Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis: results of the INJOURNEY trial
Carlo Vancheri,1 Michael Kreuter,2 Luca Richeldi,3 Christopher J. Ryerson,4 Dominique Valeyre,5 Jan C Grutters,6 Sabrina Wiebe,7 Wibke Stansen,8 Manuel Quaresma,2,8 Susanne Stowasser,8 Wim A Wuyts9 on behalf of the INJOURNEY™ trial investigators
Funding source: The INJOURNEY trial was funded by Boehringer Ingelheim. Author contributions: All the authors were involved in study design, interpretation of data, and revising the manuscript for important intellectual content.
Running title: Nintedanib with add-on pirfenidone in IPF Descriptor number: 9.23 Interstitial Lung Disease Word count: approx. 3061/3500
This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org
At a Glance Commentary
Scientific Knowledge on This Subject:The antifibrotic drugs nintedanib and pirfenidone reduce the progression of idiopathic pulmonary fibrosis (IPF), as shown by a slower decline in FVC versus placebo, but ultimately the disease continues to progress. Nintedanib and pirfenidone are thought to target different aspects of the fibrotic cascade, so combined therapy with both drugs may provide better outcomes than monotherapy.
What This Study Adds to the Field:
In the open-label randomized INJOURNEY trial, treatment with nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse profiles of the individual drugs. Plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone.
Decline in FVC over 12 weeks appeared to be smaller in patients treated with nintedanib with add-on pirfenidone than with nintedanib alone, but these results should be interpreted with caution given the exploratory nature of this analysis. These data support further research into combination regimens in the treatment of IPF.
Abstract
Rationale: Nintedanib and pirfenidone slow the progression of IPF, but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone.
Objectives: To investigate safety, tolerability, pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone.
Methods: Patients with IPF and FVC ≥50% predicted at screening who completed a 4– 5 week run-in with nintedanib 150 mg bid without dose reduction or treatment interruption were randomized to nintedanib 150 mg bid with add-on pirfenidone (titrated to 801 mg tid), or nintedanib 150 mg bid alone, open-label for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to week 12. Analyses were descriptive and exploratory.
Measurements and main results: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Pre-dose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at week 12 were −13.3 (17.4) mL and −40.9 (31.4) mL in patients treated with nintedanib with add-on pirfenidone (n=48) and nintedanib alone (n=44), respectively.
Conclusions: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF.
Abstract word count: 249
Key words: Interstitial Lung Diseases; Clinical Trial Drug Therapy; Adverse Drug Event
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia characterized by progressive decline in lung function (1). The pathogenesis of IPF is believed to be driven by dysfunction of the alveolar epithelium following recurrent episodes of injury. Activated alveolar epithelial cells release fibrogenic growth factors that promote the migration, activation and differentiation of fibroblasts and myofibroblasts, resulting in excessive deposition of extracellular matrix and the destruction of the lung architecture (2).
Nintedanib, a potent intracellular inhibitor of tyrosine kinases, has been approved for the treatment of IPF in several countries, including the US (3). In the two placebo- controlled 52-week Phase III INPULSIS® trials, nintedanib 150 mg twice daily (bid) significantly reduced the decline in forced vital capacity (FVC) in patients with IPF. Gastrointestinal adverse events, particularly diarrhea, were the most frequent adverse events (4). Pirfenidone, a pyridone derivative, has also been widely approved for the treatment of IPF, including in the US (5). In the Phase III ASCEND trial, pirfenidone 2403 mg/day (801 mg three times daily [tid]) significantly reduced decline in FVC in patients with IPF, with nausea and rash being the most frequent adverse events (6).
Nintedanib and pirfenidone both received conditional recommendations for use in the most recent clinical practice guideline for the treatment of IPF, indicating that they would be an appropriate treatment choice for a majority of patients (7). The guideline provided no recommendations for or against the use of combination regimens or sequential therapies.
Although both nintedanib and pirfenidone reduce the rate of disease progression in patients with IPF, the disease continues to progress and is ultimately fatal. With the availability of two antifibrotic drugs, it is expected that combination therapy is likely to be the future of treatment of IPF (8), similar to the management of other chronic progressive diseases, such as pulmonary arterial hypertension and several types of cancer. Nintedanib and pirfenidone have pleiotropic effects and are thought to target different aspects of the fibrotic cascade (9, 10), suggesting that therapy with both drugs may provide additive or even synergistic effects, resulting in a greater improvement in outcomes than either monotherapy. However, given the overlapping adverse event profiles of nintedanib and pirfenidone, data on potential additive adverse events and the overall benefit:risk ratio of combined therapy are needed.
