New England Journal of Medicine May 29, 2014

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis (INPULSIS-1 and INPULSIS-2)

Luca Richeldi, Roland M. du Bois, Ganesh Raghu, et al., for the INPULSIS Trial Investigators

Bottom Line

In two replicate Phase 3 trials, the intracellular tyrosine kinase inhibitor nintedanib significantly slowed disease progression by halving the annual rate of lung function decline in patients with idiopathic pulmonary fibrosis.

Key Findings

1. InINPULSIS-1, theadjustedannualrateofFVCdeclinewas−114.7mLwithnintedanibversus−239.9mLwithplacebo(differenceof125.3mL/year;95%CI, 77.7to172.8;P<0.001)[1.5].

2. In INPULSIS-2, the adjusted annual rate of FVC decline was −113.6 mL with nintedanib versus −207.3 mL with placebo (difference of 93.7 mL/year; 95% CI, 44.8 to 142.7; P<0.001).

3. Time to first acute exacerbation of IPF was significantly delayed with nintedanib in INPULSIS-2 (hazard ratio, 0.38; P=0.005) but showed no significant difference in INPULSIS-1 (hazard ratio, 1.15; P=0.67).

4. Health-related quality of life, measured by the St. George's Respiratory Questionnaire (SGRQ), showed significantly less deterioration with nintedanib in INPULSIS-2 (difference of −2.69 points; P=0.02) but no significant difference in INPULSIS-1.

5. Diarrhea was the most frequent adverse event, occurring in 61.5% of nintedanib-treated patients versus 18.6% of placebo-treated patients, though it led to premature discontinuation of the study drug in less than 5% of patients.

6. Elevations in liver enzymes (ALT and/or AST ≥3 times the upper limit of normal) were more frequent in the nintedanib group compared to placebo (4.9% vs 0.5% in INPULSIS-1; 5.2% vs 0.9% in INPULSIS-2).

Study Design

Design

RCT

Double-Blind

Sample

1,066

Patients

Duration

52 wk

Median

Setting

Multicenter, multinational

Population Adults over 40 years of age with a diagnosis of idiopathic pulmonary fibrosis (IPF) within the past 5 years, high-resolution CT evidence of usual interstitial pneumonia, FVC ≥50% of the predicted value, and a carbon monoxide diffusing capacity (DLCO) of 30-79% of the predicted value.

Intervention Nintedanib 150 mg orally twice daily.

Comparator Matching placebo orally twice daily.

Outcome Annual rate of decline in forced vital capacity (FVC) over 52 weeks.

Study Limitations

• The trials were not powered to detect a survival benefit, and no significant difference in all-cause mortality was observed between groups over the 52-week study period.

• Discrepant findings between the two replicate trials regarding secondary endpoints (time to first acute exacerbation and SGRQ scores) complicate the interpretation of nintedanib's impact on these outcomes.

• Patients with severe lung impairment (FVC <50% predicted or DLCO <30% predicted) were excluded, limiting the initial generalizability of the findings to patients with advanced disease.

• The high incidence of gastrointestinal side effects, particularly diarrhea, necessitates active symptom management and dose modification in real-world clinical practice, which can impact patient adherence and quality of life.

Clinical Significance

The INPULSIS trials established nintedanib as a standard-of-care therapy for idiopathic pulmonary fibrosis. By consistently reducing the annual decline in FVC by approximately 50%, nintedanib effectively slows the progression of this historically untreatable and universally fatal fibrotic lung disease. Although the treatment does not halt or reverse fibrosis, and proactive management of gastrointestinal toxicities is required, slowing lung function decline represents a major milestone in improving the trajectory of IPF.

Historical Context

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease with a median survival of 2.5 to 5 years after diagnosis. Prior to 2014, there were no FDA-approved disease-modifying therapies, and immunosuppressive regimens (such as the triple therapy of prednisone, azathioprine, and N-acetylcysteine) had recently been shown to increase mortality in the PANTHER-IPF trial. The INPULSIS trials of the tyrosine kinase inhibitor nintedanib were published concurrently with the ASCEND trial of the anti-fibrotic pirfenidone in the May 2014 issue of the New England Journal of Medicine. Both agents demonstrated significant efficacy in reducing FVC decline, leading to their simultaneous FDA approval in October 2014 and fundamentally transforming the therapeutic landscape for fibrosing interstitial lung diseases.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of nintedanib specifically target the underlying pathophysiology of idiopathic pulmonary fibrosis (IPF) compared to traditional, older therapies like corticosteroids?

