|Year : 2020 | Volume
| Issue : 2 | Page : 48-52
Nintedanib for the treatment of idiopathic pulmonary fibrosis: An Indian perspective
Anubhuti Singh1, Kislay Kishore2, Ajay K Verma3, Arpita Singh4
1 Department of Respiratory Medicine, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India
2 Department of Respiratory Medicine, Base Hospital Delhi Cantt, Delhi, India
3 Department of Respiratory Medicine, King George Medical University, Lucknow, Uttar Pradesh, India
4 Department of Pharmacology, Dr Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
|Date of Submission||29-Aug-2019|
|Date of Acceptance||20-Jun-2020|
|Date of Web Publication||10-Sep-2020|
Dr. Kislay Kishore
MD, Graded Specialist (Respiratory Medicine), Department of Respiratory Medicine, Base Hospital, Delhi Cantt, Delhi 110010
Source of Support: None, Conflict of Interest: None
Idiopathic pulmonary fibrosis (IPF) is a chronic disease associated with progressive deterioration of lung function and ultimately death. Until recent past, no drug therapy was approved for the management of IPF and patients either received symptomatic treatment or were enrolled in clinical trials. Since 2014, two new drugs with anti-fibrotic potential have been approved following positive outcomes in large-scale clinical trials. Nintedanib is the latest drug in this category and has recently been launched in India. Here we present a review about nintedanib, covering its mechanism of action, efficacy, adverse effect profile, cost effectiveness and implications in the Indian setting.
Keywords: Anti-fibrotic agents, idiopathic pulmonary fibrosis, nintedanib
|How to cite this article:|
Singh A, Kishore K, Verma AK, Singh A. Nintedanib for the treatment of idiopathic pulmonary fibrosis: An Indian perspective. J Assoc Chest Physicians 2020;8:48-52
|How to cite this URL:|
Singh A, Kishore K, Verma AK, Singh A. Nintedanib for the treatment of idiopathic pulmonary fibrosis: An Indian perspective. J Assoc Chest Physicians [serial online] 2020 [cited 2020 Dec 3];8:48-52. Available from: https://www.jacpjournal.org/text.asp?2020/8/2/48/294587
For a long time, the diagnosis of IPF has been synonymous with a slow death sentence. With all the major trials using nintedanib providing a favorable response and a number of other drugs under trial, all, it seems, is not lost for the unfortunate patients suffering from this disease.
| Introduction|| |
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease associated with progressive symptoms of dyspnea and cough, progressive deterioration of lung function and ultimately death. It was earlier known with various names such as Hamman Rich syndrome, cryptogenic fibrosing alveolitis and cirrhosis of the lung. After diagnosis, the patients usually undergo a downhill course until they succumb to the disease. The nihilistic attitude towards IPF is understandable, considering its poor prognosis. The prognosis of IPF is said to be poorer than certain malignancies. A number of drugs have been used for the management of these patients worldwide, without any concrete evidence. In fact, up to 2011, the only approved treatment for IPF was supplemental oxygen, lung transplantation and pulmonary rehabilitation. Since 2014, two new drugs have been approved for the treatment of IPF by the United States Food and Drug Administration (U.S. FDA), pirfenidone and nintedanib. Although pirfenidone has been in use in India for the last few years, nintedanib has been commercially available since 2017. This is a review of nintedanib, its use in patients with IPF and its relevance in the Indian scenario.
| Epidemiology of ipf|| |
Worldwide data for the incidence and prevalence of IPF are not standardized because of differences in diagnostic criteria used. The data from United States show that the prevalence of IPF varies between 14.0 to 42.7 per 100,000 population. A recent systematic review has demonstrated that the incidence of IPF ranges from 3-9 cases per 100,000 per year in North America and Europe. Data from India are lacking with only retrospective studies from single centers being reported. The recently concluded interstitial lung disease (ILD) India registry reported 13.7% patients with IPF among 1084 patients enrolled. There has been an increase in incidence of ILDs worldwide. A possible explanation for this can be the increasing awareness or easy availability of high resolution computed tomography (HRCT) facilities.
| Pathophysiology of ipf|| |
To understand the mechanism of action of nintedanib, it is vital to understand the patho-physiology of IPF. Earlier, IPF was thought to result from inflammation, secondary to alveolar insult (smoking, viral infections or occupational exposure being commonly implicated). But, recent theories suggest minimal inflammation, rather the role of aberrant wound healing as causative for IPF. Alveolar epithelial cells (AECs) are the master orchestrator of these events. These cells produce a pro-fibrotic micro-environment by secreting growth factors, which lead to migration, proliferation and differentiation of fibroblast into myo-fibroblast and by producing matrix metalloproteinase (MMP) 2 and 9, which leads to basement membrane disruption and myofibroblast migration into alveolar spaces.
