NINTEDANIB MEDIA BACKGROUNDER

Transcription

1 NINTEDANIB MEDIA BACKGROUNDER 1. What is nintedanib? 2. How does nintedanib work? 3. Data overview 4. International treatment guidelines for IPF 1. What is nintedanib? Nintedanib (OFEV a ) is a small molecule tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim. 1,2 Nintedanib a is currently approved in the US, the European Union, Japan and other countries for the treatment of idiopathic pulmonary fibrosis (IPF). It is an oral treatment, given as one capsule twice daily. 1 It has been demonstrated to consistently slow disease progression with approximately 50% reduction in lung function decline (as measured by forced vital capacity) across a broad range of IPF patient types. 3-8 It has been shown to consistently slow disease progression in IPF across three clinical trials. 3,9,10 Nintedanib is also being investigated as a potential treatment for people with systemic sclerosis who have also developed interstitial lung disease (SSc-ILD) in the SENSCIS study (Safety and Efficacy of Nintedanib in Systemic SClerosIS, NCT ), and in a range of progressive fibrosing lung conditions other than idiopathic pulmonary fibrosis (IPF) in the PF-ILD (progressive fibrosing interstital lung disease, NCT ) trial. b 2. How does nintedanib work? Nintedanib targets growth factor receptors, which have been shown to be involved in the mechanisms by which pulmonary fibrosis occurs. 2 Most importantly nintedanib inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). 2 It is believed that nintedanib reduces disease progression in IPF and slows the decline in lung function by blocking the signalling pathways that are involved in fibrotic processes. 2 Nintedanib shows anti-fibrotic and anti-inflammatory effects in experiments with human lung fibroblasts and in animal models of lung fibrosis, indicating potential for an efficacious treatment effect in interstitial lung diseases other than IPF Data overview Nintedanib has been studied in a comprehensive clinical trial programme, including the Phase II TOMORROW dose finding trial 10, the Phase III INPULSIS -1 and 2 trials 3 as well as the open-label INPULSIS -ON extension trial, and the phase IV INJOURNEY combination study. 2,16,17 a Nintedanib is approved under the brand name OFEV in the US, EU, Japan and other territories for use in patients with IPF b Nintedanib is currently not approved for use in SSc-ILD or PF-ILD (other than IPF) and its safety and efficacy has not yet been established 1

2 INPULSIS -1 and 2 are two global Phase III trials which evaluated the efficacy and safety of nintedanib in the treatment of IPF. The trials were identical in design, e.g. with matching dosing, inclusion criteria and endpoints. 3 INPULSIS recruited a broad range of patient types similar to those seen in clinical practice including patients with minimal lung function impairment (FVC > 90% pred), no honeycombing on HRCT and/or concomitant emphysema. 3-6 Forced vital capacity (FVC) FVC is a lung function test measuring the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. As IPF progresses, lung function gradually and irreversibly deteriorates and this is measured by FVC decline. In the absence of another identifiable cause, a progressive decline of FVC in patients with IPF is regarded as a manifestation of disease progression. 18 In the pre-specified pooled analysis of the two INPULSIS trials, nintedanib, reduced the decline in FVC by approximately 50% compared with placebo: the difference in annual rate of FVC decline between nintedanib and placebo groups was 109.9ml/year.3 The annual rate of FVC decline in the two trials was: 3 INPULSIS -1: mL (nintedanib) vs mL (placebo) INPULSIS -2: mL (nintedanib) vs mL (placebo) Sub-group analysis of the trial results demonstrated the consistency of the effect of nintedanib on FVC decline across a range of IPF patient types including patients with minimal lung function impairment (FVC>90% predicted), no honeycombing on HRCT and/or concomitant emphysema. 3-8 An interim analysis of the INPULSIS extension trial (INPULSIS -ON) indicates that the annual rate of decline in forced vital capacity (FVC) in patients taking nintedanib in the extension trial over 144 weeks was comparable to what was observed in patients taking nintedanib in the 52 week INPULSIS parent trials. The analysis suggests that the beneficial effect of nintedanib on slowing disease progression is maintained beyond 3 years. 16 Acute exacerbations All patients with IPF are at risk of an acute exacerbation. Defined as rapid deteriorations of symptoms within days or weeks, an acute exacerbation can occur at any point in the course of the disease and can have a devastating impact on patients lives and prognosis, even at first presentation. 18,19,20 IPF exacerbations can impact the course of the disease, often leading to death within a few months. 21 Of those patients hospitalised for an acute IPF exacerbation, 50% die during hospitalisation. 21 Approximately 5-10% of all IPF patients may experience an exacerbation over a year. 21 In the pooled analysis of the TOMORROW and INPULSIS trials, nintedanib demonstrated a significant reduction the risk of acute IPF exacerbation by approximately 50%. 22 Safety and Tolerability 2