Key Response

Nintedanib is an intracellular inhibitor of multiple tyrosine kinases (including VEGFR, FGFR, and PDGFR) that directly suppresses fibroblast proliferation, migration, and differentiation into myofibroblasts. This targets the core fibrotic pathway in IPF, explaining why general anti-inflammatory agents or immunosuppressants like corticosteroids are largely ineffective and sometimes harmful in this disease.

Resident

When initiating nintedanib for a patient newly diagnosed with IPF, what are the most common adverse effects you need to preemptively manage, and how might they impact long-term medication adherence?

Key Response

Diarrhea is the most frequent adverse event, reported in over 60% of patients in the INPULSIS trials, alongside nausea and elevated liver enzymes. Residents must know to proactively counsel patients, prescribe anti-diarrheals like loperamide, and monitor LFTs to prevent early drug discontinuation, which is a major clinical hurdle.

Fellow

Given that both nintedanib and pirfenidone are approved for IPF, what specific patient factors, comorbidities, and distinct side-effect profiles should guide your choice between these two antifibrotic agents in the pulmonary clinic?

Key Response

Since there are no head-to-head trials showing superiority, the choice depends on side effect profiles (diarrhea and bleeding/cardiovascular risks with nintedanib vs. photosensitivity, rash, and dyspepsia with pirfenidone). Fellows must weigh these against patient comorbidities, such as concomitant anticoagulant use or severe gastrointestinal baseline issues.

Attending

How do you reframe the concept of 'treatment success' during shared decision-making with patients starting nintedanib, given that the drug slows progressive disease but does not cure it or significantly improve baseline lung function?

Key Response

Attendings must skillfully manage patient expectations. Success in IPF treatment is defined as a reduction in the annual rate of forced vital capacity (FVC) decline rather than symptom reversal. Clear communication prevents early, unwarranted discontinuation by patients who might feel the drug 'is not working' simply because they are not feeling better.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The INPULSIS trials used the annual rate of decline in forced vital capacity (FVC) as the primary endpoint. From a methodological standpoint, what are the limitations of using a slope-based analysis for FVC in a progressive disease with acute exacerbations, and how does the handling of missing data impact the robustness of this endpoint?

Key Response

Slope analysis assumes a linear trajectory of decline, which may not accurately capture the step-wise deterioration caused by acute exacerbations. Furthermore, handling missing data in high-dropout populations (due to drug toxicity like diarrhea) requires robust sensitivity analyses, such as multiple imputation or random-effects models, to prevent attrition bias and ensure the intent-to-treat estimate remains valid.

Journal Editor

Although INPULSIS-1 and INPULSIS-2 were identically designed replicate trials, INPULSIS-2 showed a significant delay in the time to first acute exacerbation, while INPULSIS-1 did not. As an editor, how do you critically evaluate this discrepancy in secondary endpoints, and what does it suggest about the statistical fragility of these findings?

Key Response

Replicate trials are powerful but can expose heterogeneity. A critical editor would flag that the acute exacerbation benefit was inconsistent, suggesting the event rate was either too low to adequately power this secondary endpoint, or that random variation played a large role. This cautions against overstating the drug's effect on acute exacerbations without subsequent pooled meta-analyses.

Guideline Committee

Based on the findings of the INPULSIS trials, how should the ATS/ERS/JRS/ALAT guidelines update their recommendations for pharmacological management in IPF, specifically regarding the strength of recommendation for antifibrotics versus historical triple therapy?

Key Response

The INPULSIS data led to a paradigm shift, prompting international guidelines to issue a conditional recommendation FOR the use of nintedanib (and pirfenidone) based on high-quality evidence for slowing FVC decline, while simultaneously maintaining a strong recommendation AGAINST historical PANTHER-IPF triple therapy (prednisone, azathioprine, N-acetylcysteine), establishing antifibrotics as the new standard of care.

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: Nintedanib reduced lung function decline and decreased the incidence of acute exacerbations over 52 weeks.

2011

CAPACITY Trials

n = 779 · Lancet

Tested

Pirfenidone 2403 mg/day

Population

Patients with mild to moderate idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Change in FVC percentage of predicted value at week 72

Key result: Pirfenidone reduced the decline in FVC in one of the two concurrent trials, providing initial phase 3 evidence of its efficacy.

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 week 52

Key result: Pirfenidone significantly reduced disease progression and improved progression-free survival compared to placebo.

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