The US Food and Drug Administration (FDA) has approved Boehringer Ingelheim's 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.

Until today there were no FDA-approved treatments for IPF. 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 US 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.

Nintedanib is the first targeted treatment for IPF to consistently meet the primary endpoint in two identically designed Phase III clinical trials.

Nintedanib also significantly reduced the risk of adjudicated acute exacerbations‡. IPF exacerbations – events of acute respiratory worsening – can significantly impact the course of the disease.  Approximately half of patients hospitalised for an acute IPF exacerbation die during hospitalisation.

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). Side effects with nintedanib can be effectively managed in most patients.

“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.

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).

The phase II TOMORROW trial was a 12-month, randomised, double-blind, placebo-controlled trial conducted at 92 sites in 25 countries. 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).

The primary endpoint for the TOMORROW trial was annual rate of decline in forced vital capacity (FVC). Secondary endpoints included acute exacerbations, quality of life measured with the St. Georges Respiratory Questionnaire (SGRQ) and total lung capacity.  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. 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) 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. 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.

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. 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.

Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF). 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%. This can be crucial given that approximately 50% of patients hospitalised for an acute IPF exacerbation die during hospitalisation. Side effects with nintedanib can be effectively managed in most patients.