Long-Term Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Results from the Open-Label Extension Study, INPULSIS-ON
Summary
Background
The efficacy and safety of nintedanib, an intracellular tyrosine kinase inhibitor, in patients with idiopathic pulmonary fibrosis were investigated in two phase 3, placebo-controlled INPULSIS trials. Patients who completed the 52-week treatment period in an INPULSIS trial could receive open-label nintedanib in the extension study, INPULSIS-ON. The aim was to assess the long-term efficacy and safety of nintedanib in INPULSIS-ON.
Methods
Patients completing the 52-week treatment period and 4-week follow-up in INPULSIS were eligible for INPULSIS-ON. The off-treatment period between trials could range from 4 to 12 weeks. Patients receiving nintedanib 150 mg twice daily or placebo at the end of INPULSIS entered INPULSIS-ON receiving open-label nintedanib 150 mg twice daily. Patients previously receiving 100 mg twice daily of nintedanib or placebo could receive 100 mg twice daily or 150 mg twice daily in INPULSIS-ON. Spirometric tests were performed at baseline, and at weeks 2, 4, 6, 12, 24, 36, 48, then every 16 weeks. The primary outcome was to characterize the long-term safety and tolerability of nintedanib.
Findings
Of 807 patients who completed INPULSIS, 734 (91%) entered INPULSIS-ON. Of these, 430 had received nintedanib and continued treatment, while 304 had received placebo and initiated nintedanib. Median exposure among patients treated with nintedanib in both INPULSIS and INPULSIS-ON was 44.7 months (11.9–68.3). The safety profile remained consistent with INPULSIS. Diarrhoea was the most common adverse event, leading to discontinuation in 5% of continuing patients and 10% of initiating patients. Progression of idiopathic pulmonary fibrosis was the leading reason for permanent discontinuation. Bleeding occurred at event rates of 8.4 per 100 patient exposure-years in continuing patients and 6.7 in initiating patients. Event rates of major adverse cardiovascular events were 3.6 and 2.4 per 100 patient exposure-years, respectively. Myocardial infarction rates were 1.3 and 0.7 events, respectively.
Interpretation
Nintedanib has a manageable safety and tolerability profile over long-term use, with no new safety signals identified. Long-term nintedanib treatment can slow disease progression in idiopathic pulmonary fibrosis.
Funding
Boehringer Ingelheim.
Introduction
Idiopathic pulmonary fibrosis is a chronic fibrosing interstitial lung disease characterized by progressive loss of lung function, persistent dyspnoea, and impaired quality of life. Prognosis is poor: before antifibrotic therapies became available in 2014, median survival after diagnosis was reported to be 3 to 5 years. Acute exacerbations, often with unknown causes, are a major contributor to morbidity and mortality.
Nintedanib is an intracellular inhibitor of tyrosine kinases and is an approved treatment for idiopathic pulmonary fibrosis. Clinical guidelines provide a conditional recommendation for nintedanib, recognizing it as an appropriate therapy for most patients while acknowledging individual preference in decision-making.
Earlier evidence from the TOMORROW phase 2 trial and INPULSIS phase 3 trials demonstrated that nintedanib reduced the annual decline in forced vital capacity (FVC), with a manageable safety profile heavily characterized by mild gastrointestinal side effects such as diarrhoea. Since idiopathic pulmonary fibrosis is a progressive disease that requires prolonged treatment, there is a need to assess efficacy and safety beyond 52 weeks.
The open-label extension of the TOMORROW trial suggested sustained benefit with no new safety signals, but only 35 patients on the 150 mg twice daily dose enrolled. Patients who completed INPULSIS could continue treatment with nintedanib in INPULSIS-ON. This paper presents the final results of INPULSIS-ON.
Methods
Study Design and Participants
Eligibility in INPULSIS trials required patients to be 40 years or older, with FVC at least 50% predicted, and carbon monoxide diffusing capacity between 30% and 79% predicted. Randomized patients received nintedanib 150 mg twice daily or placebo. Dose reductions and temporary treatment interruptions were permitted. After completing INPULSIS, patients were eligible for INPULSIS-ON, provided they satisfied protocol-specific conditions.
