579365
research-article2015
TAR0010.1177/1753465815579365Therapeutic Advances in Respiratory DiseaseME Mazzei, L Richeldi
Therapeutic Advances in Respiratory Disease
Review
Nintedanib in the treatment of idiopathic pulmonary fibrosis Mariano E. Mazzei, Luca Richeldi and Harold R. Collard
Ther Adv Respir Dis 2015, Vol. 9(3) 121–129 DOI: 10.1177/ 1753465815579365 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease that occurs in older adults. The clinical course of IPF is variable and hard to predict in an individual patient. Nintedanib is a tyrosine kinase inhibitor that has recently been approved in the US and European Union for the treatment of IPF. Preclinical studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation and the secretion of extracellular matrix. The safety and efficacy of nintedanib have been investigated in the phase II TOMORROW trial and in two replicate 52-week randomized, placebo-controlled phase III trials known as the INPULSIS trials. These trials demonstrated that nintedanib slowed disease progression by reducing the annual rate of decline in forced vital capacity, with a manageable side-effect profile. In this review, we summarize key data supporting nintedanib as a treatment for patients with IPF and address key questions regarding the use of nintedanib in the clinical setting. Keywords: interstitial lung disease, treatment outcome, disease progression, forced vital capacity, safety, tyrosine kinase Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of older adults characterized by a specific histopathologic pattern known as usual interstitial pneumonia (UIP) [Raghu et al. 2011]. The diagnosis of IPF can be made in the absence of lung biopsy with a UIP pattern on lung high-resolution computed tomography (HRCT), or with the careful integration of HRCT and surgical lung biopsy findings [Raghu et al. 2011]. As such, multidisciplinary discussion among pulmonologists, radiologists and pathologists is essential to establishing an accurate diagnosis of IPF. Estimates of the incidence and prevalence of IPF vary widely according to the methodology used and the population studied, with estimates of incidence ranging from 0.6 to 17.4 per 100,000 person years and estimates of prevalence ranging from 0.7 to 63.0 per 100,000 [Ley and Collard, 2013]. In a recent study assessing the incidence and prevalence of IPF in the US Medicare population (age 65 years or over) between 2001 and 2011, the incidence was 93.7 cases per 100,000 person years. In this cohort, the cumulative prevalence increased from 202.2 cases per 100,000 in 2001 to 494.5 cases per 100,000 in 2011 [Raghu et al. 2014].
IPF is ultimately a fatal disease, with a median survival time of 2–3 years after diagnosis [Raghu et al. 2011; Natsuizaka et al. 2014]. The natural course of IPF is highly variable, however, with some patients experiencing a rapid decline, others progressing relatively slowly, and some patients having periods of relative stability punctuated by acute deteriorations in respiratory function [Ley et al. 2011]. Where these acute deteriorations have no identifiable cause, they are known as acute exacerbations [Collard et al. 2007]. Acute deteriorations occur in up to a third of patients with IPF per year and are associated with substantial morbidity and mortality [Ryerson and Collard, 2014; Song et al. 2011; Natsuizaka et al. 2014; Kishaba et al. 2014].
Correspondence to: Harold R. Collard, MD University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA [email protected] Mariano E. Mazzei, MD University of Buenos Aires, Buenos Aires, Argentina Luca Richeldi, MD, PhD National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, UK
While the pathogenic mechanisms involved in IPF are not well understood, evidence suggests that lung fibrosis occurs as a result of alveolar epithelial cell senescence/dysfunction and myofibroblast activation, culminating in excessive synthesis and deposition of collagen and remodeling of the extracellular matrix [Fernandez and Eickelberg, 2012; Wolters et al. 2014]. This is almost certainly related to aging and the attendant changes in cellular function. Genetics also play a central role, with a number of genetic variants strongly associated with the
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Figure 1. Nintedanib blocks the autophosphorylation of VEGF, PDGF and FGF tyrosine kinase receptors, thereby blocking the downstream signaling cascades mediated by these receptors. This results in reduced proliferation, migration and survival of fibroblasts and potentially also of cells involved in angiogenesis in the lung. FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. From Ahluwalia et al. [2014]. Adapted with permission of the American Thoracic Society. Copyright© 2015 American Thoracic Society.
risk of IPF (e.g. mutations in the telomerase gene family and polymorphisms in MUC5B) [Fingerlin et al. 2013; Garcia, 2011]. In October 2014, the US Food and Drug Administration (FDA) approved the first drugs for the treatment of IPF in the US: nintedanib (OFEV) [Boehringer Ingelheim Pharmaceuticals, Inc., 2014] and pirfenidone (ESBRIET) [InterMune, Inc., 2014]. Pirfenidone had already been licensed for the treatment of IPF in Europe, Japan and several other countries, and nintedanib was approved as a treatment for IPF in Europe in January 2015 [Boehringer Ingelheim, 2015]. This manuscript reviews the data supporting nintedanib as a treatment for patients with IPF and addresses several key questions regarding the use of nintedanib in the clinical setting. Nintedanib Nintedanib, an indolinone derivative, is an intracellular inhibitor of tyrosine kinases, including fibroblast growth factor receptor 1, 2 and 3,
platelet-derived growth factor receptor α and β, and vascular endothelial growth factor receptor 1, 2 and 3 [Hilberg et al. 2008; Wollin et al. 2014]. Nintedanib competitively binds to the adenosine triphosphate binding pocket of these receptors, blocking substrate binding and so inhibiting a number of downstream signaling cascades [Wollin et al. 2014, 2015] (Figure 1). By so doing, nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation and the secretion of extracellular matrix [Hostettler et al. 2014; Wollin et al. 2015]. In mouse models of bleomycin- and silica-induced lung fibrosis, nintedanib demonstrated antifibrotic and anti-inflammatory activity by reducing the number of lymphocytes and neutrophils in bronchoalveolar lavage fluid, reducing levels of inflammatory cytokines in lung tissue, and diminishing lung inflammation, granuloma formation and fibrosis [Wollin et al. 2014]. In humans, orally administered nintedanib is rapidly absorbed and reaches maximum plasma
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ME Mazzei, L Richeldi et al.