Tyrosine kinase receptors play a key role in fibroblast activation, migration and differentiation. These are trans-membrane receptors, wherein binding of extra-cellular ligand causes their auto-phosphorylation and leads to downstream signaling cascade. The signaling pathways implicated in IPF are platelet derived growth factor/ platelet derived growth factor receptor (PDGF/PDGFR), fibroblast growth factor/ fibroblast growth factor receptor (FGF/FGFR) and vascular endothelial growth factor/ vascular endothelial growth factor receptor (VEGF/VEGFR). PDGF is responsible for proliferation, migration and survival of myofibroblasts. FGF-2 is responsible for synthesis of collagen in lung fibroblast and myofibroblast. It also reduces fibroblast growth, inhibits differentiation into myofibroblast and causes fibroblast apoptosis. Transforming growth factor-β (TGF-β) regulates FGF/FGFR signaling cascade by up-regulation of FGFR-1 and FGF-2.
Evidence suggests that the milieu inside IPF lungs is pro-coagulant and anti-fibrinolytic. After tissue or lung injury, activation of coagulation cascade causes formation of fibrin plugs and release of proteinases which cause wound healing. These proteinases can be activated by either a tissue factor dependent extrinsic coagulation pathway or anti-thrombin dependent intrinsic pathway., It has been shown that the former is the primary pathway responsible for creating an anti-fibrinolytic environment.
Eventually, the activated myofibroblasts secrete extra-cellular collagen and result in deposition of extra-cellular matrix. This phenomenon, along with the absence of myofibroblast apoptosis, ultimately causes abnormal wound healing, the basic pathology of IPF.
| Mechanism of action|| |
Nintedanib has a multi-pronged mechanism of action. First of all, it is a multi-kinase inhibitor. It has been under trial for a number of cancers, such as lung, ovary and colo-rectal. It is an indolinone derivative which binds to the intracellular adenosine tri-phosphate (ATP) binding site of FGFR 1, 2 and 3, VEGFR 1, 2 and 3 and PDGFR α and β, thus inhibiting proliferation, migration and survival of fibroblasts as well as inhibition of angiogenesis. It inhibits FGF-, PDGF- and VEGF-induced fibrosis and reduces transforming growth factor-β (TGF-β) induced deposition of collagen. Lehtonen et al found that both nintedanib and pirfenidone cause a significant reduction in stromal cell proliferation and when given concomitantly, there was more reduction in cell proliferation than when each drug was given alone. Nintedanib reduces the steady state concentration of extra-cellular matrix proteins, fibronectin and collagen 1a1. Also, it causes increased expression of α-smooth muscle actin, which is responsible for transformation of fibroblast to myofibroblast. It up-regulates the expression of pulmonary surfactant protein D (SP-D), which has shown to reduce bleomycin induced lung fibrosis in animal studies. Lastly, the Insulin like growth factor binding protein (IGFBP) has been implicated in the pathogenesis of IPF too. Guiot et al. found elevated serum levels of IGFBP 1 and 2 in patients with IPF and fall in IGFBP-2 in response to anti-fibrotic therapy with nintedanib and pirfenidone.
