Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216, Ingelheim am Rhein, Germany
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01XE31
Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and VEGFR 1-3. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling. In addition nintedanib inhibits Flt-3 (Fms-like tyrosine-protein kinase), Lck (lymphocyte-specific tyrosine-protein kinase), Lyn (tyrosine-protein kinase lyn) and Src (proto-oncogene tyrosine-protein kinase src) kinases.
Nintedanib inhibits the activation of FGFR and PDGFR signalling cascades which are critically involved in proliferation, migration and differentiation of lung fibroblasts/myofibroblasts, the hallmark cells in the pathology of IPF. The potential impact of VEGFR inhibition by nintedanib and the anti-angiogenic activity of nintedanib on IPF pathology are currently not fully elucidated. In preclinical disease models of lung fibrosis nintedanib exerts potent anti-fibrotic and anti-inflammatory activity. Nintedanib inhibits proliferation, migration and fibroblast to myofibroblast transformation of human lung fibroblasts from patients with IPF.
The clinical efficacy of nintedanib has been studied in patients with IPF in two phase III, randomised, double-blind, placebo-controlled studies with identical design (INPULSIS-1 (1199.32) and INPULSIS-2 (1199.34)). Patients with FVC baseline <50% predicted or carbon monoxide diffusing capacity (DLCO, corrected for haemoglobin) <30% predicted at baseline were excluded from the trials. Patients were randomized in a 3:2 ratio to treatment with Ofev 150 mg or placebo twice daily for 52 weeks.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). The key secondary endpoints were change from baseline in Saint George’s Respiratory Questionnaire (SGRQ) total score at 52 weeks and time to first acute IPF exacerbation.
The annual rate of decline of FVC (in mL) was significantly reduced in patients receiving nintedanib compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 2 for individual and pooled study results.
Table 2. Annual rate of decline in FVC (mL) in trials INPULSIS-1, INPULSIS-2 and their pooled data – treated set:
| INPULSIS-1 | INPULSIS-2 | INPULSIS-1 and INPULSIS-2 Pooled | ||||
|---|---|---|---|---|---|---|
| Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | |
| Number of analysed patients | 204 | 309 | 219 | 329 | 423 | 638 |
| Rate1 (SE) of decline over 52 weeks | −239,9 (18,71) | −114,7 (15,33) | −207,3 (19,31) | −113,6 (15,73) | −223,5 (13,45) | −113,6 (10,98) |
| Comparison vs placebo | ||||||
| Difference1 | 125,3 | 93,7 | 109,9 | |||
| 95% CI | (77,7, 172,8) | (44,8, 142,7) | (75,9, 144,0) | |||
| p-value | <0,0001 | 0,0002 | <0,0001 | |||
1 Estimated based on a random coefficient regression model.
CI: confidence interval
The robustness of the effect of nintedanib in reducing the annual rate of decline in FVC was confirmed in all pre-specified sensitivity analyses. In patients with missing data, the primary analysis assumes that the decline in FVC after the last observed value would be similar to the decline in other patients in the same treatment group. In a sensitivity analysis which assumed that in patients with missing data at week 52 the FVC decline after the last observed value would be the same as in all placebo patients, the adjusted difference in the annual rate of decline between nintedanib and placebo was 113.9 mL/year (95% CI 69.2, 158.5) in INPULSIS-1 and 83.3 mL/year (95% CI 37.6, 129.0) in INPULSIS-2.
In addition, similar effects were observed on other lung function endpoints e.g. change from baseline in FVC at week 52 and FVC responder analyses providing further substantiation of the effects of nintedanib on slowing disease progression. See Figure 1 for the evolution of change from baseline over time in both treatment groups, based on the pooled analysis of studies INPULSIS-1 and INPULSIS-2.
Figure 1. Mean (SEM) observed FVC change from baseline (mL) over time, studies INPULSIS-1 and INPULSIS-2 pooled:
In both INPULSIS trials, the proportion of FVC responders, defined as patients with an absolute decline in FVC % predicted no greater than 5% (a threshold indicative of the increasing risk of mortality in IPF), was significantly higher in the nintedanib group as compared to placebo. Similar results were observed in analyses using a conservative threshold of 10%. See Table 3 for individual and pooled study results.