Data from a Phase II randomized, placebo-controlled (within each dose group), dose-escalation study of nintedanib in 50 Japanese patients with IPF, with a maximum treatment duration of 28 days, suggested a trend towards lower exposure of nintedanib, with moderate to high inter-patient variability, when nintedanib was added to chronic pirfenidone treatment than when it was given alone (11). Co-administration of nintedanib had no effect on the pharmacokinetics (PK) of pirfenidone (11). Patients who completed this trial and were still receiving pirfenidone could receive combination therapy with nintedanib and pirfenidone in an open-label extension study. After a mean exposure of 27 months in this extension study, no new safety signals were identified, but definite conclusions could not be drawn based on the small number of patients (n=20) (12).
No data on the safety, tolerability and efficacy of nintedanib with add-on pirfenidone have been presented. Here we present results from the INJOURNEY trial, which evaluated safety, tolerability, PK and exploratory efficacy endpoints in patients treated with nintedanib with add-on pirfenidone versus nintedanib alone. Some of these results have been submitted to the European Respiratory Society International Congress 2017 in abstract form.
Methods
Trial design
This was an open-label, randomized trial of nintedanib with add-on pirfenidone, compared with nintedanib alone, in patients with IPF (NCT02579603). Following a 4–5 week run-in with nintedanib 150 mg bid, patients were randomized (1:1) to receive add- on pirfenidone, or to continue on nintedanib 150 mg bid alone, for 12 weeks with a follow-up visit 4 weeks later (Figure 1). Patients who had a nintedanib dose reduction or treatment interruption during the run-in were not randomized. Pirfenidone dose was titrated as recommended in the prescribing information: 267 mg tid from randomization to week 1, 534 mg tid from week 1 to week 2, 801 mg tid from week 2.
Investigators were provided with recommendations for the management of diarrhea, phototoxicity/rash, liver enzyme elevations and adverse events that the investigator regarded as drug-related (Table E1; Figure E1). In the randomized period, nintedanib dose could be reduced from 150 mg bid to 100 mg bid or interrupted to manage adverse events. After resolution of the adverse event, the dose of nintedanib could be re-escalated to 150 mg bid, or resumed following treatment interruption at a dose of 150 mg bid or 100 mg bid (with the option to increase to 150 mg bid).
Pirfenidone dose could be reduced from 801 mg tid to 534 mg tid or 267 mg tid, or interrupted, to manage adverse events. After resolution of the adverse event, the dose could be re-escalated to the maximum dose. Pirfenidone could be resumed at the dose taken prior to an interruption if the interruption was <14 days, but was re-initiated using the initial 2-week titration scheme if the interruption was ≥14 days. The trial was approved by local ethics committees and was carried out in compliance with the protocol, the principles of the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. The principal investigators are listed in the online supplement. Trial population To be eligible to participate in this trial, patients had to be aged ≥40 years, with an FVC ≥50% predicted at screening. Diagnosis of IPF, according to ATS/ERS/JRS/ALAT guidelines (1), was confirmed by the investigator based on a chest high-resolution computed tomography scan performed within 12 months of screening. Both patients who were taking nintedanib prior to entering the trial and patients who were nintedanib- naïve were eligible to participate. Exclusion criteria included: alanine transaminase (ALT) or aspartate aminotransferase (AST) or total bilirubin >1.5 × upper limit of normal (ULN); history of myocardial infarction within 6 months or unstable angina within 1 month of screening; bleeding risk (e.g., requiring full-dose anticoagulation or high-dose antiplatelet therapy); and history of thrombotic event within 12 months of screening .Patients who had previously received pirfenidone, had previously discontinued nintedanib due to adverse events, or who required dose reduction or treatment interruption during the run-in period with nintedanib 150 mg bid were excluded.