| Efficacy|| |
The positive response obtained in the pre-clinical studies using nintedanib was followed by three international trials which proved the efficacy and safety of nintedanib in patients with IPF. These are TOMORROW, INPULSIS-1 and INPULSIS-2; resulting in the recommendation of its use by the international guidelines published in 2015. In the TOMORROW trial (a phase II, randomized placebo controlled study), 428 patients with IPF were given increasing doses (out of four) of nintedanib versus placebo over a 52 week period. This trial showed that nintedanib at a dose of 150 mg bid decreased the annual rate of forced vital capacity (FVC) decline, reduced the St. George’s respiratory questionnaire (SGRQ) score and reduced the incidence of acute exacerbations. The success of TOMORROW trial paved the way for two replicate, phase III randomized studies-INPULSIS-1 and INPULSIS-2. They were conducted across 24 countries. The patients enrolled in INPULSIS trials were >40 years of age, had baseline FVC≥50% predicted, diffusion capacity of lung for carbon monoxide (DLCO)>30% predicted and a forced expiratory volume in 1st second/ forced vital capacity ratio (FEV1/FVC) ≥0.7. A total of 1066 patients with IPF were randomized to receive 150 mg bid nintedanib versus placebo over a 52 week period. Both these trials demonstrated that nintedanib caused significant reduction in rate of annual FVC decline. In INPULSIS-1, there was no significant difference in reduction in SGRQ score or increase in time to first exacerbation, while it was so in INPULSIS-2. None of these trials showed any mortality benefit over placebo. In the INPULSIS-1 trial, the difference in the adjusted rate of decline in FVC between nintedanib and placebo group was 125.3 ml per year (p<0.0001), while it was 93.7 ml per year (p=0.0002) in INPULSIS-2. Also, the rate of FVC decline was studied in sub-groups obtained from pooled data of the two INPULSIS trials. Nintedanib had similar efficacy in sub-groups divided on the basis of demographic features (gender, age and race), baseline lung function (FVC% predicted), baseline symptoms (SGRQ score), smoking status and use of steroids or bronchodilators at the initiation of therapy.
Regarding long term efficacy of nintedanib, an extension trial was performed on patients enrolled in the INPULSIS trial, labeled as the INPULSIS-ON trial. patients who completed the study period of 52 weeks were continued at the same dose of nintedanib. It was found that the rate of FVC decline persisted upto three years.
| Adverse effect profile|| |
Across all the three trials, nintedanib was found to have minor adverse effects; most of which were tolerable. The most commonly reported adverse event was diarrhea. More than half (62.4%) the patients receiving nintedanib in the INPULSIS trials developed diarrhea as compared to 18.4% patients in placebo group. Diarrhea was mild to moderate in severity in most (94.5%) of the patients. Majority (78.6%) of patients who had diarrhea improved without dose reduction or cessation of therapy. A small number of patients (19.3%) discontinued medications before the completion of trial because of an adverse event. The other reported adverse events were nausea, vomiting, elevated liver enzymes, loss of appetite, epistaxis, bleeding tendency, cardiac adverse events and loss of weight. Based on these findings, Corte et al suggested that as soon as symptoms develop, the treatment of diarrhea should be given. Dose reduction to 100 mg bid can be considered and nintedanib should be stopped in patients having persistent diarrhea. Also, it should be used with caution in patients with risk factors for bleeding due to risk of bleeding and thrombo-embolism. They also found that liver function test (LFT) abnormalities were reversible after with-holding or stopping nintedanib. Hughes et al observed the adverse effect profile of nintedanib in 124 patients with IPF over a period of 18 months in a real world setting (outside a clinical trial). They found that around 82% patients reported ≥2 adverse event. The most common among them were diarrhea (24%), nausea (13%) and appetite loss (10%). Discontinuation of treatment was required in 26% patients while dose reduction was required in 15%.
| Nintedanib in early ipf|| |
Similar to pirfenidone, a controversy existed about the use of nintedanib in patients with preserved lung function. It was unclear whether patients with minimal symptoms and early changes on high resolution computed tomography (HRCT) would benefit from therapy or not. To assess the efficacy of nintedanib in this group of patients, pooled data from the two INPULSIS trials were used to perform post hoc analyses in sub-group of patients with baseline FVC>90% versus FVC≤90% predicted. The parameters assessed were rate of decline in FVC, time to first exacerbation, SGRQ score and adverse effect profile. It was found that irrespective of the baseline FVC, nintedanib caused a reduction in FVC decline. Similar studies have recommended the use of nintedanib early in the course of the disease, at the time of diagnosis itself.,
| Nintedanib in advanced ipf|| |
A similar apprehension surrounded the use of nintedanib in patients with advanced disease as all the major trials excluded this group of patients for assessment of efficacy and safety. Wuyts et al performed a post hoc analysis in patients enrolled for INPULSIS-ON having FVC≤50% and FVC>50% predicted at baseline. they found that the rate of FVC decline in both groups was similar, but adverse effect profile was more severe in patients with advanced disease. Harari et al conducted a real life, multi-centre study on 41 patients with FVC≤50% and/or DLCO≤35% predicted. Patients were followed up for 6 months after initiation of nintedanib treatment. They concluded that the rate of decline of DLCO was reduced significantly but there was no effect on FVC decline with nintedanib.
