INGELHEIM, Germany I November 21, 2014 I Boehringer Ingelheim today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for nintedanib* (suggested brand name OFEV®) for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Results from the Phase III INPULSIS® trials, published in the New England Journal of Medicine in May, showed that nintedanib* significantly slowed disease progression in a broad range of patients with IPF**.1 The opinion comes after the recent Food and Drug Administration (FDA) approval of nintedanib* for the treatment of IPF.
“Boehringer Ingelheim welcomes the decision by the CHMP. There has been a high unmet need for effective treatments that can slow disease progression in IPF. We look forward to making nintedanib available soon to patients with IPF in the EU,” said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim.
IPF is a debilitating and fatal lung disease with a median survival of 2–3 years after diagnosis.2 It causes progressive scarring of the lungs, resulting in continual and irreversible deterioration in lung function and difficulty breathing.3
“This decision is very encouraging as patients with IPF currently have very limited treatment options,” said INPULSIS® study investigator Professor Luca Richeldi, Professor of Respiratory Medicine, Chair of Interstitial Lung Disease at the University of Southampton, United Kingdom. “For the first time we have a drug that has consistently met the primary endpoint in two large Phase III trials, confirming the results of the Phase II trial.”
The CHMP’s positive opinion is based on pivotal data from the replicate Phase III INPULSIS® trials involving 1,066 patients from 24 countries. INPULSIS® results showed that nintedanib* slowed disease progression by reducing the annual rate of decline in lung function by 50% in a broad range of IPF patient types: this included patients with early disease (forced vital capacity (FVC) >90% pred), limited radiographic fibrosis (no honeycombing) on high resolution computed tomography (HRCT) and those with emphysema.1 As well, nintedanib* significantly reduced the risk of 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
Nintedanib* in IPF has been granted accelerated assessment by the EMA. Nintedanib*, one capsule twice a day, is the first treatment for IPF that has consistently demonstrated a significant reduction in the decline in lung function and has a manageable side effect profile.1 More than 90% of eligible patients who participated in the INPULSIS® trials opted to continue with nintedanib* treatment as part of an open-label extension trial.5
*Nintedanib is currently being assessed by the European Medicines Agency (EMA) and other regulatory organisations worldwide
**INPULSIS® recruited a broad range of patient types – similar to those seen in clinical practice including patients with early disease (FVC > 90% pred), no honeycombing on HRCT and/or concomitant emphysema
‡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
About the INPULSIS® Phase III trials with nintedanib*
The double blind, randomised, 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.1,6 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* slows disease progression in IPF by reducing the annual decline in lung function by 50% compared to patients taking placebo
- Nintedanib* significantly reduced the risk of adjudicated acute exacerbations‡ by 68% in the pooled data set
- There was a significant 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 The most frequent adverse event in the nintedanib* groups was diarrhoea, reported in 62% vs. 19% (INPULSIS®-1) and 63% vs. 18% (INPULSIS®-2) of patients in the nintedanib* vs. placebo groups, respectively. Less than 5% of patients in the nintedanib* groups of INPULSIS®-1 and INPULSIS®-2 discontinued treatment due to this event.1
About nintedanib*
Nintedanib* is a small molecule tyrosine kinase inhibitor developed by Boehringer Ingelheim for IPF.7 Nintedanib*, 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.1 This included patients with early disease (FVC >90% pred), limited radiographic fibrosis (no honeycombing) on high resolution computed tomography (HRCT) and those with 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).7,8,9 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.7,8,10
The FDA approved OFEV® (nintedanib*) for the treatment of IPF on 15 October, 2014. Nintedanib* is also in clinical development as a treatment option for cancer. The CHMP 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 of adenocarcinoma tumour histology, after first-line chemotherapy.
About 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.8,13 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, a non-productive cough and often have difficulty participating in everyday physical activities.14
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 euros. R&D expenditure corresponds to 19.5% of its net sales.
For more information please visit www.boehringer-ingelheim.com
References
1 Richeldi L, et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis N Engl J Med 2014; 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 Boehringer Ingelheim Data on file.
6 Richeldi L, et al. Design of the INPULSIS® Trials: Two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med 2014; 108 (7):1023-30.
7 Richeldi L, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079-1087.
8 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.
9 Hilberg F, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-4782.
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? nhlbi.nih.gov/health/health-topics/topics/ipf/. Last Accessed October 2014.
14 Pulmonary Fibrosis Foundation. Symptoms. pulmonaryfibrosis.org/life-with-pf/about-pf. Last Accessed October 2014.