Figure 2. Mean (standard error) adjusted annual rate of change in forced vital capacity (FVC) analyzed using a random coefficient mixed model for repeated measures. From Richeldi et al. [2011]. Copyright© 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
concentrations after 2–4 h [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Nintedanib exposure increases with increasing doses and steadystate plasma concentrations are achieved within 7 days [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. The major metabolic pathway for nintedanib is hydrolytic cleavage by esterase, with more than 90% of nintedanib and its metabolites excreted via feces [Stopfer et al. 2011]. Clinical trials of nintedanib in IPF The efficacy and safety of nintedanib in patients with IPF have been investigated in the phase II, randomized, dose-finding TOMORROW trial [Richeldi et al. 2011] and the two replicate randomized, placebo-controlled phase III INPULSIS trials [Richeldi et al. 2014a, 2014b]. In the TOMORROW trial, 432 patients with IPF were treated with one of four nintedanib doses (50 mg once daily, 50 mg twice daily, 100 mg twice daily, 150 mg twice daily), or placebo for 52 weeks. The results suggested that, compared with placebo, treatment with nintedanib 150 mg twice daily was associated with a reduced annual decline in forced vital capacity (FVC) (ml/year) (Figure 2), fewer acute exacerbations, and preservation of healthrelated quality of life assessed using the St George’s Respiratory Questionnaire (SGRQ) [Richeldi et al. 2011]. In the INPULSIS trials, 1066 patients in 24 countries were randomized 3:2 to receive nintedanib 150 mg twice daily or placebo for 52 weeks followed by a 4-week follow-up period. Treatment
interruption and dose reduction from 150 mg twice daily to 100 mg twice daily were allowed for the management of adverse events. To be eligible to enter the trials, patients had to be at least 40 years old and have an FVC of 50% of predicted value or higher, a diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% of predicted value and an forced expiratory volume in 1 s/FVC ratio of at least 0.7. The diagnosis of IPF required HRCT images showing honeycombing or a combination of reticular abnormality and traction bronchiectasis, without nodules or consolidation or features suggestive of alternative causes. Surgical lung biopsies, if available, were centrally reviewed and used to confirm eligibility to enter the trials [Richeldi et al. 2014a, 2014b]. Based on these inclusion criteria, a broader range of patient types were enrolled in the INPULSIS trials than those who would meet the strict criteria for diagnosis of IPF according to the 2011 guidelines. This was reflected in the high proportion of screened patients who met eligibility criteria. The primary endpoint in both INPULSIS trials was the annual rate of decline in FVC (ml/year). In both trials, nintedanib consistently slowed disease progression by significantly reducing the annual rate of decline in FVC compared with placebo [Richeldi et al. 2014b] (Figure 3). The adjusted annual rate of decline in FVC was −114.7 ml/year with nintedanib versus –239.9 ml/ year with placebo [a difference of 125.3 ml/year; 95% confidence interval (CI) 77.7–172.8; p < 0.001] in INPULSIS-1 and −113.6 ml/year with nintedanib versus –207.3 ml/year with placebo
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Figure 3. Between-group differences (FVC value in the nintedanib group versus FVC value in the placebo group) are shown for the adjusted annual rate of decline in FVC. Bars indicate standard error. CI, confidence interval; FVC, forced vital capacity. From Richeldi et al. [2014b]. Copyright© 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
(a difference of 93.7 ml/year; 95% CI 44.8–142.7; p < 0.001) in INPULSIS-2. The key secondary endpoints in the INPULSIS trials were time to first investigator-reported acute exacerbation and change from baseline in SGRQ total score. Discordant results were observed on these endpoints between the INPULSIS trials: there was a significant difference in favor of nintedanib on time to first acute exacerbation and change from baseline in SGRQ total score in INPULSIS-2, but no difference between groups in INPULSIS-1.