3 In both INPULSIS trials, the most common adverse events were of gastrointestinal nature, of mild to moderate intensity and generally manageable. 1,3,23 The most frequent adverse event in the nintedanib groups was diarrhoea, which was reported in 62.4% of patients in the nintedanib group vs. 18.4% of patients in the placebo group. Less than 5% of patients in the nintedanib group of the INPULSIS trials discontinued treatment due to this event. Side effects can be effectively managed in most patients. The proportion of patients with serious adverse events was similar in all groups. 23 About the open-label extension INPULSIS ON trial The effect and safety of nintedanib in the long-term 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 which is currently ongoing. 24 INPULSIS -ON (NCT ) 24 is a single arm study. Patients with IPF on placebo in the INPULSIS trials initiated treatment with nintedanib in the extension trial and patients treated with nintedanib continued to receive treatment. Average total exposure of patients treated with nintedanib in INPULSIS and INPULSIS -ON trials was more than 3 years (40.7 months). 16 Long-term treatment with nintedanib (up to 63.1 months) had a manageable safety and tolerability profile, consistent with the findings of the INPULSIS studies and with no new safety signals identified. 16 INJOURNEY clinical trial INJOURNEY TM was a 12-week, open-label, randomised trial evaluating the safety, tolerability, pharmacokinetics of nintedanib with add-on pirfenidone compared with nintedanib alone, in patients with IPF. Change in forced vital capacity (FVC), the most established efficacy endpoint in IPF trials, was evaluated as an exploratory endpoint. 17,25 The primary endpoint of INJOURNEY TM was the percentage of patients with on-treatment gastrointestinal (GI) adverse events (AE) from baseline to week 12 of randomised treatment. Results show that the combination of nintedanib and pirfenidone was associated with a manageable safety and tolerability profile in the majority of patients. 17,25 Diarrhoea, nausea and vomiting were the most frequent adverse events, consistent with the safety profiles of the individual drugs, with a slightly higher incidence in the pirfenidone add-on group. No new safety signals were observed in combination treatment, and serious adverse events were uncommon in both treatment groups. 25 Results also indicate there may be a slower decline in FVC in patients treated with nintedanib and add-on pirfenidone compared with nintedanib alone, suggesting a potential benefit of the combination. Due to the exploratory nature of the analysis, further research will be necessary to fully evaluate the efficacy of the combination International treatment guidelines for IPF 26 3

4 Nintedanib is included in the international treatment guideline for IPF the 2015 evidence-based Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis, jointly developed by an international committee including the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS) and the Latin American Thoracic Association (ALAT), provides a conditional recommendation for the use of OFEV in patients with IPF. 26 The committee noted the high value of OFEV on patient-important outcomes such as disease progression as measured by rate of FVC decline and mortality. The recommendation also takes into account the expected cost of treatment and potentially significant adverse effects. 26 The conditional recommendation means that clinicians are encouraged to discuss treatment preferences with their patients when making therapy decisions. 26 References: 1. OFEV Summary of Product Characteristics. Boehringer Ingelheim International GmbH. July Wollin L et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015;45: Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370: Cottin V, et al. Effect of baseline emphysema on reduction in FVC decline with nintedanib in the INPULSIS trials. Abstract presented at the 18th International Colloquium on Lung and Airway Fibrosis; Mont Tremblant, Canada, September 20-24, Available at: Accessed July Kolb M, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 2017;72: Raghu G, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med 2017; 195 (1) 78-85). 7. Costabel U, et al. Efficacy of nintedanib in idiopathic pulmonary fibrosis across pre-specified subgroups in INPULSIS. Am J Respir Crit Care Med, 2016, 193 (2), , P Keating GM. Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis. Drugs Jul;75(10): Richeldi L, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS trials. Respir Med Apr;113: Richeldi L,et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365 (12) Clinical Trials.Gov. A double blind, randomised, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with systemic sclerosis associated interstitial lung disease (SSc-ILD). Available at Last accessed August Clinical Trials.Gov. A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Nintedanib Over 52 Weeks in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD). Available at: Last accessed August 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: Tandon K, et al. Nintedanib attenudates the polorization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor. Poster presented at the American Thoracic Society Conference; Washington DC, USA, May

5 15. Thorley A, et al. Nintedanib effectively inhibits carbon nanotube-induced fibrotic responses in human alveolar epitherlial cells, fibroblasts and pulmonary microvascular endothelial cells. Poster presented at the American Thoracic Society Conference; Washington DC, USA, May Crestani B, et al. Long-term nintedanib treatment in idiopathic pulmonary fibrosis (IPF): new data from INPULSIS-ON. Presented at European Respiratory Society International Congress Milan, Italy, September 9-13, Clinical Trials.Gov. Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF. Available at Last accessed Aug 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: Kim DS, Acute exacerbations in patients with idiopathic pulmonary fibrosis. Respir Res. 2013;14: Collard H, et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2007;176: Song JW, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37: Richeldi L, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS trials. Respir Med Apr;113: Corte et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respiratory Research (2015) 16: Clinical Trials.gov. Extension Trial of the Long Term Safety of BIBF 1120 in Patients With Idiopathic Pulmonary Fibrosis. Available at: Accessed August Vancheri C, et al. Safety and tolerability of nintedanib with add-on pirfenidone in patients with idiopathic pulmonary fibrosis (IPF): results from INJOURNEY submitted to Am J Respir Crit Care Med In Press 26. 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: