Recruitment complete for two pivotal Phase III studies of nintedanib*

Boehringer Ingelheim is pleased to announce the last patients have been randomised into the Phase III sister trials assessing the efficacy and safety of nintedanib* (150 mg twice daily) in patients with idiopathic pulmonary fibrosis (IPF). The pivotal INPULSISTM Phase III trials continue as planned in study centres worldwide to assess the clinical outcomes in IPF patients treated with nintedanib*.

“Idiopathic pulmonary fibrosis is a severely debilitating condition which results in a progressive loss of lung function, associated with a clear deterioration in quality of life for our patients,” said Luca Richeldi, MD, PhD, lead study author and director of the Research Centre for Rare Lung Diseases, University of Modena and Reggio Emilia, Modena, Italy. “As a treating physician I clearly see the high unmet need for effective new treatments which may substantially change the clinical course of this deadly disease. Modifying the decline in lung function or reducing the rate of acute exacerbations would clearly be crucially important goals.”

Acute exacerbations are an unpredictable part of the clinical course of IPF, which can lead to death in one in two patients within a few months, and are in many ways different from exacerbations in other pulmonary disorders. Most importantly, in the absence of infections or alternative causes, patients experience acute worsening of dyspnoea, with evidence of new infiltrates on lung images.(1) IPF is classified as a rare disease by the European Medicines Agency(2) and the US National Institutes of Health(3) with prevalence estimated to range from 14-43 per 100,000.(4) Median survival is 2 to 3 years after diagnosis.(1)

Nintedanib* is an investigational small molecule tyrosine kinase inhibitor (TKI) which targets growth factor receptors, which have been shown to be potentially involved in pathomechanisms of pulmonary fibrosis, namely vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR).(5) The investigational compound received orphan-drug designation from the US Food and Drug Administration in June 2011 and by the Ministry of Health, Labour and Welfare of Japan in September 2011.

“Boehringer Ingelheim is committed to research in areas of unmet medical need, regardless of how many patients are affected. We strive to improve the lives of patients with idiopathic pulmonary fibrosis,” said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “Nintedanib* has shown promising results in a Phase II clinical trial and we are optimistic that the drug will further demonstrate its potential benefit in this devastating disease in the ongoing Phase III studies.”

The primary endpoint of the two Phase III trials is the annual rate of decline in forced vital capacity (FVC) over a treatment period of 52 weeks in approximately 1,000 enrolled patients. Secondary endpoints include change from baseline in quality of life, time to first acute exacerbation, respiratory mortality, overall survival and on-treatment survival.(6)

The trials are being carried out in 23 countries in Europe, the Americas, Asia and Australia.

The Phase III trials aim to build upon the promising results of the Phase II TOMORROW trial, which demonstrated a positive trend in reducing lung function decline in IPF patients treated with 150 mg of nintedanib* twice daily when compared to placebo.(7)

The two global sister Phase III clinical trials are double blind, randomised and placebo-controlled with a treatment duration of 52 weeks. The trials are evaluating the effect of oral nintedanib*, 150 mg twice daily, on annual rate of decline in Forced Vital Capacity (FVC), in patients with IPF. The trials have an identical design, matching dosing, inclusion criteria, and endpoints.(6)

The primary endpoint is the annual rate of decline in FVC (expressed in mL over 52 weeks). Among the secondary endpoints are: change from baseline in health-related quality of life, as assessed by the Saint-George’s Respiratory Questionnaire (SGRQ); time to first acute exacerbation (days); respiratory mortality; overall survival; on-treatment survival; time to death or lung transplant.(6)

Included were patients over 40 years of age with a diagnosis of IPF within five years before enrolment based on the most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) IPF guideline for diagnosis and management.(6)

The correct diagnosis was assessed by central reviewers based on a combination of high resolution computerised tomography pattern and surgical lung biopsy if available.6 More information can be found on clinicaltrials.gov (identifiers NCT01335464 and NCT01335477).

Nintedanib* is an investigational small molecule tyrosine kinase inhibitor (TKI) in development by Boehringer Ingelheim for idiopathic pulmonary fibrosis (IPF).(7) It targets growth factor receptors, which have been shown to be potentially involved in pathomechanisms of pulmonary fibrosis, most importantly the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR).(5,7,8) By blocking these signaling pathways that are involved in fibrotic processes, it is believed that nintedanib* has the potential to reduce disease progression, slowing the decline of lung function.(5,7) Nintedanib* is also in clinical development as a treatment option for cancer, including non-small cell lung cancer, ovarian cancer, colorectal cancer and hepatocellular carcinoma.(7,9)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, severely debilitating and ultimately fatal lung disease for which there are only limited treatment options available to date.(1) The incidence of IPF can vary considerably and there is some evidence that the patient population is increasing.(10) IPF is characterised by progressive scarring of lung tissue and loss of lung function over time.(1,11) Development of scarred tissue is called fibrosis.(11) 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.(11) As a result, individuals with IPF experience shortness of breath, cough and often have difficulty participating in everyday physical activities.(12)

1. Raghu G, Collard HR, Egan JJ, 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.
2. Orphanet. www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=7029&Disease_Disease_Search_diseaseGroup=idiopathic-pulmonary-fibrosis&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group of diseases=Idiopathic-pulmonary-fibrosis&title=Idiopathic-pulmonary-fibrosis&search=Disease_Search_Simple EMA ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2011. Accessed September 2012
3. U.S. National Institutes of Health. www.nhlbi.nih.gov/resources/docs/raredisrpt01.htm. Accessed September 2012
4. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810-6.
5. Selman M, King TE, Pardo A, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136-51.
6. U.S. National Institutes of Health. Clinical Trials.gov clinicaltrials.gov/ct2/show/NCT01335464?term=bibf1120&rank=14. Accessed September 2012
7. 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):1079-87.’
8. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68(12):4774-4782.
9. U.S. National Institutes of Health. Clinicaltrials.gov BIBF 1120. Available at: http://clinicaltrials.gov/ct2/results?term=BIBF+1120. Accessed September 2012.
10. Fernández Pérez E, Daniels C, Schroeder D, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129-37.
11. Pulmonary Fibrosis Foundation. What is IPF. 2011. Available at: http://www.pulmonaryfibrosis.org/ipf. Accessed September 2012.
12. Pulmonary Fibrosis Foundation. Symptoms. 2011. Available at: http://www.pulmonaryfibrosis.org/Symptoms. Accessed September 2012.