlled trial of patients with IPF (n=147). The primary endpoint was a change from baseline in FVC (a measure of lung function) over a 12-week treatment period. 3 About IPF and PPF IPF is one of the more common progressive fibrosing interstitial lung diseases (ILD). Symptoms of IPF include breathlessness during activity, a dry and persistent cough, chest discomfort, fatigue and weakness. Although considered “rare,” IPF affects approximately 3 million people worldwide. 6,7 The disease primarily affects patients over the age of 50 and affects more men than women. 6 In addition to IPF, patients with certain types of fibrosing ILD may develop a progressive phenotype known as progressive pulmonary fibrosis (PPF). In ILDs other than IPF, progressive pulmonary fibrosis is defined by worsening respiratory symptoms, physiological evidence of disease progression and radiological evidence of disease progression. 8 About Boehringer Ingelheim Boehringer Ingelheim is a biopharmaceutical company active in both human and animal health. As one of the industry’s top investors in research and development, the company focuses on developing innovative therapies that can improve and extend lives in areas of high unmet medical need. Independent since its foundation in 1885, Boehringer takes a long-term perspective, embedding sustainability along the entire value chain. More than 53,500 employees serve over 130 markets to build a healthier, more sustainable, and equitable tomorrow. Learn more at https://www.boehringer-ingelheim.com/uk (UK) or https://www.boehringer-ingelheim.com (rest of world). References: 1 Richeldi L, et al. (2023) Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF). In: BMJ Open Respir Res. 2023; 10(1): e001563. 2 Boehringer Ingelheim (2022) FDA Grants BI 1015550 Breakthrough Therapy Designation for Idiopathic Pulmonary Fibrosis. Accessed August 2024. Available at: https://www.boehringer-ingelheim.com/us/human-health/lung-diseases/pulmonary-fibrosis/fda-grants-bi-1015550-breakthrough-therapy . 3 Richeldi L, et al. (2022) Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis. In: N Engl J Med 2022;386:2178-2187. 4 Boehringer Ingelheim (2024) A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Idiopathic Pulmonary Fibrosis (IPF). Accessed August 2024. Available at: https://clinicaltrials.gov/study/NCT05321069 . 5 Boehringer Ingelheim (2024) A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs). Accessed August 2024. Available at: https://clinicaltrials.gov/study/NCT05321082?tab=results . 6 European Lung Foundation (2023) IPF – Idiopathic Pulmonary Fibrosis. Accessed August 2024. Available at: https://europeanlung.org/en/information-hub/factsheets/ipf-idiopathic-pulmonary-fibrosis/ 7 Koudstaal T, Wijsenbeek MS. Idiopathic pulmonary fibrosis. Presse Med 2023; 52(3):104166. 8 Cottin, V. Am J Respir Crit Care Med 2023; 207(1):11-13. 9 King TE Jr et al (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. In: N Engl J Med 2014:370:2083-2092. SOURCE: Boehringer Ingelheim

Boehringer Ingelheim plans to seek approval for the molecule in the U.S. and other parts of the world. Boehringer Ingelheim has ended a decade of industrywide failures in idiopathic pulmonary fibrosis (IPF) by reporting a phase 3 win for a potentially first-in-class candidate and outlining plans to seek approval.Physicians already have Boehringer’s Ofev and Roche’s Esbriet to manage IPF patients. However, those drugs only slow the progression of fibrosis. Attempts to develop molecules that further slow, or ideally stop, progression have failed to establish an alternative to Ofev and Esbriet. Boehringer tried to end the losing streak by moving its PDE4B inhibitor nerandomilast into a phase 3 program in 2022.Patients on nerandomilast performed better on the forced vital capacity test, a measure of lung function, than subjects on placebo after 52 weeks, causing the study to hit its primary endpoint. Boehringer is yet to share the numbers behind the primary endpoint hit.The decision to hold back data for presentation in the first half of 2025 makes it impossible to gauge how well nerandomilast performed. Boehringer is yet to comment on how the two different doses, the lower of which wasn’t tested in phase 2, fared or to say anything about secondary endpoints. The study has a key secondary that is tracking time to any of a set of negative events such as hospitalization and death. There are also unanswered questions about the patient population and how nerandomilast performed in different subgroups. The study accepted patients who were either on stable therapy with Ofev or Esbriet or hadn’t received either drug for at least eight weeks. Data on the subgroups could help unpick the level of benefit nerandomilast provides as an add-on drug and its potential to become the first-choice agent.Nerandomilast has a potential mechanistic advantage over the incumbent products. The candidate has a different target, PDE4B, than the existing drugs. Targeting PDE4 drives anti-inflammatory and antifibrotic effects, but attempts to develop oral inhibitors of the enzyme in respiratory diseases have been hindered by class-related systemic adverse events such as diarrhea and headaches.Boehringer designed nerandomilast to overcome those problems by preferentially targeting PDE4B over PDE4D. Hitting PDE4B, a subtype of the enzyme that is found at high levels in the lungs, could enable the molecule to cause anti-inflammatory and antifibrotic effects without the side effects associated with less selective inhibitors. Boehringer’s data drop lacks any comment on nerandomilast’s safety and tolerability.While the drugmaker is giving little away, its actions suggest it believes nerandomilast has a future in IPF. Boehringer plans to seek approval for the molecule in the U.S. and other parts of the world. Work on a second phase 3 trial, which is testing nerandomilast in progressive fibrosing interstitial lung diseases, is continuing. The study is scheduled to reach primary completion in December.