| Cost of therapy|| |
One of the major shortcomings of nintedanib therapy, especially in India, is the high cost of therapy. Studies of cost-benefit analysis are mandated. In a study by Rinciog et al. (conducted in the United Kingdom), they compared the cost effectiveness of nintedanib and pirfenidone for the treatment of IPF. In a pair-wise comparison, both the drugs were more or less similar in costs and health-related quality of life (HRQoL) advantage. Also, they reported that both nintedanib and pirfenidone provided 0.5 quality adjusted life years (QALYs) more than placebo. In India, the cost of monthly therapy with nintedanib is approximately 15 times that of perfenidone.
| Pirfenidone versus nintedanib|| |
Since the introduction of two anti fibrotic drugs, it was justified to compare both of them for efficacy and adverse effect profile. Loveman et al conducted a network meta-analysis of 11 studies. On comparing pirfenidone and nintedanib with placebo, nintedanib was found to have lesser FVC decline than pirfenidone (OR 0.67, 95% CI 0.51, P = 0.88). They found that in comparison to nintedanib, pirfenidone had lesser all cause mortality, although the difference was not significant. The important questions which need to be answered are which drug is to be preferred in newly diagnosed patients, when to switch to the other drug and when to give both of them in combination. The INJOURNEY trial was undertaken to assess the safety and efficacy of combination therapy. Patients on 150 mg BID nintedanib were given add on perfenidone (followed up for 12 weeks) and compared with patients receiving only nintedanib. They reported that the mean FVC decline was lesser in combination group than the nintedanib group; although the adverse events were also more.
| Future directions|| |
Although the approval of pirfenidone and nintedanib for the treatment of IPF has brought a glimmer of hope for patients suffering from this fatal disease, we are still a far away from the therapy which can reverse or cure this disease. Surolia et al. developed 3-D spheroids (pulmospheres) from lung tissue obtained from patients with IPF. Using pulmospheres from 20 patients and 9 controls, they reported that these pulmospheres reflect in situ conditions of the lung and can serve as a model to evaluate drug response in such patients. This is a promising field of research. Some of the drugs currently under phase II and III trials for the treatment of IPF are Lebrikizumab (anti-Interleukin (IL)-13), Tralokinumab (anti-IL-13), Tanzisertib (c-Jun N-terminal protein kinases (JNK) inhibitor), Rituximab (anti-cluster of differentiation (CD)-20) and Sirolimus (mammalian target of the rapamycin (Mtor) inhibitor). A favorable outcome is expected out of these.
| Conclusion|| |
With the approval of nintedanib and pirfenidone, the sense of helplessness associated with the treatment of IPF is gradually fading. Although pirfenidone has been in use since the last two years in India, nintedanib has recently come into the market. Considering the high cost, its acceptance into Indian medical dynamics is presumed to be slow and hesitant. A large majority of Indian patients with IPF are initially misdiagnosed as tuberculosis and are provided anti-tuberculosis treatment (especially at peripheral health canters). This causes delays in diagnosis and progression of disease in the absence of correct therapy. By the time diagnosis of IPF is established, the patient has had developed advanced disease. The efficacy of anti-fibrotic drugs at this stage needs to be validated further. With all the major trials using nintedanib providing a favorable response and a number of drugs under trial, improvement in quality of life, reduction in mortality and possible reversal or cure can be hoped for the unfortunate patients suffering from this fatal disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest
| References|| |
Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. Eur Respir J 2010;35:496-504.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK 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.
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.
Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J 2015;46:795-806.
Raghu G, Mehta S. Interstitial lung disease in India: insights and lessons from the prospective, landmark ILD India Registry. Lung India 2016;33:589-91.
] [Full text]
Gauldie J. Pro-inflammatory mechanisms are a minor component of the pathogenesis of IPF. Am J Respir Crit Care Med 2002;165:1205-06.
Selman M, Prado A. Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 2006;3:364-72.
Wollin L, Wex E, Pautsch A et al.
Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015;45:1434-45.
Bonner JC. Regulation of platelet derived growth factor and its receptors in fibrotic disease. Cytokine Growth Factor Rev 2004;15:255-73.
Thannickal VJ, Aldweib KD, Rajan T et al.
Upregulated expression of fibroblast growth factor receptor by transforming growth factor-β1 mediates enhanced mitogenic responses to fibroblast growth factors in cultured human lung fibroblasts. Biochem Biophys Res Commun 1998;251:437-41.
Betensley A, Sharif R, Karamichos D. A systematic review of the role of dysfunctional wound healing in the pathogenesis and treatment of idiopathic pulmonary fibrosis. J Clin Med 2016;26:6. doi: 10.3390/jcm6010002
Mercer PF, Chambers RC. Coagulation and coagulation signaling in fibrosis. Biochem Biophys Acta 2013;1832:1018-27.
