New England Journal of Medicine May 29, 2014

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

Luca Richeldi, Roland M. du Bois, Ganesh Raghu, Arata Azuma, Kevin K. Brown, Ulrich Costabel et al.

Bottom Line

In two replicate phase 3 trials (INPULSIS-1 and INPULSIS-2), the intracellular tyrosine kinase inhibitor nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis compared to placebo.

Key Findings

1. In INPULSIS-2, the adjusted annual rate of change in FVC was -113.6 mL with nintedanib versus -207.3 mL with placebo, resulting in a significant difference of 93.7 mL (95% CI, 44.8 to 142.7; P<0.001).

2. In INPULSIS-1, FVC decline was similarly reduced (-114.7 mL with nintedanib vs -239.9 mL with placebo; difference, 125.3 mL; P<0.001).

3. Time to the first acute exacerbation was significantly delayed with nintedanib in INPULSIS-2 (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005), but there was no significant difference in INPULSIS-1 (hazard ratio, 1.15; P=0.67).

4. Nintedanib was associated with a smaller deterioration in health-related quality of life as measured by the St. George's Respiratory Questionnaire (SGRQ) in INPULSIS-2 (difference of -2.69 points), but not in INPULSIS-1.

5. Diarrhea was the most common adverse event (63.2% in INPULSIS-2 nintedanib group vs 18.3% in placebo), though it led to study medication discontinuation in less than 5% of all nintedanib-treated patients.

Study Design

Design

RCT

Double-Blind

Sample

1,066

Patients

Duration

52 weeks

Median

Setting

Multicenter, international

Population Adults aged 40 years or older diagnosed with idiopathic pulmonary fibrosis within the previous 5 years, with forced vital capacity (FVC) at least 50% of the predicted value and diffusing capacity for carbon monoxide (DLCO) between 30% and 79% of the predicted value.

Intervention Nintedanib 150 mg administered orally twice daily.

Comparator Matching oral placebo administered twice daily.

Outcome Annual rate of decline in forced vital capacity (FVC) over a 52-week period.

Study Limitations

• Discordant findings between the two replicate trials regarding secondary endpoints (acute exacerbations and quality of life scores) leave some uncertainty about nintedanib's clinical impact beyond FVC decline.

• The 52-week follow-up was insufficient to power a definitive analysis on overall mortality or long-term survival, though subsequent pooled analyses later suggested positive trends.

• The high incidence of gastrointestinal adverse events (diarrhea in over 60% of patients) requires close clinical management and may affect long-term real-world medication adherence.

• Strict enrollment criteria (e.g., FVC 50% or more of the predicted value) limit the generalizability of the findings to patients presenting with more severe baseline fibrotic lung disease.

Clinical Significance

The INPULSIS trials established nintedanib as a standard-of-care, disease-modifying treatment for idiopathic pulmonary fibrosis. By reducing the rate of lung function decline by approximately 50%, nintedanib fundamentally shifted the paradigm of IPF management from palliative and ineffective anti-inflammatory treatments to targeted anti-fibrotic therapy that meaningfully slows disease progression.

Historical Context

Prior to 2014, idiopathic pulmonary fibrosis was considered a relentlessly progressive disease with no proven FDA-approved pharmacotherapy. Historical mainstays of treatment, such as immunosuppressants (prednisone, azathioprine, and N-acetylcysteine), were proven harmful in the 2012 PANTHER-IPF trial. Nintedanib, a multi-targeted tyrosine kinase inhibitor originally developed for oncology, demonstrated anti-fibrotic activity by inhibiting PDGF, FGF, and VEGF receptors. Published in the same NEJM issue as the ASCEND trial for pirfenidone, the INPULSIS trials marked a watershed moment, leading to simultaneous FDA approval for both drugs and initiating the modern era of anti-fibrotic therapies for interstitial lung diseases.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of nintedanib target the underlying pathophysiology of idiopathic pulmonary fibrosis compared to traditional immunosuppressive therapies?

Key Response

Nintedanib is a multiple tyrosine kinase inhibitor targeting VEGFR, FGFR, and PDGFR. These receptors are crucial in the proliferation, migration, and transformation of fibroblasts into myofibroblasts, which drive extracellular matrix deposition in IPF. This highlights the paradigm shift from viewing IPF as an inflammatory disease, where steroids and azathioprine failed, to an aberrant fibrotic wound-healing disorder.

