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Products Next higher product group tyrosine kinase inhibitor (TKI)
Period Status 2014-10-16 registration start
Organisation Organisation Boehringer Ingelheim (Group)

Boehringer Ingelheim. (10/16/14). "Press Release: Boehringer Ingelheim’s OFEV (nintedanib) Approved by the FDA for the Treatment of Idiopathic Pulmonary Fibrosis [For media outside UK, US and Canada]". Ingelheim.

For media outside UK, US and Canada

> The approval follows Breakthrough Therapy designation granted by the FDA and nintedanib* will be available to patients in the US within 10 days

> Approval based on Phase III data that show nintedanib* reduces annual decline in lung function by approximately 50%1

> Nintedanib* is under review by the European Medicines Agency (EMA) and has been granted accelerated assessment

Boehringer Ingelheim announced today that the US Food and Drug Administration (FDA) has approved OFEV™ (nintedanib*) for the treatment of idiopathic pulmonary fibrosis (IPF), a debilitating and fatal lung disease, which has a median survival of 2-3 years after diagnosis.2 Until today there were no FDA-approved treatments for IPF.2 Granted Breakthrough Therapy designation during its review by the FDA, nintedanib* is the first and only tyrosine kinase inhibitor (TKI) approved to treat IPF. Nintedanib* is taken as one capsule twice daily and will be available to patients within 10 days.

“While the cause of IPF is unknown and there is no known curative treatment, the unfortunate patients confronted with the disease and physicians caring for patients in the U.S. have been anxiously awaiting FDA-approved treatments,” said Ganesh Raghu, M.D., Professor of Medicine, University of Washington in the Division of Pulmonary and Critical Care Medicine and Director of Center for Interstitial Lung Diseases at University of Washington Medical Center, Seattle, WA. “In three clinical trials, nintedanib slowed lung function decline compared to placebo. This approval is a welcome development for patients and caregivers and it provides hope for those who are living with this devastating disease.”

In clinical trials, nintedanib* reduced the annual decline in lung function by approximately 50%. This also included patients with early disease (forced vital capacity [FVC]>90% pred), no honeycombing on a high resolution computed tomography (HRCT) and/or concomitant emphysema.1 Nintedanib* is the first targeted treatment for IPF to consistently meet the primary endpoint in two identically designed Phase III clinical trials.1 Nintedanib* also significantly reduced the risk of adjudicated acute exacerbations‡.1 IPF exacerbations – events of acute respiratory worsening – can significantly impact the course of the disease.3 Approximately half of patients hospitalised for an acute IPF exacerbation die during hospitalisation.4

The mechanism of action of nintedanib* in IPF is understood. Nintedanib*, a TKI, targets growth factor receptors involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly nintedanib* inhibits the platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).5,6,7 Side effects with nintedanib* can be effectively managed in most patients.1

“The approval of nintedanib in the United States marks a truly significant moment in the history of IPF, and we are highly delighted to provide this new treatment to patients, their caregivers and physicians who are very much in need. Patients are at the heart of everything we do at Boehringer Ingelheim, and we continue to work with all regulatory bodies to ensure patients have access to this innovative treatment as soon as possible,” said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim.

Boehringer Ingelheim announced in June 2014 that the application for marketing authorisation of nintedanib* for the treatment of IPF has been validated and granted accelerated assessment by the EMA.

Notes to Editor

The FDA-approval of nintedanib* is based on the findings from one Phase II trial (TOMORROW) and two Phase III trials (INPULSIS™-1 and INPULSIS™-2).

About the TOMORROW trial

The Phase II TOMORROW trial was a 12-month, randomised, double-blind, placebo-controlled trial conducted at 92 sites in 25 countries.5 The trial evaluated the safety and efficacy of oral nintedanib* at four dosage levels in 432 patients diagnosed with IPF, consistent with the criteria published by the American Thoracic Society (ATS) and European Respiratory Society (ERS).2,5

The primary endpoint for the TOMORROW trial was annual rate of decline in forced vital capacity (FVC).5 Secondary endpoints included acute exacerbations, quality of life measured with the St. Georges Respiratory Questionnaire (SGRQ) and total lung capacity.5,8 In patients treated with 150 mg twice daily nintedanib*, FVC declined by 0.06 litres per year as compared with 0.19 litres per year in patients treated with placebo.5 This dose also resulted in a lower incidence of acute exacerbations versus placebo (2.4 versus 15.7 per 100 patient years; p=0.02)5 and was also associated with a preserved quality of life when compared to placebo as measured by the SGRQ.