In a prespecified analysis of pooled data from both trials, no significant difference was seen between nintedanib and placebo on time to first acute exacerbation [hazard ratio (HR) 0.64; 95% CI 0.39–1.05 in favor of nintedanib; p = 0.08] or on change from baseline in SGRQ total score (difference of −1.43 points; 95% CI −3.09, 0.23 in favor of nintedanib; p = 0.09) [Richeldi et al. 2014b]. In a pooled analysis of data from the TOMORROW and INPULSIS trials, there was a non-significant reduction in all-cause mortality in patients treated with nintedanib 150 mg twice daily compared with placebo over 52 weeks (HR
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ME Mazzei, L Richeldi et al. Table 1. Adverse events in the INPULSIS trials. N (%)
Nintedanib (n = 638)
Placebo (n = 423)
Any adverse event(s) Most frequent adverse events* Diarrhea Nausea Nasopharyngitis Cough Progression of IPF$ Bronchitis Dyspnea Decreased appetite Vomiting Serious adverse event Fatal adverse events Adverse events leading to treatment discontinuation‡ Progression of IPF$ Diarrhea Nausea Decreased appetite Pneumonia Weight decreased Abdominal pain Vomiting Asthenia Increased alanine aminotransferase
609 (95.5)
379 (89.6) 78 (18.4) 28 (6.6) 68 (16.1) 57 (13.5) 61 (14.4) 45 (10.6) 48 (11.3) 24 (5.7) 11 (2.6) 127 (30.0) 31 (7.3) 55 (13.0) 21 (5.0) 1 (0.2) 0 (0.0) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)
398 (62.4) 156 (24.5) 87 (13.6) 85 (13.3) 64 (10.0) 67 (10.5) 49 (7.7) 68 (10.7) 74 (11.6) 194 (30.4) 37 (5.8) 123 (19.3) 13 (2.0) 28 (4.4) 13 (2.0) 9 (1.4) 6 (0.9) 6 (0.9) 5 (0.8) 5 (0.8) 4 (0.6) 4 (0.6)
Based on adverse events with onset after first dose and up to 28 days after the last dose of trial medication. *Adverse events reported by more than10% of patients in either treatment group based on pooled data. $Corresponds to the Medical Dictionary for Regulatory Activities (MedDRA) term ‘IPF’, which included disease worsening and IPF exacerbations. ‡Adverse events leading to treatment discontinuation in more than 0.5% of patients in either treatment group based on pooled data. IPF, idiopathic pulmonary fibrosis.
0.70; 95% CI 0.46–1.08; p = 0.0954) [Richeldi et al. 2014c]. Similar findings were seen for respiratory mortality (HR 0.62; 95% CI 0.37–1.06; p = 0.0779) based on causes of death adjudicated by a committee blinded to treatment assignment [Boehringer Ingelheim Pharmaceuticals, Inc., 2014].
moderate in intensity and only 4.4% of patients treated with nintedanib discontinued trial medication prematurely due to diarrhea [Richeldi et al. 2014b].
Nintedanib had an acceptable safety profile and a manageable tolerability profile. In the INPULSIS trials, the proportion of patients who had at least one serious adverse event was similar in the nintedanib (30.4%) and placebo (30.0%) groups. The most frequently reported adverse event in the nintedanib group was diarrhea, which was reported in 62.4% of patients compared with 18.4% of patients in the placebo group (Table 1). Almost all diarrhea adverse events were mild or
Which patients should be treated with nintedanib? Nintedanib is approved for the treatment of patients with IPF in the US [Boehringer Ingelheim Pharmaceuticals, Inc., 2014] and Europe [Boehringer Ingelheim, 2015]. A broad range of patients were recruited into the INPULSIS trials, including patients with relatively preserved FVC, patients with features of a ‘possible UIP’ pattern on HRCT and patients
Management questions
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Therapeutic Advances in Respiratory Disease 9(3) with emphysema. Subgroup analyses of pooled data from the INPULSIS trials demonstrated a consistent effect of nintedanib on slowing disease progression across subgroups of patients defined by a variety of baseline characteristics [Costabel et al. 2014; Cottin et al. 2014; Kolb et al. 2014]. No phenotype was identified in which nintedanib was more or less effective. Importantly, no data are available on the efficacy and safety of nintedanib in patients with FVC less than 50% predicted. We believe that nintedanib is an appropriate first-line therapy for patients with IPF across a wide spectrum of disease severity. We also believe it is appropriate for patients who have failed to respond to therapy with pirfenidone. When to choose nintedanib or pirfenidone as initial therapy for patients with IPF is an open question. Even patients with limited physiological impairment appear to benefit from treatment with nintedanib. The benefits and risks of nintedanib in patients with severe impairment of FVC are not known, and its use in this population should be carefully considered. No patients with moderate or severe liver impairment (alanine aminotransferase or aspartate aminotransferase or bilirubin greater than 1.5 x upper limit of normal) were enrolled in the INPULSIS trials and nintedanib is not recommended for use in such patients. Inhibition of VEGFR by nintedanib may potentially increase the risk of bleeding or gastrointestinal perforation. Patients at known risk for bleeding or gastrointestinal perforation should be treated with nintedanib only if the anticipated benefit outweighs the potential risk. Overall, cardiac disorder adverse events were reported in similar proportions of patients treated with nintedanib and placebo in the INPULSIS trials. However, arterial thromboembolic events have been reported in patients taking nintedanib and caution should be exercised when treating patients at higher cardiovascular risk, including known coronary artery disease. When should a patient be started on nintedanib? Treatment options should be discussed with a patient on diagnosis of IPF to enable them to make an informed decision about their treatment. Some patients with limited symptoms may not wish to start pharmacological therapy immediately due to concerns over the side effects of treatment, but this should be decided with the knowledge that the earlier patients with IPF