Resident

When starting a patient with newly diagnosed IPF on nintedanib, what are the most common adverse effects you must counsel them about and how do you clinically manage them to prevent premature drug discontinuation?

Key Response

Diarrhea is the most frequent adverse event, occurring in over 60 percent of patients in the INPULSIS trials, and a common cause for discontinuation. Residents must know to counsel patients on dietary modifications, prompt use of loperamide, and potential dose reductions (from 150 mg BID to 100 mg BID) to maximize adherence to this disease-modifying therapy.

Fellow

The INPULSIS trials showed discordant results regarding the time to first acute exacerbation between INPULSIS-1 and INPULSIS-2. How should a pulmonology fellow interpret this discrepancy when discussing the benefits of nintedanib on acute exacerbations with patients?

Key Response

While INPULSIS-2 showed a significant delay in the time to first acute exacerbation, INPULSIS-1 did not show this benefit. Fellows should recognize that acute exacerbation was a secondary endpoint, the event rate was relatively low, and pooled analyses or larger observational data are needed to definitively prove an effect on exacerbations, requiring a nuanced discussion about managing patient expectations.

Attending

Given that nintedanib slows disease progression but does not halt or reverse it, how do you integrate the findings of the INPULSIS trials into a shared decision-making framework, particularly regarding timing of initiation and concurrent palliative or transplant evaluations?

Key Response

Attendings must balance the statistical benefit of reduced FVC decline with the clinical reality of side effects and cost. The discussion should focus on framing the drug as a tool to buy time, emphasizing that early initiation is generally preferred, but it must be coupled with ongoing symptom management, pulmonary rehab, and timely lung transplant referral since the ultimate disease trajectory remains fatal.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The INPULSIS trials utilized a random-coefficient regression model to analyze the annual rate of decline in FVC. What are the methodological advantages and potential vulnerabilities of this statistical approach in a progressive, fatal disease with high dropout rates?

Key Response

A random-coefficient regression model accounts for all available data points and within-patient correlation, effectively handling missing data assuming it is missing at random. However, in IPF, dropouts are often due to death or severe progression (Missing Not At Random), which can potentially bias the slope estimates. PhDs must critically evaluate how missingness mechanisms impact longitudinal analyses in terminal diseases.

Journal Editor

From an editorial perspective, how does the allowance of certain baseline concomitant medications and the specific exclusion criteria in the INPULSIS trials impact the external validity, and what supplementary data would you demand as a reviewer to ensure the results are robust?

Key Response

The trials excluded patients with severe lung impairment (FVC under 50 percent or DLCO under 30 percent) and those with recent acute exacerbations, yet real-world populations often present late. A rigorous reviewer would flag this limited generalizability and request post-hoc or subgroup analyses evaluating efficacy in more advanced disease or concomitant use with other specific therapies to justify publishing broad clinical claims.

Guideline Committee

Based on the combined efficacy data from the INPULSIS trials, how should international guidelines formulate the strength of recommendation for antifibrotic therapy in IPF, and what evidence gaps remain for updating these guidelines?

Key Response

The ATS/ERS/JRS/ALAT guidelines provide a conditional recommendation for the use of nintedanib in IPF based on moderate-quality evidence from the INPULSIS trials. The committee must weigh the consistent benefit in reducing FVC decline against the high cost, side effect profile, and lack of definitive mortality benefit. Current gaps requiring guideline updates include the use of combination therapy with pirfenidone and extending treatment to non-IPF progressive fibrosing interstitial lung diseases.

Clinical Landscape

Noteworthy Related Trials

2011

TOMORROW Trial

n = 432 · NEJM

Tested

Nintedanib 150 mg twice daily

Population

Patients with idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Annual rate of decline in FVC

Key result: Treatment with nintedanib resulted in a significantly lower rate of decline in FVC and fewer acute exacerbations compared to placebo.

2012

PANTHER-IPF Trial

n = 238 · NEJM

Tested

Prednisone, azathioprine, and N-acetylcysteine

Population

Patients with mild-to-moderate idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Change in forced vital capacity over 60 weeks

Key result: The triple-therapy arm was stopped early due to significantly increased risks of death and hospitalizations compared to placebo.

2014

ASCEND Trial

n = 555 · NEJM

Tested

Pirfenidone 2403 mg/day

Population

Patients with idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Change in FVC or death at 52 weeks

Key result: Pirfenidone significantly reduced disease progression as measured by a decline in FVC or death compared to placebo.

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