Chambers RC. Pro-coagulant signaling mechanism in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br J Pharmacol 2008;153:S367-S378.
Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006;3:350-356.
Hostettler KE, Papakonstantinou E, Klagas I et al.
Anti-fibrotic effects of nintedanib in primary human lung fibroblasts derived from idiopathic pulmonary fibrosis and non-fibrotic controls. Am J Respir Crit Care Med 2013;187:A3374.
Lehtonen ST, Veijola A, Karvonen H et al.
Pirfenidone and nintedanib modulate properties of fibroblast and myofibroblast in idiopathic pulmonary fibrosis. Respir Res 2016;17:14.
Rangarajan S, Kurundkar A, Kurundkar D et al.
Novel mechanisms for the anti-fibrotic action of nintedanib. Am J Respir Cell Mol Biol 2016;54:51-59.
Kamio K, Usuki J, Azuma A et al.
Nintedanib modulates surfactant protein D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase activator protein-1 pathway. Pulm Pharmacol Ther 2015;32:29-36.
Guiot J, Bondue B, Henket M, Corhay JL, Louis R. Raised serum levels of Insulin like growth factor binding protein-1 and 2 in idiopathic pulmonary fibrosis. BMC Pulm Med 2016;16:86.
Raghu G, Rochwerg B, Zhang Y, Carlos A, Garcia C, Azuma A et al.
An official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2015;192:e3-e19.
Richeldi L, Costabel U, Selman M et al.
Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079-87.
Richeldi L, Du Bois RM, Raghu G et al.
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
Costabel U, Richeldi L, Azuma A et al.
Pre-specified sub-group analyses of pooled data from the INPULSIS trials of Nintedanib in idiopathic pulmonary fibrosis. The International Colloquium on Lung and Airway Fibrosis, 18th
International Colloquium on Lung and Airway Fibrosis, 2014.
Crestani B, Quaresma M, Kaye M, Stansen W, Stowasser S, Kreuter M. Long term nintedanib treatment in idiopathic pulmonary fibrosis: new data from INPULSIS. In: The European Respiratory Society International Congress. Milan, 9-13 September 2017; pp 1-11.
Corte T, Bonella F, Crestani B et al.
Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res 2015;16:116.
Hughes G, Toellner H, Morris H, Leonard C, Chaudhari N. Real world experience: Pirfenidone and nintedanib are effective and well tolerated treatment for idiopathic pulmonary fibrosis. J Clin Med 2016;5:78.
Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S et al.
Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 2016. Doi: 10.1136/thoraxjnl-2016-208710.
Cottin V, Richeldi L. Neglected evidence in idiopathic pulmonary fibrosis and the importance of early diagnosis and treatment. Eur Respir Rev 2014;23:106-10.
Thickett DR, Kendall C, Spencer LG et al.
Improving care for patients with idiopathic pulmonary fibrosis in the United Kingdom: a round table discussion. Thorax 2014;69:1136-40.
Wuyts WA, Kolb M, Stowasser S, Stansen W, Huggins JT, Raghu G. First data on efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and FVC≤50% of predicted value. Lung 2016;194:739-43.
Harari S, Caminati A, Poletti V, Confalonieri M, Gasparini S, Lacedonia D et al.
A real life multicentre national study on Nintedanib in severe Idiopathic Pulmonary Fibrosis. Respiration 2018;95:433-40.
Rinciog C, Watkins M, Chang S et al.
A cost effectiveness analysis of nintedanib in idiopathic pulmonary fibrosis in the United Kingdom. Pharmaco Economics 2016. Doi: 10.1007/s40237-016-0480-2.
Loveman E, Copey VR, Scott DA, Colquitt JL, Clegg AJ, O’Riley KMA. Comparing new treatment for idiopathic pulmonary fibrosis-a network meta-analysis. BMC Pulm Med 2015;15:37. Doi: 10.1186/s
Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC et al.
Nintedanib with add on perfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY trial. Am J Respir Crit Care Med 2018;197:356-63.
Surolia R, Li FJ, Wang Z et al.
3-D pulmospheres serve as a personalized and predictive multicellular model for assessment of anti-fibrotic drugs. JCI Insight 2017;2:e91377.
Borie R, Justet A, Beltramog G et al.
Pharmacological management of idiopathic pulmonary fibrosis. Respirology 2016;21:615-25.