receive treatment, the more lung function remains to be preserved. How should side effects of nintedanib be managed? Dose reduction to 100 mg twice daily or treatment interruption are recommended for the management of adverse events related to nintedanib. Following treatment interruption, treatment may be reinstituted at a dose of 150 mg twice daily, or at a dose of 100 mg twice daily, which may later be increased to 150 mg twice daily. In the event of gastrointestinal adverse events such as diarrhea, nausea or vomiting, patients should maintain hydration and take antidiarrheal therapy (e.g. loperamide) or antiemetics as soon as symptoms occur. If severe diarrhea, nausea or vomiting persists despite symptomatic treatment, nintedanib should be discontinued. In the INPULSIS trials, diarrhea adverse events resolved without the need for dose reduction or treatment interruption in 78.6% of nintedanib-treated patients who reported diarrhea, and only 4.4% of patients treated with nintedanib permanently discontinued treatment due to diarrhea. Liver enzymes should be monitored before treatment with nintedanib, every month for 3 months and then every 3 months during treatment [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Dose reduction or treatment interruption may be required for the management of liver enzyme elevations. Should nintedanib be used in combination with other treatments? There will be tremendous pressure to add a second therapy in patients who are continuing to progress on a single agent and combination therapy may be a future option for treatment of IPF [Wuyts et al. 2014]. Patients receiving pirfenidone were excluded from the INPULSIS trials. There are no data to support the use of a combination of nintedanib and pirfenidone in patients with IPF and there is real potential for increased adverse events with combination therapy. A recently published pharmacokinetic study showed a trend toward lower exposure of nintedanib when nintedanib was added to pre-existing pirfenidone therapy in Japanese patients with IPF. However, due to the short study duration and the low number of patients, no definite conclusions about
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ME Mazzei, L Richeldi et al. safety could be drawn [Ogura et al. 2014]. We strongly believe that a combination of nintedanib and pirfenidone should not be recommended until adequate data, in particular safety data, are available to support it. Nintedanib is a substrate of P-glycoprotein and, to a minor extent, the cytochrome P450 3A4 (CYP3A4) enzyme. Patients receiving concomitant treatment with nintedanib and inhibitors of P-glycoprotein or CYP3A4 (e.g. ketoconazole, erythromycin, verapamil) should be monitored closely for adverse events. Concomitant use of nintedanib with P-glycoprotein or CYP3A4 inducers (e.g. rifampin, carbamazepine, phenytoin, St John’s wort) should be avoided [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Nonpharmacological therapies, such as supplemental oxygen, pulmonary rehabilitation, and referral to patient support groups should be offered to patients with IPF to ensure a comprehensive approach to patient care [Lee et al. 2011]. How long should treatment with nintedanib be continued? The effect of nintedanib in an individual patient with IPF cannot be known for certain, as the course of the disease is variable and it is impossible to know how the disease would have progressed if the patient had not been treated. Physicians need to take care to set reasonable expectations in their patients so that patients do not expect treatment to halt or reverse the course of their disease. There is no evidence to suggest a point after which nintedanib would no longer be efficacious. However, in situations when a second agent is available, a change in therapy should be considered for patients who have clinically significant disease progression on nintedanib. The long-term effects of treatment with nintedanib are being investigated in an open-label extension of the INPULSIS trials (INPULSIS-ON) [ClinicalTrials.gov identifier: NCT01619085]. Conclusion Nintedanib is the first tyrosine kinase inhibitor to be approved for the treatment of IPF in the US, having received approval from the FDA in October 2014. Nintedanib has also been approved for the treatment of IPF in Europe. In patients with IPF and mild or moderate impairment of FVC (⩾50% predicted), nintedanib significantly reduces decline in FVC, consistent with a slowing of disease
progression. No patient subgroups have been identified that have a greater or lesser response to nintedanib. The most common side effects associated with nintedanib are gastrointestinal events, particularly diarrhea. Management of adverse events through treatment interruption, dose reduction, and symptomatic treatment of gastrointestinal side effects enables most patients to stay on nintedanib. Combination therapy with nintedanib and pirfenidone should not be recommended until the efficacy and safety of combination therapy have been determined. Acknowledgements Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Julie Fleming and Wendy Morris of Fleishman-Hillard Group Ltd, London, UK during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development, and have approved the final version. Conflict of interest statement Mariano Mazzei has no conflict of interest. Luca Richeldi has received grants for research and fees for lectures, advisory boards meetings, and steering committee meetings from Biogen Idec, Boehringer Ingelheim, Cipla, ImmuneWorks, InterMune, MedImmune, Roche, SanofiAventis, Shionogi and Takeda. Harold Collard has received consultancy fees (paid to his institution) from AstraZeneca/ImmuneWorks, Bayer, Biogen, FibroGen, Five Prime, Genentech/ InterMune, Genoa, Gilead, GlaxoSmithKline, Mesoblast, Moerae Matrix, Pfizer, Promedior, Prometic, and Stromedix; grants from Boehringer Ingelheim and the NIH/NHLBI; royalties from UpToDate; and payments for the development of educational presentations (paid to his institution) from Medscape and The France Foundation. Funding The TOMORROW and INPULSIS trials were funded by Boehringer Ingelheim.
