Boehringer Ingelheim receives positive CHMP opinion for a third nintedanib indication in pulmonary fibrosis1

Ingelheim, Germany, 29 May 2020 – Boehringer Ingelheim today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending an additional indication for nintedanib in adults for the treatment of other chronic fibrosing interstitial lung diseases with a progressive phenotype beyond IPF.¹ The opinion is based on the positive results of the INBUILD® phase III trial, the first study to evaluate patients with a broad range of chronic fibrosing interstitial lung diseases (ILDs) and a progressive disease behaviour.² This follows the FDA’s and Health Canada’s approval of nintedanib as the first treatment for the same patient population.^3,4

Interstitial lung diseases encompass a large group of more than 200 disorders that may involve the threat of pulmonary fibrosis – an irreversible scarring of lung tissue that negatively impacts lung function.⁵ People living with fibrosing ILD can develop a progressive phenotype, leading to lung function decline, deterioration in quality of life and early mortality similar to those with IPF, the most frequent form of idiopathic interstitial pneumonias.⁶ The course of the disease and the symptoms are similar in progressive forms of chronic fibrosing ILDs regardless of the underlying ILD diagnosis, and as many as 18% to 32% of patients with non-IPF ILDs are estimated to be at risk for developing a progressive fibrosing disease behavior.^7,8 

“Pulmonary fibrosis is a major challenge for people suffering with ILDs and can lead to irreversible harm to the lungs, resulting in worsening respiratory symptoms and reduced quality of life,” commented Peter Fang, Senior Vice President and Head of Therapeutic Area Inflammation at Boehringer Ingelheim. “We are very pleased with the Committee’s opinion, which can bring a new therapy to people where there are no currently approved treatment options available.” 

The positive opinion is based on the results of INBUILD®, a randomized, double-blind, placebo-controlled, parallel-group phase III trial, which evaluated the efficacy, safety, and tolerability of nintedanib in patients with chronic fibrosing ILDs with a progressive phenotype.² The primary endpoint was the annual rate of decline in forced vital capacity (FVC) in mL assessed over a 52-week period. Patients on placebo lost 188mL lung volume over a year, while patients on nintedanib lost 81mL. This was measured as adjusted annual rate of decline over 52 weeks and meant that nintedanib slowed the lung function decline by 57% versus placebo.² The treatment effect of nintedanib in slowing FVC decline compared with placebo seen in INBUILD® was consistent for all patients, regardless of the fibrotic pattern on high-resolution computed tomography (HRCT) and it was also consistent with the results in nintedanib trials studying patients with IPF and SSc-ILD.^2,9,10,11

In the trial, nintedanib was associated with numerical reductions in the risk of acute exacerbation or death versus placebo.² Treatment benefit may also be accompanied by reduced worsening of patient-reported outcomes such as dyspnea and cough.¹² In addition, the safety profile observed in INBUILD® was consistent to what has been seen in IPF and SSc-ILD patients treated with nintedanib previously.² 

Notes to editors

INBUILD® trial 
The INBUILD® trial was a randomized, double-blind, placebo-controlled, parallel-group phase III trial of 663 patients, conducted at 153 sites in 15 countries, which evaluated the efficacy, safety, and tolerability of nintedanib (150 mg, twice daily) over 52 weeks in patients with progressive fibrosing ILD.² Eligible patients were aged ≥ 18 years with a physician-diagnosed ILD other than IPF and features of fibrosing lung disease of >10% extent in HRCT.² Patients were required to meet criteria for ILD progression within the 24 months before screening, based on decline in FVC, increased fibrotic changes on imaging, or worsening of symptoms, despite treatment with drugs commonly used in clinical practice to treat ILD.² 

A total of 663 patients, of whom 412 (62%) had UIP like pattern on HRCT, were randomized 1:1 to receive oral nintedanib (150 mg twice daily) or placebo.² The primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks.² FVC is a lung function test measuring the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. As fibrosis progresses, lung function gradually and irreversibly deteriorates.² Main secondary endpoints were absolute change from baseline in King’s Brief Interstitial Lung Disease (K-BILD) questionnaire total score at week 52; time to first acute exacerbation of ILD or death over 52 weeks; and time to death over 52 weeks.² An acute exacerbation is a sudden, clinically significant deterioration in respiratory function, in many cases with unknown cause, which negatively impacts the disease course and often leads to death.² Nintedanib was associated with numerical reductions in the risk of acute exacerbation or death versus placebo.² 

About chronic fibrosing ILDs with a progressive phenotype
The course of the disease and the symptoms are similar in chronic fibrosing interstitial lung diseases with a progressive phenotype regardless of the underlying condition.⁸ There is an accelerated loss of lung function, a deterioration in quality of life and the disease is associated with a poor prognosis.⁶ 