Table 3. Proportion of FVC responders at 52 weeks in trials INPULSIS-1, INPULSIS-2 and their pooled data – treated set:
| INPULSIS-1 | INPULSIS-2 | INPULSIS-1 and INPULSIS-2 pooled | ||||
|---|---|---|---|---|---|---|
| Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | |
| Number of analysed patients | 204 | 309 | 219 | 329 | 423 | 638 |
| 5% threshold | ||||||
| Number (%) of FVC responders1 | 78 (38,2) | 163 (52,8) | 86 (39,3) | 175 (53,2) | 164 (38,8) | 338 (53,0) |
| Comparison vs placebo | ||||||
| Odds ratio | 1,85 | 1,79 | 1,84 | |||
| 95% CI | (1,28, 2,66) | (1,26, 2,55) | (1,43, 2,36) | |||
| p-value2 | 0,0010 | 0,0011 | <0,0001 | |||
| 10% threshold | ||||||
| Number (%) of FVC responders1 | 116 (56,9) | 218 (70,6) | 140 (63,9) | 229 (69,6) | 256 (60,5) | 447 (70,1) |
| Comparison vs placebo | ||||||
| Odds ratio | 1,91 | 1,29 | 1,58 | |||
| 95% CI | (1,32, 2,79) | (0,89, 1,86) | (1,21, 2,05) | |||
| p-value2 | 0,0007 | 0,1833 | 0,0007 | |||
1 Responder patients are those with no absolute decline greater than 5% or greater than 10% in FVC % predicted, depending on the threshold and with an FVC evaluation at 52 weeks.
2 Based on a logistic regression.
In both INPULSIS trials, the risk of progression was statistically significantly reduced for patients treated with nintedanib compared with placebo. In the pooled analysis, the HR was 0.60 indicating a 40% reduction in the risk of progression for patients treated with nintedanib compared with placebo.
Table 4. Frequency of patients with ≥10% absolute decline of FVC % predicted or death over 52 weeks and time to progression in trials INPULSIS-1, INPULSIS-2, and their pooled data – treated set:
| INPULSIS-1 | INPULSIS-2 | INPULSIS-1 and INPULSIS-2 pooled | ||||
|---|---|---|---|---|---|---|
| Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | |
| Number at risk | 204 | 309 | 219 | 329 | 423 | 638 |
| Patients with events, N (%) | 83 (40,7) | 75 (24,3) | 92 (42,0) | 98 (29,8) | 175 (41,4) | 173 (27,1) |
| Comparison vs placebo1 | ||||||
| p-value2 | 0,0001 | 0,0054 | <0,0001 | |||
| Hazard ratio3 | 0,53 | 0,67 | 0,60 | |||
| 95% CI | (0,39, 0,72) | (0,51, 0,89) | (0,49, 0,74) | |||
1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.
SGRQ total score measuring health related quality of life (HRQoL) was analysed at 52 weeks. In INPULSIS-2, patients receiving placebo had a larger increase from baseline SGRQ total score as compared to patients receiving nintedanib 150 mg twice daily. The deterioration of HRQoL was smaller in the nintedanib group; the difference between the treatment groups was statistically significant (-2.69; 95% CI: -4.95, -0.43; p=0.0197).
In INPULSIS-1, the increase from baseline in SGRQ total score at week 52 was comparable between nintedanib and placebo (difference between treatment groups: -0.05; 95% CI: -2.50, 2.40; p=0.9657). In the pooled analysis of the INPULSIS trials, the estimated mean change from baseline to week 52 in SGRQ total score was smaller in the nintedanib group (3.53) than in the placebo group (4.96), with a difference between the treatment groups of -1.43 (95% CI: -3.09, 0.23; p=0.0923). Overall, the effect of nintedanib on health-related quality of life as measured by the SGRQ total score is modest, indicating less worsening compared to placebo.
In the INPULSIS-2 trial, the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving nintedanib compared to placebo, in the INPULSIS-1 trial there was no difference between the treatment groups. In the pooled analysis of the INPULSIS trials, a numerically lower risk of first acute exacerbation was observed in patients receiving nintedanib compared to placebo. See Table 5 for individual and pooled study results.
Table 5. Frequency of patients with acute IPF exacerbations over 52 weeks and time to first exacerbation analysis based on investigator-reported events in trials INPULSIS-1, INPULSIS-2, and their pooled data-treated set:
| INPULSIS-1 | INPULSIS-2 | INPULSIS-1 and INPULSIS-2 pooled | ||||
|---|---|---|---|---|---|---|
| Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | |
| Number at risk | 204 | 309 | 219 | 329 | 423 | 638 |
| Patients with events, N (%) | 11 (5,4) | 19 (6,1) | 21 (9,6) | 12 (3,6) | 32 (7,6) | 31 (4,9) |
| Comparison vs placebo1 | ||||||
| p-value2 | 0,6728 | 0,0050 | 0,0823 | |||
| Hazard ratio3 | 1,15 | 0,38 | 0,64 | |||
| 95% CI | (0,54, 2,42) | (0,19, 0,77) | (0,39, 1,05) | |||
1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.