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research-article2015
TAR0010.1177/1753465815579365Therapeutic Advances in Respiratory DiseaseME Mazzei, L Richeldi
Therapeutic Advances in Respiratory Disease
Review
Nintedanib in the treatment of idiopathic pulmonary fibrosis Mariano E. Mazzei, Luca Richeldi and Harold R. Collard
Ther Adv Respir Dis 2015, Vol. 9(3) 121–129 DOI: 10.1177/ 1753465815579365 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease that occurs in older adults. The clinical course of IPF is variable and hard to predict in an individual patient. Nintedanib is a tyrosine kinase inhibitor that has recently been approved in the US and European Union for the treatment of IPF. Preclinical studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation and the secretion of extracellular matrix. The safety and efficacy of nintedanib have been investigated in the phase II TOMORROW trial and in two replicate 52-week randomized, placebo-controlled phase III trials known as the INPULSIS trials. These trials demonstrated that nintedanib slowed disease progression by reducing the annual rate of decline in forced vital capacity, with a manageable side-effect profile. In this review, we summarize key data supporting nintedanib as a treatment for patients with IPF and address key questions regarding the use of nintedanib in the clinical setting. Keywords: interstitial lung disease, treatment outcome, disease progression, forced vital capacity, safety, tyrosine kinase Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of older adults characterized by a specific histopathologic pattern known as usual interstitial pneumonia (UIP) [Raghu et al. 2011]. The diagnosis of IPF can be made in the absence of lung biopsy with a UIP pattern on lung high-resolution computed tomography (HRCT), or with the careful integration of HRCT and surgical lung biopsy findings [Raghu et al. 2011]. As such, multidisciplinary discussion among pulmonologists, radiologists and pathologists is essential to establishing an accurate diagnosis of IPF. Estimates of the incidence and prevalence of IPF vary widely according to the methodology used and the population studied, with estimates of incidence ranging from 0.6 to 17.4 per 100,000 person years and estimates of prevalence ranging from 0.7 to 63.0 per 100,000 [Ley and Collard, 2013]. In a recent study assessing the incidence and prevalence of IPF in the US Medicare population (age 65 years or over) between 2001 and 2011, the incidence was 93.7 cases per 100,000 person years. In this cohort, the cumulative prevalence increased from 202.2 cases per 100,000 in 2001 to 494.5 cases per 100,000 in 2011 [Raghu et al. 2014].
IPF is ultimately a fatal disease, with a median survival time of 2–3 years after diagnosis [Raghu et al. 2011; Natsuizaka et al. 2014]. The natural course of IPF is highly variable, however, with some patients experiencing a rapid decline, others progressing relatively slowly, and some patients having periods of relative stability punctuated by acute deteriorations in respiratory function [Ley et al. 2011]. Where these acute deteriorations have no identifiable cause, they are known as acute exacerbations [Collard et al. 2007]. Acute deteriorations occur in up to a third of patients with IPF per year and are associated with substantial morbidity and mortality [Ryerson and Collard, 2014; Song et al. 2011; Natsuizaka et al. 2014; Kishaba et al. 2014].
Correspondence to: Harold R. Collard, MD University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA [email protected] Mariano E. Mazzei, MD University of Buenos Aires, Buenos Aires, Argentina Luca Richeldi, MD, PhD National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, UK
While the pathogenic mechanisms involved in IPF are not well understood, evidence suggests that lung fibrosis occurs as a result of alveolar epithelial cell senescence/dysfunction and myofibroblast activation, culminating in excessive synthesis and deposition of collagen and remodeling of the extracellular matrix [Fernandez and Eickelberg, 2012; Wolters et al. 2014]. This is almost certainly related to aging and the attendant changes in cellular function. Genetics also play a central role, with a number of genetic variants strongly associated with the
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Figure 1. Nintedanib blocks the autophosphorylation of VEGF, PDGF and FGF tyrosine kinase receptors, thereby blocking the downstream signaling cascades mediated by these receptors. This results in reduced proliferation, migration and survival of fibroblasts and potentially also of cells involved in angiogenesis in the lung. FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. From Ahluwalia et al. [2014]. Adapted with permission of the American Thoracic Society. Copyright© 2015 American Thoracic Society.
risk of IPF (e.g. mutations in the telomerase gene family and polymorphisms in MUC5B) [Fingerlin et al. 2013; Garcia, 2011]. In October 2014, the US Food and Drug Administration (FDA) approved the first drugs for the treatment of IPF in the US: nintedanib (OFEV) [Boehringer Ingelheim Pharmaceuticals, Inc., 2014] and pirfenidone (ESBRIET) [InterMune, Inc., 2014]. Pirfenidone had already been licensed for the treatment of IPF in Europe, Japan and several other countries, and nintedanib was approved as a treatment for IPF in Europe in January 2015 [Boehringer Ingelheim, 2015]. This manuscript reviews the data supporting nintedanib as a treatment for patients with IPF and addresses several key questions regarding the use of nintedanib in the clinical setting. Nintedanib Nintedanib, an indolinone derivative, is an intracellular inhibitor of tyrosine kinases, including fibroblast growth factor receptor 1, 2 and 3,
platelet-derived growth factor receptor α and β, and vascular endothelial growth factor receptor 1, 2 and 3 [Hilberg et al. 2008; Wollin et al. 2014]. Nintedanib competitively binds to the adenosine triphosphate binding pocket of these receptors, blocking substrate binding and so inhibiting a number of downstream signaling cascades [Wollin et al. 2014, 2015] (Figure 1). By so doing, nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation and the secretion of extracellular matrix [Hostettler et al. 2014; Wollin et al. 2015]. In mouse models of bleomycin- and silica-induced lung fibrosis, nintedanib demonstrated antifibrotic and anti-inflammatory activity by reducing the number of lymphocytes and neutrophils in bronchoalveolar lavage fluid, reducing levels of inflammatory cytokines in lung tissue, and diminishing lung inflammation, granuloma formation and fibrosis [Wollin et al. 2014]. In humans, orally administered nintedanib is rapidly absorbed and reaches maximum plasma
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ME Mazzei, L Richeldi et al.