The progressive fibrosis of the lung leads to an irreversible loss of lung function and is associated with high morbidity and mortality. On average, 18–32% of patients with ILD might develop a progressive pulmonary fibrosis.⁷ These ILDs may occur in a range of clinical diagnoses, including hypersensitivity pneumonitis, sarcoidosis, autoimmune ILDs such as rheumatoid arthritis-associated ILD, systemic sclerosis-associated ILD, mixed connective tissues disease-associated ILD, idiopathic non-specific interstitial pneumonia, and unclassified idiopathic interstitial pneumonia.⁶

Patients with progressive forms of chronic fibrosing ILDs are a patient population for whom no approved treatment options exist that effectively influence the course of their disease.¹³ Therapy of these ILDs is a challenge that requires interdisciplinary care, especially by pulmonologists and rheumatologists.⁸ 

Nintedanib 
Nintedanib is a tyrosine kinase inhibitor targeting key receptors involved in signaling pathways that lead to pulmonary fibrosis.¹⁴ It is already approved in more than 80 countries for the treatment of patients living with idiopathic pulmonary fibrosis (IPF) – a chronic and ultimately fatal disease characterized by a decline in lung function. It is estimated that over 80,000 people with IPF have been treated with nintedanib, and it is recommended for use in IPF patients by international guidelines.¹⁵

In September 2019, nintedanib was approved in the U.S. as the first and only therapy to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated ILD.¹⁶ Submissions have been made to other regulatory bodies across the globe and so far, regulatory approvals have been granted in more than 40 geographies including the European Union, Brazil, Canada and Japan.

Nintedanib has also been granted Breakthrough Therapy Designation by the FDA and received subsequent approval for the treatment of chronic fibrosing interstitial lung diseases with a progressive phenotype in March 2020 in the U.S.³ 

Boehringer Ingelheim
Making new and better medicines for humans and animals is at the heart of what we do. Our mission is to create breakthrough therapies that change lives. Since its founding in 1885, Boehringer Ingelheim is independent and family-owned. We have the freedom to pursue our long-term vision, looking ahead to identify the health challenges of the future and targeting those areas of need where we can do the most good.

As a world-leading, research-driven pharmaceutical company, more than 51,000 employees create value through innovation daily for our three business areas: Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. In 2019, Boehringer Ingelheim achieved net sales of 19 billion euros. Our significant investment of almost 3.5 billion euros in R&D drives innovation, enabling the next generation of medicines that save lives and improve quality of life. 

We realize more scientific opportunities by embracing the power of partnership and diversity of experts across the life-science community. By working together, we accelerate the delivery of the next medical breakthrough that will transform the lives of patients now, and in generations to come.

More information about Boehringer Ingelheim can be found at www.boehringer-ingelheim.com or in our annual report: https://annualreport.boehringer-ingelheim.com.

Intended audiences
This press release is issued from our corporate headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where we do business.

References

1 OFEV® positive opinion. European Medicines Agency. Available at www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-ofev-ii-27_en.pdf. Last accessed May 2020.
2 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi: 10.1056/NEJMoa1908681.
3 U.S. Food and Drug Administration news release. FDA Approves First Treatment for Group of Progressive Interstitial Lung Diseases. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-group-progressive-interstitial-lung-diseases. Last accessed May 2020.
4 Ofev® Product Monograph. Boehringer Ingelheim (Canada) Ltd. May 19, 2020. Available at https://www.boehringer-ingelheim.ca/sites/ca/files/ofevpmen_4.pdf. Last accessed May 2020 
5 British Lung Foundation. What is pulmonary fibrosis? Available at https://www.blf.org.uk/support-for-you/pulmonary-fibrosis/what-is-pulmonary-fibrosis. Last accessed May 2020.
6 Cottin V, Hirani NA, Hotchkin DL, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev 2018;27(150):pii:180076.
7 Wijsenbeek M, Kreuter M, Fischer A, et al. Non-IPF progressive fibrosing interstitial lung disease (PF-ILD): the patient journey. Am J Respir Crit Care Med 2018;197:A1678.
8 Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respiratory Research 2019:20:57.
9 Richeldi L, du Bois RM, Raghu G, et al; INPULSIS® Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
10 Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087.
11 Distler O, Highland KB, Gahlemann M, et al; the SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated lung disease. N Engl J Med. 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076.
12 Swigris JJ, Richeldi L, Wijsenbeek M, et al. Effects of Nintedanib on Dyspnea, Cough and Quality of Life in Patients with Progressive Fibrosing Interstitial Lung Diseases: Findings from the INBUILD trial. ID number: 9455. 
13 Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Resp Res 2017;4:e000212. doi:10.1136/bmjresp-2017-000212
14 Ofev Summary of Product Characteristics. Available at https://www.ema.europa.eu/en/documents/product-information/ofev-epar-product-information_en.pdf (Date of latest renewal: 23 September 2019). Last accessed May 2020.
15 Raghu G, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary. Am J Respir Crit Care Med. 2015; 192(2)238 – 248.
16 U.S. Food and Drug Administration news release. FDA approves first treatment for patients with rare type of lung disease. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-rare-type-lung-disease. Last accessed April 2020