All adverse events of acute IPF exacerbation reported by the investigator were adjudicated by a blinded adjudication committee. A pre-specified sensitivity analysis of the time to first ‘confirmed’ or ‘suspected’ adjudicated acute IPF exacerbation was performed on the pooled data. The frequency of patients with at least 1 adjudicated exacerbation occurring within 52 weeks was lower in the nintedanib group (1.9% of patients) than in the placebo group (5.7% of patients). Time to event analysis of the adjudicated exacerbation events using pooled data yielded a hazard ratio (HR) of 0.32 (95% CI 0.16, 0.65; p=0.0010). This indicates that the risk of having a first acute adjudicated IPF exacerbation was statistically significantly lower in the nintedanib group than in the placebo group at any time point.
In the pre-specified pooled analysis of survival data of the INPULSIS trials, overall mortality over 52 weeks was lower in the nintedanib group (5.5%) compared with the placebo group (7.8%). The analysis of time to death resulted in a HR of 0.70 (95% CI 0.43, 1.12; p=0.1399). The results of all survival endpoints (such as on-treatment mortality and respiratory mortality) showed a consistent numerical difference in favour of nintedanib.
Table 6. All-cause mortality over 52 weeks in trials INPULSIS-1, INPULSIS-2, and their pooled data-treated set:
| INPULSIS-1 | INPULSIS-2 | INPULSIS-1 and INPULSIS-2 Pooled | ||||
|---|---|---|---|---|---|---|
| Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | Placebo | Ofev 150 mg twice daily | |
| Number at risk | 204 | 309 | 219 | 329 | 423 | 638 |
| Patients with events, N (%) | 13 (6,4) | 13 (4,2) | 0 (9,1) | 22 (6,7) | 33 (7,8) | 35 (5,5) |
| Comparison vs placebo1 | ||||||
| p-value2 | 0,2880 | 0,2995 | 0,1399 | |||
| Hazard ratio3 | 0,63 | 0,74 | 0,70 | |||
| 95% CI | (0,29, 1,36) | (0,40, 1,35) | (0,43, 1,12) | |||
1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.
Additional evidence of efficacy is provided by the randomised, double-blind, placebo-controlled, dose finding phase II trial including a nintedanib 150 mg twice daily dose group.
The primary endpoint, rate of decline in FVC over 52 weeks was lower in the nintedanib arm (-0.060 L/year, N=84) than the placebo arm (-0.190 L/year, N=83). The estimated difference between the treatment groups was 0.131 L/year (95% CI 0.027, 0.235). The difference between the treatment groups reached nominal statistical significance (p=0.0136).
The estimated mean change from baseline in SGRQ total score at 52 weeks was 5.46 for placebo, indicating worsening of the health-related quality of life and -0.66 for nintedanib, indicating stable health-related quality of life. The estimated mean difference for nintedanib compared with placebo was -6.12 (95% CI: -10.57, -1.67; p=0.0071).
The number of patients with acute IPF exacerbations over 52 weeks was lower in the nintedanib group (2.3%, N=86) compared to placebo (13.8%, N=87). The estimated hazard ratio of nintedanib versus placebo was 0.16 (95% CI 0.04, 0.71; p=0.0054).
Concomitant treatment with nintedanib and pirfenidone has been investigated in an exploratory open-label, randomised trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomised patients for 12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to week 12. Gastrointestinal adverse events were frequent and in line with the established safety profile of each component. Diarrhoea, nausea and vomiting were the most frequent adverse events reported in 20 (37.7%) versus 16 (31.4%), in 22 (41.5%) versus 6 (11.8%) and in 15 (28.3%) versus 6 (11.8%) patients, treated with pirfenidone added to nintedanib versus nintedanib alone, respectively.
Mean (SE) absolute changes from baseline in FVC at week 12 were −13.3 (17.4) mL in patients treated with nintedanib with add-on pirfenidone (n=48) compared to −40.9 (31.4) mL in patients treated with nintedanib alone (n=44).
In a dedicated study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
The European Medicines Agency has waived the obligation to submit the results of studies with Ofev in all subsets of the paediatric population in IPF (see section 4.2 for information on paediatric use).