Figure 2. Mean (standard error) adjusted annual rate of change in forced vital capacity (FVC) analyzed using a random coefficient mixed model for repeated measures. From Richeldi et al. [2011]. Copyright© 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
concentrations after 2–4 h [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Nintedanib exposure increases with increasing doses and steadystate plasma concentrations are achieved within 7 days [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. The major metabolic pathway for nintedanib is hydrolytic cleavage by esterase, with more than 90% of nintedanib and its metabolites excreted via feces [Stopfer et al. 2011]. Clinical trials of nintedanib in IPF The efficacy and safety of nintedanib in patients with IPF have been investigated in the phase II, randomized, dose-finding TOMORROW trial [Richeldi et al. 2011] and the two replicate randomized, placebo-controlled phase III INPULSIS trials [Richeldi et al. 2014a, 2014b]. In the TOMORROW trial, 432 patients with IPF were treated with one of four nintedanib doses (50 mg once daily, 50 mg twice daily, 100 mg twice daily, 150 mg twice daily), or placebo for 52 weeks. The results suggested that, compared with placebo, treatment with nintedanib 150 mg twice daily was associated with a reduced annual decline in forced vital capacity (FVC) (ml/year) (Figure 2), fewer acute exacerbations, and preservation of healthrelated quality of life assessed using the St George’s Respiratory Questionnaire (SGRQ) [Richeldi et al. 2011]. In the INPULSIS trials, 1066 patients in 24 countries were randomized 3:2 to receive nintedanib 150 mg twice daily or placebo for 52 weeks followed by a 4-week follow-up period. Treatment
interruption and dose reduction from 150 mg twice daily to 100 mg twice daily were allowed for the management of adverse events. To be eligible to enter the trials, patients had to be at least 40 years old and have an FVC of 50% of predicted value or higher, a diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% of predicted value and an forced expiratory volume in 1 s/FVC ratio of at least 0.7. The diagnosis of IPF required HRCT images showing honeycombing or a combination of reticular abnormality and traction bronchiectasis, without nodules or consolidation or features suggestive of alternative causes. Surgical lung biopsies, if available, were centrally reviewed and used to confirm eligibility to enter the trials [Richeldi et al. 2014a, 2014b]. Based on these inclusion criteria, a broader range of patient types were enrolled in the INPULSIS trials than those who would meet the strict criteria for diagnosis of IPF according to the 2011 guidelines. This was reflected in the high proportion of screened patients who met eligibility criteria. The primary endpoint in both INPULSIS trials was the annual rate of decline in FVC (ml/year). In both trials, nintedanib consistently slowed disease progression by significantly reducing the annual rate of decline in FVC compared with placebo [Richeldi et al. 2014b] (Figure 3). The adjusted annual rate of decline in FVC was −114.7 ml/year with nintedanib versus –239.9 ml/ year with placebo [a difference of 125.3 ml/year; 95% confidence interval (CI) 77.7–172.8; p < 0.001] in INPULSIS-1 and −113.6 ml/year with nintedanib versus –207.3 ml/year with placebo
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Figure 3. Between-group differences (FVC value in the nintedanib group versus FVC value in the placebo group) are shown for the adjusted annual rate of decline in FVC. Bars indicate standard error. CI, confidence interval; FVC, forced vital capacity. From Richeldi et al. [2014b]. Copyright© 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
(a difference of 93.7 ml/year; 95% CI 44.8–142.7; p < 0.001) in INPULSIS-2. The key secondary endpoints in the INPULSIS trials were time to first investigator-reported acute exacerbation and change from baseline in SGRQ total score. Discordant results were observed on these endpoints between the INPULSIS trials: there was a significant difference in favor of nintedanib on time to first acute exacerbation and change from baseline in SGRQ total score in INPULSIS-2, but no difference between groups in INPULSIS-1.