Patients came from 24 countries worldwide. Those with abnormal liver function, high bleeding risk, or recent major thromboembolic events were excluded. The study complied with Good Clinical Practice and the Declaration of Helsinki.
Procedures
At entry into INPULSIS-ON, patients continued nintedanib open-label at 150 mg twice daily. Those on 100 mg could remain at that dose or escalate. Dose changes were permitted after a protocol amendment. Spirometry was repeated according to international standards every 16 weeks until trial completion.
Outcomes
The primary objective was to characterize long-term safety and tolerability based on clinical evaluation, laboratory findings, and reported adverse events. Events of special interest included bleeding, major cardiovascular events, and myocardial infarction. Exploratory endpoints included annual change in FVC over 192 weeks, absolute change in lung function, time to first acute exacerbation, and time to death. Subgroup analyses evaluated sex, age, race, baseline FVC, concomitant medications, and dose intensities.
Statistical Analysis
Analyses were descriptive. Event rates were calculated per 100 patient exposure-years. FVC decline was calculated using mixed-effects regression. Kaplan-Meier methods were used for time-to-event outcomes.
Role of the Funding Source
The sponsor contributed to trial operations but investigators retained responsibility for analysis and submission.
Results
The first patient entered INPULSIS-ON in July 2012. Of the 807 patients completing INPULSIS, 734 enrolled. Baseline characteristics in both groups—continuing and initiating nintedanib—were similar to those at the start of INPULSIS.
Median exposure to nintedanib during INPULSIS-ON was about 31 months overall. Patients who had nintedanib in both INPULSIS and INPULSIS-ON had a median cumulative exposure of 44.7 months.
Discontinuation occurred in 69% of continuing patients and 72% of initiating patients, largely due to adverse events, lung transplantation, death, or progression of disease. A small percentage discontinued because of diarrhoea. Dose reductions, interruptions, or both occurred in nearly half of all patients. About two thirds of patients maintained high dose intensity above 90%.
Diarrhoea was the most common adverse event across groups. About 3–7% of patients had increased liver enzymes greater than three times normal limits. Bleeding occurred at expected low rates. Cardiovascular events and myocardial infarction occurred with frequency similar to placebo groups in the original INPULSIS study.
Mean decline in FVC over 192 weeks was approximately 135 mL/year across all patients, consistent with results of previous trials. Declines were similar across subgroups of age, race, sex, and baseline lung function, except with a slightly higher decline observed in male patients compared to females and in those who were receiving N-acetylcysteine at baseline.
Incidence of acute exacerbations was about 5–6 per 100 patient-years in both continuing and initiating groups. Death during follow-up occurred in about one quarter of patients.
Discussion
These long-term data from INPULSIS-ON confirm that the safety, tolerability, and efficacy profile of nintedanib in idiopathic pulmonary fibrosis is sustained over extended treatment. The most common adverse event was diarrhoea, consistent with earlier trials, with no new safety signals detected even with exposure lasting up to 68 months.
Cardiovascular safety remained reassuring, with no increase in adverse events relative to placebo-treated patients in INPULSIS. Declines in lung function (FVC) remained consistent with earlier findings, indicating nintedanib slows disease progression beyond four years.
The consistency of results across patient subgroups, including those with severely impaired baseline lung function, suggests broad clinical applicability. Treatment interruptions or dose adjustments did not diminish efficacy in terms of slowing FVC decline, indicating robust durability of effect even when management of side effects is required.
Incidence of acute exacerbations mirrored that of earlier studies, providing further evidence of nintedanib’s potential to reduce exacerbation risk.
Limitations include the open-label design, absence of a comparator group, and possible selection bias for patients who tolerated or responded better to initial treatment. Declining patient numbers over follow-up also limit interpretation. Nevertheless, this represents the largest dataset of patients with idiopathic pulmonary fibrosis receiving long-term antifibrotic therapy.
Conclusion
Findings from INPULSIS-ON demonstrate that nintedanib maintains efficacy in slowing disease progression of idiopathic pulmonary fibrosis over more than four years of treatment. Its safety and tolerability profile remain manageable, with no new safety concerns. These results strengthen evidence for the long-term use of nintedanib as an effective antifibrotic therapy for patients with idiopathic pulmonary fibrosis.