Trial endpoints
The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to week 12. On-treatment adverse events were defined as adverse events with onset from the day of the first dose to the day of the last dose of randomized treatment (inclusive). Gastrointestinal adverse events were defined as adverse events in the system organ class “gastrointestinal disorders” in the Medical Dictionary for Regulatory Activities (MedDRA) v19.1. Secondary endpoints were pre-dose plasma concentrations at steady state of nintedanib (at baseline, week 2, week 4) and of pirfenidone (at weeks 2 and 4). Further safety endpoints included time to first gastrointestinal adverse event, percentage of patients with ALT and/or AST ≥3 × ULN during the randomized treatment period, and time to first ALT and/or AST ≥3 × ULN. In addition, safety was assessed via physical examination, vital signs, laboratory parameters, 12-lead electrocardiogram and the recording of adverse events. Adverse events were coded using MedDRA v19.1.
Exploratory efficacy endpoints were absolute and relative changes from baseline in FVC (mL and % predicted) at week 12, rate of decline in FVC (mL/12 weeks), and change from baseline in EuroQoL-5D (EQ-5D) total score at week 12. FVC was measured at baseline and weeks 2, 4, 8 and 12. Spirometry was conducted in accordance with criteria published by the American Thoracic Society and European Respiratory Society (13). Spirometric measurements were performed on devices provided by the sponsor and were centrally reviewed. The EQ-5D was completed as per the visit schedule for FVC and prior to any other trial-related procedures.
Statistical methods
Safety and efficacy endpoints were assessed in randomized patients who received ≥1 dose of trial medication. PK endpoints were assessed in patients who had received ≥1 dose of trial medication and who provided evaluable data for ≥1 PK endpoint without important protocol violations relevant to the evaluation of PK (e.g. missed dose, blood taken post-dose rather than pre-dose). Analyses were descriptive and exploratory. Adjusted rate of decline in FVC (mL/12 weeks) was based on a random coefficient regression with fixed effects for treatment, baseline FVC and random effect of patient- specific intercept and time. For the analyses of FVC, values measured after week 12 but within 27 days after the last dose of randomized treatment were assigned to the week 12 time-point. Time to first event endpoints were analyzed using Kaplan-Meier estimates calculated from the time of first intake of randomized trial drug.
Results
Patients
Of 136 screened patients, 111 were treated with nintedanib 150 mg bid in the run-in period. Six patients prematurely discontinued nintedanib during the run-in period and 105 were randomized to receive nintedanib 150 mg bid alone (n=52) or nintedanib 150 mg bid with add-on pirfenidone titrated to 801 mg tid (n=53). One patient randomized to nintedanib alone was not treated (Figure 2).
Baseline characteristics were generally similar between treatment groups (Table 1). Most patients were male (82.7%) and White (96.2%). Mean age was 68.9 years, mean FVC was 84.0% predicted and mean DLco was 47.0% predicted. Medical conditions and baseline therapies of interest are presented in Table E2 and Table E3. In total, 30 patients (56.6%) treated with nintedanib with add-on pirfenidone and 30
patients (58.8%) treated with nintedanib alone were nintedanib-naïve before entering the trial.
Exposure
Mean (SD) exposure to nintedanib during the randomized period was 11.3 (2.7) weeks in patients treated with nintedanib with add-on pirfenidone and 10.9 (2.9) weeks in patients treated with nintedanib alone. Mean (SD) exposure to pirfenidone during the randomized period was 9.8 (3.7) weeks in patients treated with nintedanib with add-on pirfenidone. Nintedanib dose reductions occurred in four patients (7.5%) treated with nintedanib with add-on pirfenidone and six patients (11.8%) treated with nintedanib alone. Nintedanib was prematurely discontinued in seven patients (13.2%) treated with nintedanib with add-on pirfenidone and nine patients (17.6%) treated with nintedanib alone (Table E4). In patients treated with nintedanib with add-on pirfenidone, pirfenidone dose reductions occurred in 19 patients (35.8%) and pirfenidone was prematurely discontinued in 19 patients (35.8%) (Table E5).
Dose intensity was defined as the amount of drug administered over the study divided by the amount that would have been received had the protocol-defined dose been administered throughout the treatment period or until permanent treatment discontinuation. Mean (SD) dose intensity of nintedanib was 99.6 (6.6) % and 98.6 (8.0) % in patients treated with nintedanib with add-on pirfenidone and nintedanib alone, respectively. Mean (SD) dose intensity of pirfenidone was 88.4 (20.2) % in patients treated with nintedanib with add-on pirfenidone. In total, 50 patients (94.3%) treated with nintedanib with add-on pirfenidone and 45 patients (88.2%) treated with nintedanib
(20.8%) and 30 (56.6%) patients received pirfenidone 267 mg tid, 534 mg tid and 801 mg tid, respectively, as their last dose.