In a prespecified analysis of pooled data from both trials, no significant difference was seen between nintedanib and placebo on time to first acute exacerbation [hazard ratio (HR) 0.64; 95% CI 0.39–1.05 in favor of nintedanib; p = 0.08] or on change from baseline in SGRQ total score (difference of −1.43 points; 95% CI −3.09, 0.23 in favor of nintedanib; p = 0.09) [Richeldi et al. 2014b]. In a pooled analysis of data from the TOMORROW and INPULSIS trials, there was a non-significant reduction in all-cause mortality in patients treated with nintedanib 150 mg twice daily compared with placebo over 52 weeks (HR
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ME Mazzei, L Richeldi et al. Table 1. Adverse events in the INPULSIS trials. N (%)
Nintedanib (n = 638)
Placebo (n = 423)
Any adverse event(s) Most frequent adverse events* Diarrhea Nausea Nasopharyngitis Cough Progression of IPF$ Bronchitis Dyspnea Decreased appetite Vomiting Serious adverse event Fatal adverse events Adverse events leading to treatment discontinuation‡ Progression of IPF$ Diarrhea Nausea Decreased appetite Pneumonia Weight decreased Abdominal pain Vomiting Asthenia Increased alanine aminotransferase
609 (95.5)
379 (89.6) 78 (18.4) 28 (6.6) 68 (16.1) 57 (13.5) 61 (14.4) 45 (10.6) 48 (11.3) 24 (5.7) 11 (2.6) 127 (30.0) 31 (7.3) 55 (13.0) 21 (5.0) 1 (0.2) 0 (0.0) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)
398 (62.4) 156 (24.5) 87 (13.6) 85 (13.3) 64 (10.0) 67 (10.5) 49 (7.7) 68 (10.7) 74 (11.6) 194 (30.4) 37 (5.8) 123 (19.3) 13 (2.0) 28 (4.4) 13 (2.0) 9 (1.4) 6 (0.9) 6 (0.9) 5 (0.8) 5 (0.8) 4 (0.6) 4 (0.6)
Based on adverse events with onset after first dose and up to 28 days after the last dose of trial medication. *Adverse events reported by more than10% of patients in either treatment group based on pooled data. $Corresponds to the Medical Dictionary for Regulatory Activities (MedDRA) term ‘IPF’, which included disease worsening and IPF exacerbations. ‡Adverse events leading to treatment discontinuation in more than 0.5% of patients in either treatment group based on pooled data. IPF, idiopathic pulmonary fibrosis.
0.70; 95% CI 0.46–1.08; p = 0.0954) [Richeldi et al. 2014c]. Similar findings were seen for respiratory mortality (HR 0.62; 95% CI 0.37–1.06; p = 0.0779) based on causes of death adjudicated by a committee blinded to treatment assignment [Boehringer Ingelheim Pharmaceuticals, Inc., 2014].
moderate in intensity and only 4.4% of patients treated with nintedanib discontinued trial medication prematurely due to diarrhea [Richeldi et al. 2014b].
Nintedanib had an acceptable safety profile and a manageable tolerability profile. In the INPULSIS trials, the proportion of patients who had at least one serious adverse event was similar in the nintedanib (30.4%) and placebo (30.0%) groups. The most frequently reported adverse event in the nintedanib group was diarrhea, which was reported in 62.4% of patients compared with 18.4% of patients in the placebo group (Table 1). Almost all diarrhea adverse events were mild or
Which patients should be treated with nintedanib? Nintedanib is approved for the treatment of patients with IPF in the US [Boehringer Ingelheim Pharmaceuticals, Inc., 2014] and Europe [Boehringer Ingelheim, 2015]. A broad range of patients were recruited into the INPULSIS trials, including patients with relatively preserved FVC, patients with features of a ‘possible UIP’ pattern on HRCT and patients
Management questions
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Therapeutic Advances in Respiratory Disease 9(3) with emphysema. Subgroup analyses of pooled data from the INPULSIS trials demonstrated a consistent effect of nintedanib on slowing disease progression across subgroups of patients defined by a variety of baseline characteristics [Costabel et al. 2014; Cottin et al. 2014; Kolb et al. 2014]. No phenotype was identified in which nintedanib was more or less effective. Importantly, no data are available on the efficacy and safety of nintedanib in patients with FVC less than 50% predicted. We believe that nintedanib is an appropriate first-line therapy for patients with IPF across a wide spectrum of disease severity. We also believe it is appropriate for patients who have failed to respond to therapy with pirfenidone. When to choose nintedanib or pirfenidone as initial therapy for patients with IPF is an open question. Even patients with limited physiological impairment appear to benefit from treatment with nintedanib. The benefits and risks of nintedanib in patients with severe impairment of FVC are not known, and its use in this population should be carefully considered. No patients with moderate or severe liver impairment (alanine aminotransferase or aspartate aminotransferase or bilirubin greater than 1.5 x upper limit of normal) were enrolled in the INPULSIS trials and nintedanib is not recommended for use in such patients. Inhibition of VEGFR by nintedanib may potentially increase the risk of bleeding or gastrointestinal perforation. Patients at known risk for bleeding or gastrointestinal perforation should be treated with nintedanib only if the anticipated benefit outweighs the potential risk. Overall, cardiac disorder adverse events were reported in similar proportions of patients treated with nintedanib and placebo in the INPULSIS trials. However, arterial thromboembolic events have been reported in patients taking nintedanib and caution should be exercised when treating patients at higher cardiovascular risk, including known coronary artery disease. When should a patient be started on nintedanib? Treatment options should be discussed with a patient on diagnosis of IPF to enable them to make an informed decision about their treatment. Some patients with limited symptoms may not wish to start pharmacological therapy immediately due to concerns over the side effects of treatment, but this should be decided with the knowledge that the earlier patients with IPF