Gastrointestinal side effects were common in the nintedanib* 150 mg bid group, but the majority of these effects were of mild or moderate intensity.5 Severe adverse events occurred with similar frequency in the placebo and active-treatment groups but numerically lower in the 150 mg twice daily dose group.5

About the INPULSIS™ Phase III trials with nintedanib*

The double blind, randomised and placebo-controlled trials, involving 1,066 patients across 24 countries, evaluated the effect of oral nintedanib* 150 mg twice daily, on the annual rate of decline in forced vital capacity (FVC), in patients with IPF over 52 weeks. The trials had an identical design, matched dosing, inclusion criteria and endpoints.1,9 The primary endpoint was the annual rate of decline in FVC (expressed in mL over 52 weeks). Key secondary endpoints were: change from baseline in health-related quality of life, as assessed by the Saint George’s Respiratory Questionnaire (SGRQ) and time to first acute exacerbation.

Key results showed:1

> Nintedanib* reduced the decline in lung function by 50% compared to patients taking placebo.

> Nintedanib* significantly reduced the risk of adjudicated acute exacerbations‡ by 68%.

> There was a significant, albeit small benefit of nintedanib* versus placebo in change in SGRQ total score in INPULSIS™-2, but no significant difference between groups in INPULSIS™-1.

In both INPULSIS™ trials, the most common adverse events were gastrointestinal in nature, of mild or moderate intensity, generally manageable and rarely leading to treatment discontinuation.1 The proportion of patients with serious adverse events was similar in all groups.1

About OFEVTM (nintedanib*)

Nintedanib* is a small molecule tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF).5 Nintedanib*, only one capsule twice a day, slows disease progression by reducing the annual rate of decline in lung function by 50% in a broad range of IPF patient types - including patients with early disease (FVC>90% pred), no honeycombing on HRCT and/or concomitant emphysema.1 Only nintedanib* reduces adjudicated acute exacerbations‡ by 68%.1 This can be crucial given that approximately 50% of patients hospitalised for an acute IPF exacerbation die during hospitalisation.4 Side effects with nintedanib* can be effectively managed in most patients.1

Nintedanib* targets growth factor receptors, which have been shown to be involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly nintedanib* inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).5,6,7 By blocking the signaling pathways that are involved in fibrotic processes, it is believed that nintedanib* has the potential to reduce disease progression in IPF by slowing the decline of lung function.5,6,10 Nintedanib* is also in clinical development as a treatment option for cancer. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has just recently issued a positive opinion for the approval of nintedanib* in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology, after first-line chemotherapy.

About idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, severely debilitating and ultimately lethal lung disease for which there are limited treatment options.2 IPF affects as many as 14–43 people per 100,000 worldwide.11,12 IPF is characterised by progressive scarring of lung tissue and loss of lung function over time.6,13 Development of scarred tissue is called fibrosis.2 Over time, as the tissue thickens and stiffens with scarring, the lungs lose their ability to take in and transfer oxygen into the bloodstream, and vital organs do not get enough oxygen.3 As a result, individuals with IPF experience shortness of breath cough and often have difficulty participating in everyday physical activities.14

*Nintedanib is currently being assessed by the European Medicines Agency (EMA) and other regulatory organisations worldwide

‡Adjudicated exacerbations’ was a pre-specified sensitivity analysis in the pooled data set. Time to first Investigator-reported exacerbation was a secondary endpoint which was met in TOMORROW and INPULSIS™-2 but not in INPULSIS™-1

More information on nintedanib:

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about €14.1 billion. R&D expenditure corresponds to 19.5% of its net sales.

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[1] Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014 May; 370(22):2071-82.
[2] Raghu G, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824.
[3] Collard H, et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2007;176:636–643.
[4] Song JW, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 37: 356-363.
[5] Richeldi L, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079-1087.
[6] Selman M, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136-51.
[7] Hilberg F, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-4782.
[8] Jones PW, et al. The St George's Respiratory Questionnaire. Respir Med September 1991; 85(Suppl B):25-31; discussion 33-7.
[9] Richeldi L, et al. Design of the INPULSIS™ Trials: Two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med 2014 Jul; 108 (7):1023-30.
[10] Wollin L, et al. Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis.
J Pharmacol Exp Ther 2014;349:209–220.
[11] Raghu G, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:810-816.
[12] Fernández Pérez E, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. 
Chest. 2010;137:129-37.
[13] NHLBI, NIH. What Is Idiopathic Pulmonary Fibrosis? Last Accessed April 2014.
[14] Pulmonary Fibrosis Foundation. Symptoms. Last Accessed October 2014.

Media contact

Dr. Kristin Jakobs
Boehringer Ingelheim
Media & PR
Binger Str. 173
55216 Ingelheim am Rhein
Phone +49/6132/77 144553
Fax +49/6132/77 6601

Record changed: 2020-03-01


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