Safety outcomes
On-treatment gastrointestinal adverse events were reported in 37 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 patients (52.9%) treated with nintedanib alone. Time to first gastrointestinal adverse event is shown in Figure E2. During the randomized treatment period, ALT and/or AST ≥3 × ULN were reported in three patients (5.7%) treated with nintedanib with add-on pirfenidone and no patients treated with nintedanib alone (Table 2). No cases of Hy’s law were observed.
Pharmacokinetic outcomes
Pre-dose plasma trough concentrations of nintedanib were similar at each time point, irrespective of whether nintedanib 150 mg bid was administered alone or with add-on pirfenidone 534 mg or 801 mg tid (Table 3; Figure E3). Moderate to high variability was observed in both treatment groups. Pre-dose geometric mean (geometric coefficient of variation %) concentrations of pirfenidone were 1120 (122) and 1220 (91) ng/mL at week 2 and week 4, respectively (Figure E4).
Exploratory efficacy outcomes
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) and −40.9 (31.4) mL in patients treated with nintedanib alone (n=44) (Figure 2). Mean (SE) absolute changes from baseline in FVC % predicted at week 12 were −0.3 (0.5) % and −1.3 (0.8) % in these groups, respectively. The rate of change in FVC was 3.6 mL/12 weeks (increase) in patients treated with nintedanib with add-on pirfenidone and −48.0 mL/12 weeks (decrease) in patients treated with nintedanib alone (difference 51.7 [95% CI: −13.3, 116.6] mL). Relative changes from baseline in FVC at week 12 (mL and % predicted) are presented in Figures E5 and E6. Mean (SE) absolute changes from baseline in EQ-5D total score at week 12 were −1.1 (2.7) in patients treated with nintedanib with add-on pirfenidone and −1.0 (1.7) in patients treated with nintedanib alone.
Adverse events
Adverse events were reported in 47 patients (88.7%) treated with nintedanib with add- on pirfenidone and 45 patients (88.2%) treated with nintedanib alone. Serious adverse events were reported in two patients (3.8%) and five patients (9.8%) in these treatment groups, respectively (Table E6). No fatal adverse events occurred. Diarrhea, nausea and vomiting were the most frequent adverse events (Table 4). Diarrhea was reported in 20 patients (37.7%) treated with nintedanib with add-on pirfenidone and 16 patients (31.4%) treated with nintedanib alone. Nausea was reported in 22 (41.5%) and six (11.8%) patients, and vomiting in 15 (28.3%) and six (11.8%) patients, treated with nintedanib with add-on pirfenidone and with nintedanib alone, respectively.
Discussion
In this 12-week, open-label, randomized trial, the adverse event profile of nintedanib with add-on pirfenidone was in line with the safety and tolerability profiles of the individual drugs (3, 5) and was manageable in the majority of patients. Serious adverse events were uncommon in both treatment groups. Gastrointestinal adverse events were reported in approximately half and two-thirds of patients treated with nintedanib and nintedanib with add-on pirfenidone, respectively. Diarrhea was reported in 31% of patients treated with nintedanib and 38% treated with nintedanib with add-on pirfenidone (based on 12 weeks’ treatment) in the INJOURNEY trial compared with 62% of patients treated with nintedanib and 22% of patients treated with pirfenidone in the INPULSIS and ASCEND trials, respectively (based on 52 weeks’ treatment) (4,6).