Nintedanib reached maximum plasma concentrations approximately 2-4 h after oral administration as soft gelatine capsule under fed conditions (range 0.5-8 h). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism. Dose proportionality was shown by increase of nintedanib exposure (dose range 50-450 mg once daily and 150-300 mg twice daily). Steady state plasma concentrations were achieved within one week of dosing at the latest.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 95.3-152.5%) and absorption was delayed (median tmax fasted: 2.00 h; fed: 3.98 h).
Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (Vss: 1,050 L, 45.0% gCV) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.869.
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by uridine 5'-diphospho-glucuronosyltransferase enzymes (UGT) enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide.
Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human ADME study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage. Nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes in preclinical studies, either. Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are therefore not expected.
Total plasma clearance after intravenous infusion was high (CL: 1,390 mL/min, 28.8% gCV). Urinary excretion of the unchanged active substance within 48 h was about 0.05% of the dose (31.5% gCV) after oral and about 1.4% of the dose (24.2% gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4% of dose, 2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50%).
The pharmacokinetics (PK) of nintedanib can be considered linear with respect to time (i.e. single-dose data can be extrapolated to multiple-dose data). Accumulation upon multiple administrations was 1.04-fold for Cmax and 1.38-fold for AUCτ. Nintedanib trough concentrations remained stable for more than one year.
Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, see section 4.5. Nintedanib was shown to be not a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weak inhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be of low clinical relevance. The same applies for nintedanib being a substrate of OCT-1.
The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, and cancer patients. Based on results of a Population PK (PopPK) analysis in patients with IPF and non small cell lung cancer (NSCLC) (N=1,191) and descriptive investigations, exposure to nintedanib was not influenced by sex (body weight corrected), mild and moderate renal impairment (estimated by creatinine clearance), alcohol consumption, or P-gp genotype. PopPK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight, and race (see below). Based on the high inter-individual variability of exposure observed moderate effects are considered not clinically relevant (see section 4.4).
Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16% for a 45-year old patient and increased by 13% for a 76-year old patient relative to a patient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years; approximately 5% of the population were older than 75 years. Based on a PopPK model, an increase in nintedanib exposure of approximately 20-25% was observed in patients ≥75 years compared with patients under 65 years.
Studies in paediatric populations have not been performed.
An inverse correlation between body weight and exposure to nintedanib was observed. AUCτ,ss increased by 25% for a 50 kg patient (5 th percentile) and decreased by 19% for a 100 kg patient (95 th percentile) relative to a patient with the median weight of 71.5 kg.
The population mean exposure to nintedanib was 33-50% higher in Chinese, Taiwanese, and Indian patients and 16% higher in Japanese patients while it was 16-22% lower in Koreans compared to Caucasians (body weight corrected). Data from Black individuals were very limited but in the same range as for Caucasians.
In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib based on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% CI 1.3–3.7 for Cmax and 1.2–3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI 4.4–13.2) and 8.7-fold higher (90% CI 5.7–13.1) based on AUC, respectively, compared to healthy volunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone was investigated in patients with IPF. Group 1 received a single dose of 150 mg nintedanib before and after uptitration to 801 mg pirfenidone three times a day at steady state (N=20 patients treated). Group 2 received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling before and after at least 7 days of co-treatment with 150 mg nintedanib twice daily (N=17 patients treated). In group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57%-151%) and 96% (70%-131%) for Cmax and AUC0-tz of nintedanib, respectively (n=12 for intraindividual comparison). In group 2, the adjusted geometric mean ratios (90% CI)) were 97% (86%-110%) and 95% (86%-106%) for Cmax,ss and AUCτ,ss of pirfenidone, respectively (n=12 for intraindividual comparison).
Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination (see section 4.4).
Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. In repeat dose toxicology studies in rats, adverse effects (e.g. thickening of epiphyseal plates, lesions of the incisors) were mostly related to the mechanism of action (i.e. VEGFR-2 inhibition) of nintedanib. These changes are known from other VEGFR-2 inhibitors and can be considered class effects.
Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight were observed in toxicity studies in non-rodents.
There was no evidence of liver enzyme increases in rats, dogs, and Cynomolgus monkeys. Mild liver enzyme increases, which were not due to serious adverse effects such as diarrhoea were only observed in Rhesus monkeys.
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the MRHD of 150 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryo-foetal lethality and teratogenic effects were observed at an exposure approximately 3 times higher than at the MRHD but equivocal effects on the embryo-foetal development of the axial skeleton and the heart were noted already at an exposure below that at the MRHD of 150 mg twice daily.
In a pre- and postnatal development study in rats, effects on pre- and post-natal development were seen at an exposure below the MRHD.
A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤0.5% of the administered dose).
From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib.
Genotoxicity studies indicated no mutagenic potential for nintedanib.
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