receive treatment, the more lung function remains to be preserved. How should side effects of nintedanib be managed? Dose reduction to 100 mg twice daily or treatment interruption are recommended for the management of adverse events related to nintedanib. Following treatment interruption, treatment may be reinstituted at a dose of 150 mg twice daily, or at a dose of 100 mg twice daily, which may later be increased to 150 mg twice daily. In the event of gastrointestinal adverse events such as diarrhea, nausea or vomiting, patients should maintain hydration and take antidiarrheal therapy (e.g. loperamide) or antiemetics as soon as symptoms occur. If severe diarrhea, nausea or vomiting persists despite symptomatic treatment, nintedanib should be discontinued. In the INPULSIS trials, diarrhea adverse events resolved without the need for dose reduction or treatment interruption in 78.6% of nintedanib-treated patients who reported diarrhea, and only 4.4% of patients treated with nintedanib permanently discontinued treatment due to diarrhea. Liver enzymes should be monitored before treatment with nintedanib, every month for 3 months and then every 3 months during treatment [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Dose reduction or treatment interruption may be required for the management of liver enzyme elevations. Should nintedanib be used in combination with other treatments? There will be tremendous pressure to add a second therapy in patients who are continuing to progress on a single agent and combination therapy may be a future option for treatment of IPF [Wuyts et al. 2014]. Patients receiving pirfenidone were excluded from the INPULSIS trials. There are no data to support the use of a combination of nintedanib and pirfenidone in patients with IPF and there is real potential for increased adverse events with combination therapy. A recently published pharmacokinetic study showed a trend toward lower exposure of nintedanib when nintedanib was added to pre-existing pirfenidone therapy in Japanese patients with IPF. However, due to the short study duration and the low number of patients, no definite conclusions about
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ME Mazzei, L Richeldi et al. safety could be drawn [Ogura et al. 2014]. We strongly believe that a combination of nintedanib and pirfenidone should not be recommended until adequate data, in particular safety data, are available to support it. Nintedanib is a substrate of P-glycoprotein and, to a minor extent, the cytochrome P450 3A4 (CYP3A4) enzyme. Patients receiving concomitant treatment with nintedanib and inhibitors of P-glycoprotein or CYP3A4 (e.g. ketoconazole, erythromycin, verapamil) should be monitored closely for adverse events. Concomitant use of nintedanib with P-glycoprotein or CYP3A4 inducers (e.g. rifampin, carbamazepine, phenytoin, St John’s wort) should be avoided [Boehringer Ingelheim Pharmaceuticals, Inc., 2014]. Nonpharmacological therapies, such as supplemental oxygen, pulmonary rehabilitation, and referral to patient support groups should be offered to patients with IPF to ensure a comprehensive approach to patient care [Lee et al. 2011]. How long should treatment with nintedanib be continued? The effect of nintedanib in an individual patient with IPF cannot be known for certain, as the course of the disease is variable and it is impossible to know how the disease would have progressed if the patient had not been treated. Physicians need to take care to set reasonable expectations in their patients so that patients do not expect treatment to halt or reverse the course of their disease. There is no evidence to suggest a point after which nintedanib would no longer be efficacious. However, in situations when a second agent is available, a change in therapy should be considered for patients who have clinically significant disease progression on nintedanib. The long-term effects of treatment with nintedanib are being investigated in an open-label extension of the INPULSIS trials (INPULSIS-ON) [ClinicalTrials.gov identifier: NCT01619085]. Conclusion Nintedanib is the first tyrosine kinase inhibitor to be approved for the treatment of IPF in the US, having received approval from the FDA in October 2014. Nintedanib has also been approved for the treatment of IPF in Europe. In patients with IPF and mild or moderate impairment of FVC (⩾50% predicted), nintedanib significantly reduces decline in FVC, consistent with a slowing of disease
progression. No patient subgroups have been identified that have a greater or lesser response to nintedanib. The most common side effects associated with nintedanib are gastrointestinal events, particularly diarrhea. Management of adverse events through treatment interruption, dose reduction, and symptomatic treatment of gastrointestinal side effects enables most patients to stay on nintedanib. Combination therapy with nintedanib and pirfenidone should not be recommended until the efficacy and safety of combination therapy have been determined. Acknowledgements Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Julie Fleming and Wendy Morris of Fleishman-Hillard Group Ltd, London, UK during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of development, and have approved the final version. Conflict of interest statement Mariano Mazzei has no conflict of interest. Luca Richeldi has received grants for research and fees for lectures, advisory boards meetings, and steering committee meetings from Biogen Idec, Boehringer Ingelheim, Cipla, ImmuneWorks, InterMune, MedImmune, Roche, SanofiAventis, Shionogi and Takeda. Harold Collard has received consultancy fees (paid to his institution) from AstraZeneca/ImmuneWorks, Bayer, Biogen, FibroGen, Five Prime, Genentech/ InterMune, Genoa, Gilead, GlaxoSmithKline, Mesoblast, Moerae Matrix, Pfizer, Promedior, Prometic, and Stromedix; grants from Boehringer Ingelheim and the NIH/NHLBI; royalties from UpToDate; and payments for the development of educational presentations (paid to his institution) from Medscape and The France Foundation. Funding The TOMORROW and INPULSIS trials were funded by Boehringer Ingelheim.
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