Nausea was reported in 12% and 42% of patients treated with nintedanib and nintedanib with add-on pirfenidone, respectively, in the INJOURNEY trial (12 weeks’ treatment) compared with 25% of patients treated with nintedanib and 36% of patients treated with pirfenidone in the INPULSIS and ASCEND trials (52 weeks’ treatment), respectively (4,6). In the INPULSIS and ASCEND trials, the majority of gastrointestinal adverse events occurred within the first 3 months (15,16). The safety/tolerability findings from the INJOURNEY trial were consistent with the findings of the Phase II dose escalation trial of nintedanib stratified by pirfenidone use at baseline in Japanese patients with IPF (11). In that trial, 24 patients received nintedanib 150 mg bid for 28 days, of whom 13 patients had been taking chronic pirfenidone therapy (at different doses). Nausea and vomiting were the most commonly reported adverse events. These were reported more commonly in the 13 patients who took nintedanib 150 mg bid on top of pirfenidone background therapy (in 4 and 5 patients, respectively) compared to the 11 patients who received nintedanib 150 mg bid only (in 1 and no patients, respectively)
An interim analysis of data from a 24-week single-arm study assessing the safety and tolerability of pirfenidone with add-on nintedanib in patients treated for at least 12 weeks (n=41) also found that diarrhea and nausea were the most frequent adverse events, reported in 46.3% and 41.5% of patients, respectively (14). Reversible elevations in hepatic enzymes have been observed in patients receiving nintedanib and pirfenidone monotherapy (3, 5). In our study, hepatic enzyme elevations ≥3 × ULN were reported in three patients (5.7%) treated with nintedanib with add-on pirfenidone and none treated with nintedanib alone. The prescribing information for nintedanib and pirfenidone recommends close monitoring for adverse events during treatment, including monitoring for hepatic enzyme elevations (3, 5). Patients with transaminases ≥1.5 x ULN at baseline were excluded from this trial, similar to the Phase III INPULSIS trials.
In the INJOURNEY trial, two-thirds of patients completed the 12-week treatment period with both drugs and one-third prematurely discontinued pirfenidone. In the INPULSIS and ASCEND trials, 25% and 20% of patients, respectively, prematurely discontinued treatment with nintedanib and pirfenidone over 52 weeks, predominantly due to adverse events. In the combination therapy group of the INJOURNEY trial, permanent discontinuations of pirfenidone were more frequent than permanent discontinuations of nintedanib. This might partially be attributed to the protocol recommendation to reduce the dose of pirfenidone before reducing the dose of nintedanib in the case of adverse events other than diarrhea. In addition, it is likely that investigators attributed more treatment-emergent adverse events in the combination therapy group to the newly-introduced pirfenidone rather than to nintedanib, which the patients had already shown they could tolerate. Further, inherent to the design of this trial, only patients who had already tolerated nintedanib in a 4–5 week run-in period were randomized. This likely reduced the rates of permanent discontinuations and dose adjustments of nintedanib during the randomized period.
It should also be noted that 41% of patients were already being treated with nintedanib at study entry. Although this trial was not designed to inform the best treatment strategy for combination treatment, i.e. concurrent or sequential, the trial design took into account a pragmatic clinical approach in which physicians would only give a second antifibrotic drug to patients who could tolerate one antifibrotic drug, given the known overlapping adverse event profiles of nintedanib and pirfenidone. The PK data obtained in this trial did not replicate the results of the Phase II Japanese trial, in which nintedanib plasma concentration tended to be lower following administration with pirfenidone (11). In our trial, plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone.
However, neither the present trial nor the Phase II Japanese trial was specifically designed to assess a drug–drug interaction between nintedanib and pirfenidone. Nintedanib and pirfenidone are metabolized via different pathways and therefore, no pharmacokinetic interaction between nintedanib and pirfenidone would be expected. Data from a recently conducted dedicated drug–drug interaction study (ClinicalTrials.gov; NCT02606877) will allow robust conclusions to be drawn on the PK interactions between nintedanib and pirfenidone.
When given as monotherapy to patients with IPF and mild or moderate impairment in lung function, nintedanib and pirfenidone reduce the rate of decline in lung function by approximately 50% (4, 6). In the present trial, we observed a smaller numerical decline in FVC over 12 weeks in patients treated with nintedanib with add-on pirfenidone than with nintedanib alone. However, as this trial was not powered for this endpoint and was too short for conclusions to be drawn about the efficacy of combination therapy, these findings should be interpreted with caution. Reassuringly there was no meaningful change in EQ5D (a generic measure of quality of life) in either treatment group.
In conclusion, in the INJOURNEY trial, treatment with nintedanib and add-on pirfenidone for 12 weeks had a manageable safety and tolerability profile in patients with IPF. Further large controlled studies are needed to confirm the benefit:risk ratio of combination antifibrotic therapy in patients with IPF.
Acknowledgments
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Julie Fleming and Wendy Morris of FleishmanHillard Fishburn, London, UK, during the preparation of this article. The authors were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development and have approved the final version.
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